Far Eastern University
Nicanor Reyes Medical Foundation
Institute of Medicine
Section D
Endocrine Mechanism
•
PHYSIOLOGY A – CELL PHYSIOLOGY
Dr. Felipe C. Barbon
•
•
Cell – basic unit of the human body that has different parts
and different activities but trying to attain the same goal –
homeostasis.
Homeostasis – maintaining the constancy of the internal
environment which is the EXTRACELLULAR FLUID – condition
of the fluids outside the cell.
Why Extracellular Fluid is referred to as the internal
environment?
•
Neural and Endocrine Control Mechanisms
Negative Feedback
•
opposition of the regulating system
against a certain activity in the body.
•
If there is an increase activity in the
body the regulating system will oppose
the activity and bring the condition
back to normal but not to the point of
below normal.
•
Negative feedback on the endocrine
mechanism:
o
Hormone that affects another
hormone
o
Stimulatory hormones if the
body is in need of hormones
o
Inhibitory hormones if there is
an increase in hormones
•
E.g.: Increase blood pressure can
damage the cardiovascular system.
Thus the regulating system will oppose
the activity will bring it down, back to
normal.
b)
Modified Negative Feedback
•
Applies ONLY in the endocrine system.
•
Maintenance of normal hormones in
the blood is non-hormonal metabolitedependent
•
Non-hormonal agent controlling a
hormonal agent in the circulation of
the body.
•
E.g. Plasma glucose in the blood being
controlled by the hormone Insulin. But
Insulin being controlled by glucose
which is a non-hormonal metabolite.
Thus, the level of the hormonal agent is
affected by the non-hormonal agent
but that non-hormonal agent is
controlled by the affected hormone.
Positive Feedback
•
progression and enhancement of the
certain condition to regain the normal
function of the body.
•
E.g. coagulation activity of the blood
during blood vessel injury. Constriction
of the injured blood vessel→activation
of the platelets→activation of clotting
factor→clotting for the prevention of
blood loss.
To attain homeostasis, constant condition of the said
environment must be maintained including the amount of
solute and the amount of water.
No balance or equilibrium especially in the amount of
solutes inside and outside the cell (e.g. more Sodium ions
outside the cell and Potassium ions inside and/or outside
the cell.) – no equal amount of ions: no equilibrium.
In homeostasis we just maintain the amount of solutes and
water in the ECF to maintain a constant or normal activities
of the different cells inside the body.
All cells and organs in the body are being regulated by the
nervous and endocrine system.
1.
Nervous System – controls the activity of different
cells or tissues in the body. They generate nerve
impulses (action potential or electrical activities
of neurons.)
Neural Control
•
•
•
Responsible for the secretory and mechanical
activities of the body which can either be
voluntary or involuntary.
Mostly affects the activity of skeletal, cardiac or
smooth muscles and the secretory cells.
Onset of action: Rapid Onset and Short duration
Two types of Neurons in the body:
2.
a.
Motor or somatic neurons
•
controls the skeletal muscles that
makes it a voluntary control.
b.
Autonomic neurons
•
controls the involuntary activity of the
cardiac and smooth muscles.
Endocrine System- make use of endocrine tissues
or cells. Releases hormones that regulate the
activity of the human body. Known as the
hormonal or the humoral control.
!
a)
Because ECF is present inside the body which is the normal
environment of the different cells present in the body.
Regulating Systems
Responsible for the metabolic activities
of the body although it affects motor
and secretory activities minimally.
Includes all cells responsible for
metabolism.
Onset of action: delayed and long
duration.
Reproduction: endocrine mechanismdependent. Failure of the endocrine
system is failure of the ability to
reproduce.
c)
Escoto, Kelvin C.E.
•
d)
E.g. Continuous increase uterine
contraction during labor to promote
birth of the baby.
Feed Forward Control
•
The body anticipates the effect of a
certain stimulus in the environment
allowing the body to react in advance
to the said stimulus that will affect the
body.
•
E.g. A person not used to exercise
being forced to exercise will have an
anticipatory reaction of increase
respiratory rate and heart rate even
without the increase muscular activity.
Up regulation vs. Down regulation
1.
2.
3.
4.
Smooth Endoplasmic Reticulum
•
Needed for lipid synthesis
Rough Endoplasmic Reticulum
•
Needed for protein synthesis
Golgi Complex
•
Concerned with the secretion that
packages the agents that are to be
secreted. Said to be numerous in
actively secreting cells
Mitochondria
•
Numerous in actively metabolizing cell.
•
Power-house of the cell
Physiology is more concerned with the cell membrane
The cell membrane
Neurons generate impulses basically action
potentials. For an impulse to be generated,
neurons should have an uninterrupted
connection but the neural connections have
gaps or spaces that are known as synapses. Thus,
for a neuron to produce an impulse, it should
have a chemical agent to overcome the gaps.
This chemical agent is also known as the
neurotransmitter. Plus, another neuron must have
a receptor to receive and continue the
transmitted impulse by the neuron with a
neurotransmitter.
For a hormone to affect effectively the cells they
control, the hormone should react to a hormone
receptor.
e)
f)
Up-Regulation
•
Decreased amount of neurons and
hormones in the regulation system
would result to decrease effect in the
action that would lessen the control on
the affected cell. Thus, the affected
cell will INCREASE the receptors.
Increase the number of receptors
would increase the effect of the
neurons or the hormones in the
controlled cell.
Down-Regulation
•
Lesser amount of the control agents
(the neurons or the hormones) The
controlled cell will DECREASE the
number of receptors to maintain the
normal activity of the body.
Structures that allow the cell to be in close contact with
another cell and prevents separation of one cell to
another:
1.
Tight Junctions (Zonula Occludens)
•
Concerned with transport of ions and
water molecules.
•
Involved in Paracellular Transportation
wherein agents pass in between cells
but they do not pass through the cell
membrane (Apical and Basal part.) It
involves two proteins:
Ø
Occludins
Ø
Claudins – determines the
characteristic permeability of
the membrane. The greater
the amount of claudins
means the tighter is its
junctions. The tighter the
junctions, the lesser the
permeability.
2.
3.
Macula Adherens (Desmosome)
Gap Junctions
•
Also known as pores or the openings in
the membrane that forms the channels
•
Promote transportation but also
concerned with cell communication.
•
Functional unit: Connexons – made up
of the connexins protein.
Escoto, Kelvin C.E.
•
4.
Contrary to paracellular transportation
is Transcellular Transportation wherein
the utilization of the agents passes or
penetrates the gap junctions of the cell
membrane.
-
Hemidesmosome
•
Allows the basal portion to be in close
contact with the basement
membrane.
-
-
Activities on the Different Parts of the Cell
1.
2.
Apical Region
•
Area of absorption and secretion.
Some of the secreted agents are
needed for cellular protection.
2.
Lateral Region
•
The cell is close contact with another
cell – transport and communication.
•
Cell contact and Adhesion
3.
Basal Region
•
Area where cells are affected if there
are activities coming from the neurons
and hormones that creates ion
gradients allowing the cell to create
electrical changes.
The Cell Membrane
§
Maintains the composition (solute) of ICF and ECF
§
Regulates cellular transport
§
Site of signal transduction or cell communication
§
Acts as an anchor for structural proteins (stability,
size and shape)
Easily transports lipid
agents that are
amphipathic (Lipid
soluble).
Phosphatidylcholine
Phosphatidylserine
Phosphatidylethonolamine
Phophatidylinositol
Ø
Cholesterol
Moderator molecule
providing mechanical
stability as well as flexibility
Makes the membrane less
permeable to water
Prevents lipid crystallization
Proteins 40-50%
•
part wherein the transport of watersoluble agents can be observed.
Responsible for the transport of watersoluble particles.
Functions:
•
Receptor for hormones and
neurotransmitter agents
•
Source of enzymes
•
Skeletal Framework
•
Stability
Two Types of Proteins:
1.
Integral proteins or the Transmembrane
proteins.
§
They are capable of functioning as:
Ø
channels
(pores/opening in the
membrane)
Ø
carriers (transporters) of
the water-soluble
particles
2.
Peripheral Protein – present mostly on the
surface of the membrane.
§
Can function as antigenic markers
3. Carbohydrates
•
Majority are present in the extracellular surface.
•
Usually combined with proteins (CHO+CHON =
glycoproteins) and lipids (CHO + Lipids
=glycolipids.) They don’t appear as pure
carbohydrates in the cell membrane.
•
Difficult to transport water-soluble agents
penetrating the lipid bilayer
•
Functions as:
§
Serve as antigenic markers
§
Provide stability
§
Attachment agent
§
Cell communication
§
Some can function as cell channels
(Glycoproteins)that transport watersoluble particles.
Composition of the Cell Membrane
1.
Lipids
•
50-60% (almost equal with the amount
of protein)
Ø
Phospholipids – major
lipids found in the cell
membrane. They are
amphipathic (can
combine with fats and
water molecules.)
Arranged as a bilayer –
Phospholipid bilayer.
Semi-permeable vs. Selectively Permeable Cell Membrane
§
§
Semi-permeable membrane
can only transport water or solvent
molecules and not of the solute.
Selectively Permeable
Capable of transporting both solvent
and solute molecules.
Selection is observed in the transport of
solutes.
Cell of the human body is selectively
permeable.
Escoto, Kelvin C.E.
-
Most of the cells in the body are
selectively permeable.
During a resting human cell its cell membrane is:
§
§
§
§
§
Note: Permeability of the membrane can be altered. E.g.
the skeletal muscle cell is in need of glucose. The
permeability can be changed allowing the permeability of
the skeletal muscle cell to become permeable to glucose.
Here come’s the importance of the hormonal control
wherein the aid of insulin will allow the membrane of the
muscle cell to let glucose be transported.
Different Transport Activities in the Cell
Active Transport
§
Needs energy for its activity
§
Transport of agent going against the direction of
the energy gradient. (activista. Against!)
§
Lower to higher pressure gradient
§
Uphill/”Pump” Transport (e.g. the Na-K ion pump.
Meaning the the action is active from a lower to
higher gradient.
§
Unidirectional (going inside)
§
E.g. In Na-K pump, sodium ions inside the cell
lesser than outside since Sodium is the major
extracellular cation, and the movement of the
active transport is from lower to higher
movement that’s sodium ions when actively
transported, the movement of the transport will
be from the inside to the outside (Dalawang
P.I.S.O. – 2 Potassium ions Inside. 3 Sodium ions
Outside)
§
Uses carriers to oppose the energy gradient to
facilitate transport agents in and out of the cell
that’s why it is energy or mitochondrial activitydependent. Thus, the greater the energy
gradient, the greater the energy consumption by
the carriers.
§
It is a continuous process because equilibrium
can never be attained. The manner of
transportation is from lower to higher. In the area
of lower concentration, the area progressively
becomes lower while in the area of higher
concentration, progressive amount of agent is
being increased. It is possible for a continuous
process as long as the cells are still alive. If the
cell dies there will be no functioning
mitochondria, no energy will be produced to
supply the process.
Limited number of carriers in the membrane. If
these are exhausted the rate of transport will
stop. If the maximum rate of active transport is
reached, you can never increase the rate of
reaction – this condition is called saturation. The
transport is continuous but the rate of transport
cannot be increased.
When plotted: initially only a few number of
carriers are utilized and then there will be a
gradual increase in the rate of transport. When
the carriers in the membrane are now involved in
the transport, the transport will still continue but it
will undergo plateau and the rate of transport will
not increase – Saturation Kinetics. In renal
physiology it is known as Transport maximum (Tm)
Active transport: they are not concerned with
the transport of fatty acids except for the short
chain fatty acids which utilizes carriers and
normally happen in the colonic mucosa.
Happens only in living things since mitochondria is
a pre-requisite for energy production.
Would ONLY utilize a transcellular transport
Passive Transport
§
Does not require energy
§
A type of transport wherein the agent goes along
with the direction of the energy gradient (go with
the flow)
§
Direction: from higher to lower gradient
§
Downhill Transport
§
Bidirectional (either going inside or outside the
cell)
§
Uses channels
§
Channels could be gated wherein the activities
can be controlled or regulated. Closing the
gates of the channel prevents the transport while
opening the gates promote transport.
§
It is a non-continuous process because if the
concentration of a certain agent transported by
the cell has the same amount of agent outside
and inside the cell there will be no presence of
energy gradient, there will be no continuous
passive transport because the agent cannot go
along the gradient since there is already
equilibrium wherein the concentration is equal
inside and outside the cell.
§
Water in passive transport is dependent upon the
effect of osmotic pressure.
§
Passive transport is more concerned with
lipophilic agents.
§
For the transport of lipid materials, they only
penetrate the lipid bilayer without utilizing
channels.
§
Can be observed in living and non-living cells. It
happens in non-living cells since it does not
require energy. E.g. a dry paper placed in water.
The paper will absorb the water by passive
process.
§
Utilizes either transcellular or paracellular
transport.
Escoto, Kelvin C.E.
Common Gradients Encountered by the Cell during
Transport:
§
Concentration gradient (Pressure gradient)
Hydrostatic or Osmotic pressures
§
Electrical Gradient
We do not use the principle of the
movement of the agent from a higher
to lower or lower to higher gradient to
electrical gradient.
For us to know whether the activity is
going along or going against the
gradient, look at the electrical charge
of the agent being transported and the
electrical charge of the area where
the agent is to be transported.
E.g. Positively charged agents
transported to a positively charged
area is considered ACTIVE
TRANSPORTATION since like charges
repel. Attraction is seen in unlike
charges wherein easy passage of the
agent won’t be hindered it’ll just go
with the flow.
Usually passive transport does not utilize carriers except to
facilitated Passive Transport. In this type of transport, the
carriers involved in the activity does not move the transport
agent against the gradient. They help facilitate the agent
to get transported in the gradient along the gradient. So,
there is no energy expenditure.
In passive transport, specific or non- specific channels can
be utilized to process the transport.
E.g. the transport of water, they utilize a specific water
channels known as aquaporins, that will not transport any
other substances aside from water. Another example is the
Na-K leak channels.
PASSIVE TRANSPORT
Along a gradient
Downhill
No ATP consumption
ACTIVE TRANSPORT
Against a gradient
Uphill/Pump
ATP utilization
(Mitochondria)
No carrier
Always involves carrier
Glycoprotein channels
Glycoprotein channels
No inhibition
Equilibrium
Bidirectional
Undergoes inhibition
Saturation
Unidirectional
Hydrophilic agents
→CHON channels
(gated/non-gated)
Hydrophilic agents
→CHON channels
(transporters)
Living/non-living cells
Living cells
Water→CHON channels
Carrier →facilitated
diffusion
Lipophilic→Lipid bilayer
Carrier vs. Channel:
•
In transport involving channels. The larger the
energy gradient the faster the passive transport.
•
Carrier-involved activities are slower compared
to channel-involved activities because they
•
need energy to perform action. They will wait for
the mitochondria to produce energy. After the
energy is produced, they have to metabolize the
ATP to have a high energy phosphate bonds.
Plus, they have to counteract the force of the
energy-gradient which will also take time.
Carrier and Channel (gated-channel) activities
can be regulated.
Factors Affecting the Transport:
•
•
•
•
•
•
Channels/pores are concerned mostly with
passive transport and the passive transport
activity is usually energy independent, they don’t
require energy for their activity. But, they can also
be specific. The selectivity and specificity
depends on the size (molecular weight), shape
and electrical charge of the agent and the
transport involving channels can be regulated by
means of its gating-properties.
Solubility
Nature of the substance
Membrane thickness
Area of transport
Energy gradient
Different Gating-Mechanisms:
•
Voltage-gated
o
A change in the electrical activity of
the cell would allow the voltagegated cell membrane to open or
close.
o
All excitable cells of the body have
electrical activities.
o
Outside surface of the cell – Positive
o
Inside surface of the cell – when the
cell is resting the cell is Negatively
charged: Inside-negative condition.
•
Ligand-gated
o
Usually associated with the guanosine
proteins which can sometimes have
an inhibitory or stimulatory effect.
o
Ligands- chemical agents involved in
creating change in membrane
permeability. In the neurons, these are
the neurotransmitter. In the endocrine
system, these are the hormones.
o
Ligands not in contact with the
channel are closed. Ligand in contact
with the channel is open.
o
For any chemical agents to exert their
effects, the cell itself must have a
receptor for the ligand.
o
Neurotransmitter
o
E.g. Acetylcholine the major
neurotransmitter must have the
cholinergic receptor.
Two types of cholinergic
receptors:
1. Muscarinic CR
2. Nicotinic CR
o
Epinephrine and
norepinephrine must have epinephrine
and norepinephrine receptors
(adrenergic receptors)
Two types of adrenergic
receptors:
1. Alpha AR
2. Beta AR
Escoto, Kelvin C.E.
Hormones – whatever the name of the
hormone is the name of their receptors
o
Growth hormone – Growth hormone
receptor
G-Protein-Linked Channels
o
Some ligands are dependent with Gproteins. For them to exert their effects
on the channel they control, the
channel must contain G-proteins. If
that is a guanosine stimulatory
proteins, the channel will be opened.
If it is an inhibitory G protein, the
transfer will be prevented.
o
E.g. In the skeletal muscle or adipose
when the cell is resting, no transport of
glucose is happening but in the
presence of insulin, which serves as the
ligand, will help open up the glucose
channels.
o
•
o
Mechanically-gated/Stress-activated
•
o
Stretching the cell-membrane can
open up the channels since the
channels are pulled apart.
Note: Not all activities of the channel can be regulated
because some channels are non-gated; They are always
open wherein it can be completely open or partial. The
activity will now be continuous transport and is known as
passive or leaky channels. These channels can be seen in
the GIT.
DIFFERENT PASSIVE TRANSPORTS
Passive transport of small amount of agents:
Osmosis – only water or solvent molecules are being
transported.
o
Allows water/solvent molecules to move from
lesser to greater solute concentration. Plus, the
solute must be osmotically active to attract
water.
o
Osmotic pressure is highly dependent on the
amount of osmotically active agents present in
the solution.
o
The greater the amount of the active osmotic
agents, the greater is the osmotic pressure, the
greater the ability to attract water.
o
RBC on an isotonic solution:
Ø
No change in volume and cell size
since they have the same
concentration of solutes; the water will
not have any net flow to any direction.
They can move in and out BUT in equal
amounts.
Isotonic concentration
Ø
Sodium Chloride (NaCl): 0.9% or
280-300 mOsm/L (ave. 290)
Ø
Glucose: 0.5%
Ø
Lesser value: Hypotonic
Ø
Greater value: Hypertonic
RBC on a hypotonic solution:
Ø
Swelling of cell will occur. If the cell has
the amount of greater solute, water will
move from the hypotonic to the cell
allowing it to swell and burst.
Ø
Irreversible
o
RBC on a hypertonic solution:
Ø
The hypertonic solution has the higher
concentration allowing the water to
move out of the cell making it crenate
or shrink. (just remember HYPERCREN)
Ø
Reversible
Diffusion – mostly concerned with solute transport; but can
also promote solvent transport.
o
o
o
Simple Diffusion – the transport of the solute does
not require any membrane or it can require a
membrane but that membrane should be
permeable to all solvents and solutes.
Facilitated Diffusion – the diffusive process
requires the activity of a carrier.
Isotonic – normal condition of the human body
fluid. Normal human cell environment.
Escoto, Kelvin C.E.
Filtration – transport of the solvents and solutes on a highly
porous membrane with numerous channels. Commonly
seen in fenestrated capillaries of the GIT and kidney
especially in the glomerulus.
o
There is selective filtration: almost everything is
being filtered in the glomerulus except the large
particles (blood and protein.)
Passive transport of large amount of agents:
Bulk Flow – e.g. flow of urine, flow of bile in the biliary ducts,
blood flow
o
They follow pressure differences
o
In the cardiovascular system, the highest pressure
can be recorded in the left ventricle while the
lowest pressure can be recorded in the right
ventricle – Central Venous Pressure (CVP)
Solvent Drag – always observed whenever there is bulk
flow. (e.g. in the plasma)
o
Van’t Hoff’s law – osmotic pressure is dependent
on the concentration of the osmotically active
particles.
Diffusion Laws
o
Fick’s Law
o
Stokes-Einstein Equation
Determination of Plasma Osmolarity
𝑷𝑶 = 𝟐 × 𝑷𝒍𝒂𝒔𝒎𝒂 𝑵𝒂 +
𝑷𝒍𝒂𝒔𝒎𝒂 𝑮𝒍𝒖𝒄𝒐𝒔𝒆 𝑩𝑼𝑵
+
𝟏𝟖
𝟐. 𝟖
Estimate of PO = Plasma Na x 2
Normal Values:
Normal Tonicity: 280-300 mosm/L
Sodium: 135-145 meq/L
Glucose: 60-110 mg/dL
BUN: 8-20 mg/dL
Note: Tonicity is dependent on the presence of solutes.
Wherein the solutes should be osmotically active; it should
be able to attract water. An osmole holding on to water
should not be able to traverse the membrane and move
out the area.
o
E.g. With a normal amount of plasma proteins,
the body can retain normal amount of water in
the vascular compartment. If the plasma proteins
will decrease the water will move out of the
vascular compartment and will go to the
interstitial spaces that will produce edema.
o
Solutes that are able to penetrate the
membrane and stays in the area are good
osmotic agents which makes the osmotic
coefficient equal to one. These are the proteins
in the blood specifically albumin.
o
If the osmotic coefficient is equal to zero that
makes the agent ineffective.
o
Plasma proteins are responsible for maintaining
the osmotic pressure in the blood while the
Electrolytes are essential in maintaining the
osmotic pressure inside the cell.
o
Regulatory Cell Volume Decrease
Ø
If the plasma is hypotonic it is expected
that the cells are going to swell but the
body will try to maintain to normalize
the shape of the red blood cell. If there
is a transient hypotonicity of the
plasma, the cell will transport some of
the electrolytes or solutes out of the cell
to lessen the number of osmotically
active agents.
o
o
o
o
Regulatory Cell Volume Increase
Ø
Vice Versa
DIFFERENT ACTIVE TRANSPORTS
Carrier mediated that involves carrier proteins
present in the cell membrane.
Some types of active transports do not require
carriers in the membrane but are involved almost
in the movement of the membrane.
Energy dependent
Steps during the Active Transport:
1.
Association – usually starts with the binding of the
agent to the carrier molecule.
2.
Translocation – The carrier will change its
configuration or shape that will promote the
movement of the agent to another location.
3.
Dissociation – When they are on their location
the carrier will release the agent allowing them to
separate from one another.
Carrier
o
Energy-dependent
o
Selectivity and specificity (dependent on the size
and shape of the binding site of the carrier
molecule. The agent should fit exactly on the
binding site of the carrier molecule)
o
Can undergo saturation or inhibition
(Competitive inhibition)
o
The activity can be regulated or mediated using
chemical agents usually a ligand (hormones)
Primary Active Transport
o
Agents are moving all against their
electrochemical gradient.
o
Can progress on their own without any
simultaneous transport happening.
1.
Uniport
Ø
Carrier transports one agent at a time.
Ø
Hydrogen pump
2.
Antiport
Ø
Exchange transport
Ø
One is transported in and another one
is transported out
Ø
E.g. Na-K exchange pump, H-K
exchange pump
Ø
Na-K exchange pump is an
electrogenic transport that happens
continuously in an excited cell like cell
of the muscles and neurons.
Ø
PISO directions cannot be changed.
Escoto, Kelvin C.E.
2PISO: 2 Potassium In. 3 Sodium Out
Influx – Transport of ions inside the cell
Efflux – transport of ions outside the cell
•
•
•
Note! Some Active Transport are non-electrogenic. It
means that the exchange of ions is in equal amounts. E.g.
the Hydrogen-Potassium Exchange pump. 2H ions in
exchange of 2K ions would still have an exchange
mechanism but will not create an electrical change in the
cell. Making it a non-electrogenic active transport or an
Electro-Neutral Pump.
Secondary Active Transport
o
Some agents are transported against their
gradient while other agents are transported
along their gradient.
o
Only occur when another active transport is
simultaneously happening.
o
Antiport-dependent
o
Mechanism will be effective when there is Na-K
exchange pump.
1.
o
2.
Similar to uniport
Hydrogen pump
ATP-Binding Cassette Transporters
o
A type of transport associated with
Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR)
•
•
Carrier independent
Do not utilize carriers but the cell membrane acts
as a whole that forms vesicles.
1.
Endocytosis – membrane of the cell takes in the
agent. Exemplified by:
Phagocytosis – ingestion of large
agents.
o
Pinocytosis – intake of agents in fluid
form.
o
Involves a “docking” process wherein
there is binding with a specific
membrane protein receptor that will
form a vesicle in the cell membrane
coated by clathrin.
o
The vesicle is initially part of the
membrane. They are coated with
clathrin. Vesicles are then separated
from the cell membrane and referred
to as vacuoles. After the vesicles
separate they will be surrounded with
lysosomes and agents will be digested.
The clathrin will separate from the
vesicle after digestion and the clathrin
will be recycled and allow the
membrane to perform another
endocytosis.
o
Once the vesicles trapped a certain
agent it will also need other accessory
proteins like adaptin and dynamin.
There is also involvement of
microtubules and the dynein protein.
o
Portions without clathrin are not
involved in endocytosis
o
Absorption can be regulated:
Ø
Fluid phase
Unregulated Absorption;
nonspecific
E.g. absorption in the GIT
Ø
Adsorptive Endocytosis
Regulated Absorption
Requires a chemical agent
or ligands which will react
with the receptors to start
the activity
Receptor mediated or
adsorptive endocytosis
Transcytosis or Cytopempsis
o
Rapid transport of substance
o
Endocytosis at the apical portion of the
cell followed by exocytosis at the basal
part of the cell.
o
Counter Transport
o
Exchange transport
o
E.g. Sodium Calcium Counter transport
that is dependent on the Na gradient
provided by the Na-K exchange pump:
Na transported inward. Ca efflux
happens simultaneously.
o
Digoxins – cardiac glycosides that
inhibits the Na-K ATPase activity that
decreases the activity of the
symporters and counter transporters.
ATP-Dependent Transporters or ATPase Ion
Transporters
o
P-Type
Ø
Similar to antiport
V-Type
Ø
Ø
Na-K exchange pump, H-K
exchange pump
VESICULAR TRANSPORT
Depends its activity with the normal NaK pump activity.
E.g. Sodium – Glucose cotransport,
Sodium-amino acid cotransport (2
substances), Na-K Chloride cotransport (3 substances)
Other Carrier-mediated Transport from Berne and Levy:
Active Transport also have another type of carriermediated active transport and this are the:
1.
o
Symport
o
Also known as Co-transport/Coupled
Transport.
o
Carries several agents at a time.
o
Usually transports 2 agents at a time
but can also transport 3 agents
simultaneously in one direction.
o
2.
Ø
2.
3.
Exocytosis/Emeiocytosis – moves the agent
outward.
o
Reverse phagocytosis and pinocytosis
Escoto, Kelvin C.E.
o
o
o
1.
2.
Also needs clathrin
In the movement of the vesicle, it
needs the protein Kinesin
Secretory vs. Excretory Activities of the Cell
Similar to the direction of transport: out of the
cell.
Secretion – releasing of agents that are need by
the body and can affect the activity of other
cells.
Excretion – excreted agents are considered
waste products and released from the body.
Renal System: major excretory system
of the body that excretes almost all
waste products of the body except
carbon dioxide that are excreted by
the respiratory system.
o
Note: Secretion and Excretion can also be
regulated, partially-regulated or non-regulated.
o
2 Pathways Involved in Exocytosis
1.
Constitutive Pathway
Ø
Continuous partially
Ø
E.g. of non-regulated
secretory activity is the
secretion of the mucus,
secretion of mucus cannot
be control or can be
controlled at least partially.
2.
Non-Constitutive Pathway
Ø
Fully regulated pathway
using a ligand that will initiate
the transport.
Passive Transport
Osmosis
Diffusion
•
•
Simple
Facilitated
Filtration
Bulk Flow
Solvent Drag
Active Transport
Carrier Mediated:
•
Uniport (Primary)
•
Symport
(Secondary)
•
Antiport (Primary)
Transcytosis
Pinocytosis
Phagocytosis
Factors that Affect the Transport of the Cell
1.
2.
3.
4.
5.
Nature of the Substance
o
Lipid soluble agents easily penetrates the
membrane since there is no need for them
to look for channels as they can directly
penetrate the lipid bilayer membrane.
Size of the Agent/Molecular Weight
o
It should be very small (>2nm or 20
Ångström) and it should be very light (69,000
MW) to easily pass through the membrane.
Membrane Thickness
o
The thicker the membrane the lesser the
rate of transport whether active or passive
transport.
Surface Area
o
The greater the area the greater the
transport; the lesser the area the lesser the
transport.
Number of Channels/Pores
o
In passive transport: the greater the
channels, the faster the rate.
Permeability coefficient –permeability of the
membrane is dependent on the number
and size of channels.
6.
Number of Carriers
o
The greater the carriers in number, the faster
the rate of transport.
7.
Membrane Permeability
o
Semi-permeable membrane can only
transport water.
8.
Exposure
o
The longer the agents are exposed to the
membrane, the greater the rate of
transport.
o
Lesser time the agent is exposed; lesser
amount of agent is being transported.
9.
Energy Gradient
o
Passive transport with greater energy
gradient = grater the force = greater the
rate
o
Active Transport with greater energy
gradient = greater force needed = the rate
of the transport is lesser
Gradient Time Limitation – combined length of exposure
and energy gradient.
o
o
o
o
Cell Signaling or Cell Communication
Also known as signal transduction
Gap junction – part of the membrane used for cell
communication by adjacent cells or cells in direct
contact with one another.
Connexons – are chemical agents made up of smaller
proteins called connexins and are used for
communication by distant cells or nearby cells that
are not directly in contact with another cell.
Communication using Chemical agents:
Ø
Synaptic communication using
neurotransmitter can be used in adjacent
cell communication.
Ø
Hormones are used during distant cellcommunication.
o
Autocrine - cells communicating with another
identical cell within the area and are not directly in
contact with one another.
Ø
Released to interstitial fluid
Ø
E.g. communication happening in the islets
of Langerhans: a group of cells present in
the pancreas. Beta cells communicating
with another beta cells.
o
Paracrine - cells communicating with another nonidentical cell within the area and are not directly in
contact with one another.
Ø
E.g. Beta cells communicating with another
alpha cells in the islets of Langerhans in the
pancreas.
For the Communication to Happen:
1.
Change must be created in the extracellular region
that will eventually affect the cell. Extracellular
change will be transformed by the affected cell into
intracellular changes or also known as intracellular
messages. Intracellular agents will be affected by the
changes allowing to produce an activity that will be
directed to extracellular change.
2.
For it to react to extracellular change affecting the
cell, ligand-receptor interaction is needed. Receptors
can be present in the cytoplasm or the nucleus
(intracellular receptors).
3.
Interaction of Ligand and receptor will produce
Ligand-receptor complex that will now activate
certain enzymes present in the intracellular surface of
Escoto, Kelvin C.E.
4.
the cell. These enzymes are known as the second
messengers.
Once these second messengers are activated, they
will affect certain type of protein or an enzyme in the
cytoplasm. Then it will create a response directed to
the extracellular change affecting the cell.
STEPS IN CELLULAR COMMUNICATION WITH CHEMICAL
AGENT USE
1.
2.
3.
4.
Synthesis of the Agent
•
Ligand is needed to activate the cell.
Release of the Agent
•
E.g. In the synapse the NTA are normally
produced in the pre-synaptic.
Transport of Agents Towards the Target Cell
•
The agents from the pre-synaptic are
released to the post-synaptic once the
agents are needed.
Interaction with the Cellular Receptor
•
The cell should have the receptor for
effective communication.
Intracellular Receptors:
Nucleus
Cytoplasm
Cell Surface (membrane) Receptors:
Ion channel linked
Cytokine linked
Catalytic linked (receptor tyrosine
kinase)
G-Protein linked – also activates ion
channels
{
Second
Messengers
7.
Adenyl Cyclase (CAMP)
Phospholipase A2
Transducin Pathway
Phospholipase C (IP3)
Agents from the pre-synaptic will interact
with the receptors of the post-synaptic.
Formation of Ligand-Receptor Complex
Activation of the Second Messengers
•
In this part the ligand-receptor complex
activates certain group of enzymes in the
intracellular surface of the cell membrane.
Cellular Change Activity
•
The activation of the 2nd messengers will
make a response or reaction on the ligand
directed towards the change affecting the
cell.
•
5.
6.
1.
2.
3.
4.
8.
Termination of Agent’s Effects
•
The effect of the agent is non-continuous.
Thus, it is terminated once the effect of the
agent is seen on the targeted cell receptor.
Common Types of Termination:
•
Reuptake
Termination of the neurotransmitter in
the neural communication.
After termination in the post-synaptic,
the agent is taken back by the presynaptic to be reutilized for another
communication.
•
Destruction of the Agent
Enzymes terminate the effects of the
agent.
The effect is delayed since the effect of
the ligand (Neurotransmitter) must be
allowed to interact with target cell first
(post-synaptic) before it is activated.
Usually happens in the target cell.
Enzymes that usually deactivate the
Agents:
1.
Acetylcholine esterase destroy the
acetylcholine
2.
Monoamino Oxidase (MAO) and
Catechol-O-methyltransferase (COMT)
destroys epinephrine and
norepinephrine
3.
Insulinase – Insulin
4.
ADH – Vasopressin
Other Communication Termination: In certain cases,
termination is made by decreasing the activity of the
target cell secreting the ligand to reduce the amount of
ligand in the area. Change in the conformation of the
receptor protein can be a mean to stop the
communication process since the ligand will not be able to
activate the receptor.
Ligand or the Chemical Agents
§
Classified base on size and solubility:
§
Small and lipophilic molecules usually affect the
target cells by interacting with receptors present
inside the cell; affects intracellular receptors since
they easily penetrate the membrane.
§
Large and lipophilic molecules – although they
are lipophilic, they still cannot penetrate the lipid
bilayer because of their large size. To affect the
activity of the cell, they interact with membrane
receptors which are seen in all hydrophilic
agents.
§
Hydrophilic molecules – affect membrane
receptors
Receptors
§
Effect of ligands is dependent on the presence
and number of receptors.
§
Located in the cytoplasm, nucleus or cell
membrane.
§
Made mostly of proteins
§
Exhibits high degree of specificity
§
High affinity to a specific signaling activity
§
§
Down regulation or desensitization
Ø
Decreases the sensitivity and increases the
threshold or stimulation.
Up regulation or super sensitization
Ø
Increases the sensitivity and decreases the
threshold or stimulation.
Escoto, Kelvin C.E.
Apoptosis
§
Programmed death of a cell
§
Rate of destruction is equal to the rate of
production.
§
Characterized by overall compaction of a cell
and its nucleus and the orderly dissection of
the chromatin by endonucleases.
§
Mediated by proteolytic enzymes called
caspases.
§
Two Phases:
Ø Activation phase
-Self destruction/suicide
Ø Execution phase “eat me”
-Markers for phagocytes
(macrophages, from monocytes)
§ Two Distinct Pathways:
Ø Extracellular pathway
-Involves a death ligand (TNF)
Ø
Intracellular Pathway
-Decreased function of the
mitochondria will release the
caspases that will cause death of
the cell.
Ø Whether extra- or intra- cellular, it
uses caspses.
Ø Erythrocytes are not included since it
is anucleated.
Escoto, Kelvin C.E.
Far Eastern University
Nicanor Reyes Medical Foundation
Institute of Medicine
Section D
Endocrine Mechanism
•
PHYSIOLOGY A – CELL PHYSIOLOGY
Dr. Felipe C. Barbon
•
•
Cell – basic unit of the human body that has different parts
and different activities but trying to attain the same goal –
homeostasis.
Homeostasis – maintaining the constancy of the internal
environment which is the EXTRACELLULAR FLUID – condition
of the fluids outside the cell.
Why Extracellular Fluid is referred to as the internal
environment?
•
Neural and Endocrine Control Mechanisms
Negative Feedback
•
opposition of the regulating system
against a certain activity in the body.
•
If there is an increase activity in the
body the regulating system will oppose
the activity and bring the condition
back to normal but not to the point of
below normal.
•
Negative feedback on the endocrine
mechanism:
o
Hormone that affects another
hormone
o
Stimulatory hormones if the
body is in need of hormones
o
Inhibitory hormones if there is
an increase in hormones
•
E.g.: Increase blood pressure can
damage the cardiovascular system.
Thus the regulating system will oppose
the activity will bring it down, back to
normal.
b)
Modified Negative Feedback
•
Applies ONLY in the endocrine system.
•
Maintenance of normal hormones in
the blood is non-hormonal metabolitedependent
•
Non-hormonal agent controlling a
hormonal agent in the circulation of
the body.
•
E.g. Plasma glucose in the blood being
controlled by the hormone Insulin. But
Insulin being controlled by glucose
which is a non-hormonal metabolite.
Thus, the level of the hormonal agent is
affected by the non-hormonal agent
but that non-hormonal agent is
controlled by the affected hormone.
Positive Feedback
•
progression and enhancement of the
certain condition to regain the normal
function of the body.
•
E.g. coagulation activity of the blood
during blood vessel injury. Constriction
of the injured blood vessel→activation
of the platelets→activation of clotting
factor→clotting for the prevention of
blood loss.
To attain homeostasis, constant condition of the said
environment must be maintained including the amount of
solute and the amount of water.
No balance or equilibrium especially in the amount of
solutes inside and outside the cell (e.g. more Sodium ions
outside the cell and Potassium ions inside and/or outside
the cell.) – no equal amount of ions: no equilibrium.
In homeostasis we just maintain the amount of solutes and
water in the ECF to maintain a constant or normal activities
of the different cells inside the body.
All cells and organs in the body are being regulated by the
nervous and endocrine system.
1.
Nervous System – controls the activity of different
cells or tissues in the body. They generate nerve
impulses (action potential or electrical activities
of neurons.)
Neural Control
•
•
•
Responsible for the secretory and mechanical
activities of the body which can either be
voluntary or involuntary.
Mostly affects the activity of skeletal, cardiac or
smooth muscles and the secretory cells.
Onset of action: Rapid Onset and Short duration
Two types of Neurons in the body:
2.
a.
Motor or somatic neurons
•
controls the skeletal muscles that
makes it a voluntary control.
b.
Autonomic neurons
•
controls the involuntary activity of the
cardiac and smooth muscles.
Endocrine System- make use of endocrine tissues
or cells. Releases hormones that regulate the
activity of the human body. Known as the
hormonal or the humoral control.
!
a)
Because ECF is present inside the body which is the normal
environment of the different cells present in the body.
Regulating Systems
Responsible for the metabolic activities
of the body although it affects motor
and secretory activities minimally.
Includes all cells responsible for
metabolism.
Onset of action: delayed and long
duration.
Reproduction: endocrine mechanismdependent. Failure of the endocrine
system is failure of the ability to
reproduce.
c)
Escoto, Kelvin C.E.
•
d)
E.g. Continuous increase uterine
contraction during labor to promote
birth of the baby.
Feed Forward Control
•
The body anticipates the effect of a
certain stimulus in the environment
allowing the body to react in advance
to the said stimulus that will affect the
body.
•
E.g. A person not used to exercise
being forced to exercise will have an
anticipatory reaction of increase
respiratory rate and heart rate even
without the increase muscular activity.
Up regulation vs. Down regulation
1.
2.
3.
4.
Smooth Endoplasmic Reticulum
•
Needed for lipid synthesis
Rough Endoplasmic Reticulum
•
Needed for protein synthesis
Golgi Complex
•
Concerned with the secretion that
packages the agents that are to be
secreted. Said to be numerous in
actively secreting cells
Mitochondria
•
Numerous in actively metabolizing cell.
•
Power-house of the cell
Physiology is more concerned with the cell membrane
The cell membrane
Neurons generate impulses basically action
potentials. For an impulse to be generated,
neurons should have an uninterrupted
connection but the neural connections have
gaps or spaces that are known as synapses. Thus,
for a neuron to produce an impulse, it should
have a chemical agent to overcome the gaps.
This chemical agent is also known as the
neurotransmitter. Plus, another neuron must have
a receptor to receive and continue the
transmitted impulse by the neuron with a
neurotransmitter.
For a hormone to affect effectively the cells they
control, the hormone should react to a hormone
receptor.
e)
f)
Up-Regulation
•
Decreased amount of neurons and
hormones in the regulation system
would result to decrease effect in the
action that would lessen the control on
the affected cell. Thus, the affected
cell will INCREASE the receptors.
Increase the number of receptors
would increase the effect of the
neurons or the hormones in the
controlled cell.
Down-Regulation
•
Lesser amount of the control agents
(the neurons or the hormones) The
controlled cell will DECREASE the
number of receptors to maintain the
normal activity of the body.
Structures that allow the cell to be in close contact with
another cell and prevents separation of one cell to
another:
1.
Tight Junctions (Zonula Occludens)
•
Concerned with transport of ions and
water molecules.
•
Involved in Paracellular Transportation
wherein agents pass in between cells
but they do not pass through the cell
membrane (Apical and Basal part.) It
involves two proteins:
Ø
Occludins
Ø
Claudins – determines the
characteristic permeability of
the membrane. The greater
the amount of claudins
means the tighter is its
junctions. The tighter the
junctions, the lesser the
permeability.
2.
3.
Macula Adherens (Desmosome)
Gap Junctions
•
Also known as pores or the openings in
the membrane that forms the channels
•
Promote transportation but also
concerned with cell communication.
•
Functional unit: Connexons – made up
of the connexins protein.
Escoto, Kelvin C.E.
•
4.
Contrary to paracellular transportation
is Transcellular Transportation wherein
the utilization of the agents passes or
penetrates the gap junctions of the cell
membrane.
-
Hemidesmosome
•
Allows the basal portion to be in close
contact with the basement
membrane.
-
-
Activities on the Different Parts of the Cell
1.
2.
Apical Region
•
Area of absorption and secretion.
Some of the secreted agents are
needed for cellular protection.
2.
Lateral Region
•
The cell is close contact with another
cell – transport and communication.
•
Cell contact and Adhesion
3.
Basal Region
•
Area where cells are affected if there
are activities coming from the neurons
and hormones that creates ion
gradients allowing the cell to create
electrical changes.
The Cell Membrane
§
Maintains the composition (solute) of ICF and ECF
§
Regulates cellular transport
§
Site of signal transduction or cell communication
§
Acts as an anchor for structural proteins (stability,
size and shape)
Easily transports lipid
agents that are
amphipathic (Lipid
soluble).
Phosphatidylcholine
Phosphatidylserine
Phosphatidylethonolamine
Phophatidylinositol
Ø
Cholesterol
Moderator molecule
providing mechanical
stability as well as flexibility
Makes the membrane less
permeable to water
Prevents lipid crystallization
Proteins 40-50%
•
part wherein the transport of watersoluble agents can be observed.
Responsible for the transport of watersoluble particles.
Functions:
•
Receptor for hormones and
neurotransmitter agents
•
Source of enzymes
•
Skeletal Framework
•
Stability
Two Types of Proteins:
1.
Integral proteins or the Transmembrane
proteins.
§
They are capable of functioning as:
Ø
channels
(pores/opening in the
membrane)
Ø
carriers (transporters) of
the water-soluble
particles
2.
Peripheral Protein – present mostly on the
surface of the membrane.
§
Can function as antigenic markers
3. Carbohydrates
•
Majority are present in the extracellular surface.
•
Usually combined with proteins (CHO+CHON =
glycoproteins) and lipids (CHO + Lipids
=glycolipids.) They don’t appear as pure
carbohydrates in the cell membrane.
•
Difficult to transport water-soluble agents
penetrating the lipid bilayer
•
Functions as:
§
Serve as antigenic markers
§
Provide stability
§
Attachment agent
§
Cell communication
§
Some can function as cell channels
(Glycoproteins)that transport watersoluble particles.
Composition of the Cell Membrane
1.
Lipids
•
50-60% (almost equal with the amount
of protein)
Ø
Phospholipids – major
lipids found in the cell
membrane. They are
amphipathic (can
combine with fats and
water molecules.)
Arranged as a bilayer –
Phospholipid bilayer.
Semi-permeable vs. Selectively Permeable Cell Membrane
§
§
Semi-permeable membrane
can only transport water or solvent
molecules and not of the solute.
Selectively Permeable
Capable of transporting both solvent
and solute molecules.
Selection is observed in the transport of
solutes.
Cell of the human body is selectively
permeable.
Escoto, Kelvin C.E.
-
Most of the cells in the body are
selectively permeable.
During a resting human cell its cell membrane is:
§
§
§
§
§
Note: Permeability of the membrane can be altered. E.g.
the skeletal muscle cell is in need of glucose. The
permeability can be changed allowing the permeability of
the skeletal muscle cell to become permeable to glucose.
Here come’s the importance of the hormonal control
wherein the aid of insulin will allow the membrane of the
muscle cell to let glucose be transported.
Different Transport Activities in the Cell
Active Transport
§
Needs energy for its activity
§
Transport of agent going against the direction of
the energy gradient. (activista. Against!)
§
Lower to higher pressure gradient
§
Uphill/”Pump” Transport (e.g. the Na-K ion pump.
Meaning the the action is active from a lower to
higher gradient.
§
Unidirectional (going inside)
§
E.g. In Na-K pump, sodium ions inside the cell
lesser than outside since Sodium is the major
extracellular cation, and the movement of the
active transport is from lower to higher
movement that’s sodium ions when actively
transported, the movement of the transport will
be from the inside to the outside (Dalawang
P.I.S.O. – 2 Potassium ions Inside. 3 Sodium ions
Outside)
§
Uses carriers to oppose the energy gradient to
facilitate transport agents in and out of the cell
that’s why it is energy or mitochondrial activitydependent. Thus, the greater the energy
gradient, the greater the energy consumption by
the carriers.
§
It is a continuous process because equilibrium
can never be attained. The manner of
transportation is from lower to higher. In the area
of lower concentration, the area progressively
becomes lower while in the area of higher
concentration, progressive amount of agent is
being increased. It is possible for a continuous
process as long as the cells are still alive. If the
cell dies there will be no functioning
mitochondria, no energy will be produced to
supply the process.
Limited number of carriers in the membrane. If
these are exhausted the rate of transport will
stop. If the maximum rate of active transport is
reached, you can never increase the rate of
reaction – this condition is called saturation. The
transport is continuous but the rate of transport
cannot be increased.
When plotted: initially only a few number of
carriers are utilized and then there will be a
gradual increase in the rate of transport. When
the carriers in the membrane are now involved in
the transport, the transport will still continue but it
will undergo plateau and the rate of transport will
not increase – Saturation Kinetics. In renal
physiology it is known as Transport maximum (Tm)
Active transport: they are not concerned with
the transport of fatty acids except for the short
chain fatty acids which utilizes carriers and
normally happen in the colonic mucosa.
Happens only in living things since mitochondria is
a pre-requisite for energy production.
Would ONLY utilize a transcellular transport
Passive Transport
§
Does not require energy
§
A type of transport wherein the agent goes along
with the direction of the energy gradient (go with
the flow)
§
Direction: from higher to lower gradient
§
Downhill Transport
§
Bidirectional (either going inside or outside the
cell)
§
Uses channels
§
Channels could be gated wherein the activities
can be controlled or regulated. Closing the
gates of the channel prevents the transport while
opening the gates promote transport.
§
It is a non-continuous process because if the
concentration of a certain agent transported by
the cell has the same amount of agent outside
and inside the cell there will be no presence of
energy gradient, there will be no continuous
passive transport because the agent cannot go
along the gradient since there is already
equilibrium wherein the concentration is equal
inside and outside the cell.
§
Water in passive transport is dependent upon the
effect of osmotic pressure.
§
Passive transport is more concerned with
lipophilic agents.
§
For the transport of lipid materials, they only
penetrate the lipid bilayer without utilizing
channels.
§
Can be observed in living and non-living cells. It
happens in non-living cells since it does not
require energy. E.g. a dry paper placed in water.
The paper will absorb the water by passive
process.
§
Utilizes either transcellular or paracellular
transport.
Escoto, Kelvin C.E.
Common Gradients Encountered by the Cell during
Transport:
§
Concentration gradient (Pressure gradient)
Hydrostatic or Osmotic pressures
§
Electrical Gradient
We do not use the principle of the
movement of the agent from a higher
to lower or lower to higher gradient to
electrical gradient.
For us to know whether the activity is
going along or going against the
gradient, look at the electrical charge
of the agent being transported and the
electrical charge of the area where
the agent is to be transported.
E.g. Positively charged agents
transported to a positively charged
area is considered ACTIVE
TRANSPORTATION since like charges
repel. Attraction is seen in unlike
charges wherein easy passage of the
agent won’t be hindered it’ll just go
with the flow.
Usually passive transport does not utilize carriers except to
facilitated Passive Transport. In this type of transport, the
carriers involved in the activity does not move the transport
agent against the gradient. They help facilitate the agent
to get transported in the gradient along the gradient. So,
there is no energy expenditure.
In passive transport, specific or non- specific channels can
be utilized to process the transport.
E.g. the transport of water, they utilize a specific water
channels known as aquaporins, that will not transport any
other substances aside from water. Another example is the
Na-K leak channels.
PASSIVE TRANSPORT
Along a gradient
Downhill
No ATP consumption
ACTIVE TRANSPORT
Against a gradient
Uphill/Pump
ATP utilization
(Mitochondria)
No carrier
Always involves carrier
Glycoprotein channels
Glycoprotein channels
No inhibition
Equilibrium
Bidirectional
Undergoes inhibition
Saturation
Unidirectional
Hydrophilic agents
→CHON channels
(gated/non-gated)
Hydrophilic agents
→CHON channels
(transporters)
Living/non-living cells
Living cells
Water→CHON channels
Carrier →facilitated
diffusion
Lipophilic→Lipid bilayer
Carrier vs. Channel:
•
In transport involving channels. The larger the
energy gradient the faster the passive transport.
•
Carrier-involved activities are slower compared
to channel-involved activities because they
•
need energy to perform action. They will wait for
the mitochondria to produce energy. After the
energy is produced, they have to metabolize the
ATP to have a high energy phosphate bonds.
Plus, they have to counteract the force of the
energy-gradient which will also take time.
Carrier and Channel (gated-channel) activities
can be regulated.
Factors Affecting the Transport:
•
•
•
•
•
•
Channels/pores are concerned mostly with
passive transport and the passive transport
activity is usually energy independent, they don’t
require energy for their activity. But, they can also
be specific. The selectivity and specificity
depends on the size (molecular weight), shape
and electrical charge of the agent and the
transport involving channels can be regulated by
means of its gating-properties.
Solubility
Nature of the substance
Membrane thickness
Area of transport
Energy gradient
Different Gating-Mechanisms:
•
Voltage-gated
o
A change in the electrical activity of
the cell would allow the voltagegated cell membrane to open or
close.
o
All excitable cells of the body have
electrical activities.
o
Outside surface of the cell – Positive
o
Inside surface of the cell – when the
cell is resting the cell is Negatively
charged: Inside-negative condition.
•
Ligand-gated
o
Usually associated with the guanosine
proteins which can sometimes have
an inhibitory or stimulatory effect.
o
Ligands- chemical agents involved in
creating change in membrane
permeability. In the neurons, these are
the neurotransmitter. In the endocrine
system, these are the hormones.
o
Ligands not in contact with the
channel are closed. Ligand in contact
with the channel is open.
o
For any chemical agents to exert their
effects, the cell itself must have a
receptor for the ligand.
o
Neurotransmitter
o
E.g. Acetylcholine the major
neurotransmitter must have the
cholinergic receptor.
Two types of cholinergic
receptors:
1. Muscarinic CR
2. Nicotinic CR
o
Epinephrine and
norepinephrine must have epinephrine
and norepinephrine receptors
(adrenergic receptors)
Two types of adrenergic
receptors:
1. Alpha AR
2. Beta AR
Escoto, Kelvin C.E.
Hormones – whatever the name of the
hormone is the name of their receptors
o
Growth hormone – Growth hormone
receptor
G-Protein-Linked Channels
o
Some ligands are dependent with Gproteins. For them to exert their effects
on the channel they control, the
channel must contain G-proteins. If
that is a guanosine stimulatory
proteins, the channel will be opened.
If it is an inhibitory G protein, the
transfer will be prevented.
o
E.g. In the skeletal muscle or adipose
when the cell is resting, no transport of
glucose is happening but in the
presence of insulin, which serves as the
ligand, will help open up the glucose
channels.
o
•
o
Mechanically-gated/Stress-activated
•
o
Stretching the cell-membrane can
open up the channels since the
channels are pulled apart.
Note: Not all activities of the channel can be regulated
because some channels are non-gated; They are always
open wherein it can be completely open or partial. The
activity will now be continuous transport and is known as
passive or leaky channels. These channels can be seen in
the GIT.
DIFFERENT PASSIVE TRANSPORTS
Passive transport of small amount of agents:
Osmosis – only water or solvent molecules are being
transported.
o
Allows water/solvent molecules to move from
lesser to greater solute concentration. Plus, the
solute must be osmotically active to attract
water.
o
Osmotic pressure is highly dependent on the
amount of osmotically active agents present in
the solution.
o
The greater the amount of the active osmotic
agents, the greater is the osmotic pressure, the
greater the ability to attract water.
o
RBC on an isotonic solution:
Ø
No change in volume and cell size
since they have the same
concentration of solutes; the water will
not have any net flow to any direction.
They can move in and out BUT in equal
amounts.
Isotonic concentration
Ø
Sodium Chloride (NaCl): 0.9% or
280-300 mOsm/L (ave. 290)
Ø
Glucose: 0.5%
Ø
Lesser value: Hypotonic
Ø
Greater value: Hypertonic
RBC on a hypotonic solution:
Ø
Swelling of cell will occur. If the cell has
the amount of greater solute, water will
move from the hypotonic to the cell
allowing it to swell and burst.
Ø
Irreversible
o
RBC on a hypertonic solution:
Ø
The hypertonic solution has the higher
concentration allowing the water to
move out of the cell making it crenate
or shrink. (just remember HYPERCREN)
Ø
Reversible
Diffusion – mostly concerned with solute transport; but can
also promote solvent transport.
o
o
o
Simple Diffusion – the transport of the solute does
not require any membrane or it can require a
membrane but that membrane should be
permeable to all solvents and solutes.
Facilitated Diffusion – the diffusive process
requires the activity of a carrier.
Isotonic – normal condition of the human body
fluid. Normal human cell environment.
Escoto, Kelvin C.E.
Filtration – transport of the solvents and solutes on a highly
porous membrane with numerous channels. Commonly
seen in fenestrated capillaries of the GIT and kidney
especially in the glomerulus.
o
There is selective filtration: almost everything is
being filtered in the glomerulus except the large
particles (blood and protein.)
Passive transport of large amount of agents:
Bulk Flow – e.g. flow of urine, flow of bile in the biliary ducts,
blood flow
o
They follow pressure differences
o
In the cardiovascular system, the highest pressure
can be recorded in the left ventricle while the
lowest pressure can be recorded in the right
ventricle – Central Venous Pressure (CVP)
Solvent Drag – always observed whenever there is bulk
flow. (e.g. in the plasma)
o
Van’t Hoff’s law – osmotic pressure is dependent
on the concentration of the osmotically active
particles.
Diffusion Laws
o
Fick’s Law
o
Stokes-Einstein Equation
Determination of Plasma Osmolarity
𝑷𝑶 = 𝟐 × 𝑷𝒍𝒂𝒔𝒎𝒂 𝑵𝒂 +
𝑷𝒍𝒂𝒔𝒎𝒂 𝑮𝒍𝒖𝒄𝒐𝒔𝒆 𝑩𝑼𝑵
+
𝟏𝟖
𝟐. 𝟖
Estimate of PO = Plasma Na x 2
Normal Values:
Normal Tonicity: 280-300 mosm/L
Sodium: 135-145 meq/L
Glucose: 60-110 mg/dL
BUN: 8-20 mg/dL
Note: Tonicity is dependent on the presence of solutes.
Wherein the solutes should be osmotically active; it should
be able to attract water. An osmole holding on to water
should not be able to traverse the membrane and move
out the area.
o
E.g. With a normal amount of plasma proteins,
the body can retain normal amount of water in
the vascular compartment. If the plasma proteins
will decrease the water will move out of the
vascular compartment and will go to the
interstitial spaces that will produce edema.
o
Solutes that are able to penetrate the
membrane and stays in the area are good
osmotic agents which makes the osmotic
coefficient equal to one. These are the proteins
in the blood specifically albumin.
o
If the osmotic coefficient is equal to zero that
makes the agent ineffective.
o
Plasma proteins are responsible for maintaining
the osmotic pressure in the blood while the
Electrolytes are essential in maintaining the
osmotic pressure inside the cell.
o
Regulatory Cell Volume Decrease
Ø
If the plasma is hypotonic it is expected
that the cells are going to swell but the
body will try to maintain to normalize
the shape of the red blood cell. If there
is a transient hypotonicity of the
plasma, the cell will transport some of
the electrolytes or solutes out of the cell
to lessen the number of osmotically
active agents.
o
o
o
o
Regulatory Cell Volume Increase
Ø
Vice Versa
DIFFERENT ACTIVE TRANSPORTS
Carrier mediated that involves carrier proteins
present in the cell membrane.
Some types of active transports do not require
carriers in the membrane but are involved almost
in the movement of the membrane.
Energy dependent
Steps during the Active Transport:
1.
Association – usually starts with the binding of the
agent to the carrier molecule.
2.
Translocation – The carrier will change its
configuration or shape that will promote the
movement of the agent to another location.
3.
Dissociation – When they are on their location
the carrier will release the agent allowing them to
separate from one another.
Carrier
o
Energy-dependent
o
Selectivity and specificity (dependent on the size
and shape of the binding site of the carrier
molecule. The agent should fit exactly on the
binding site of the carrier molecule)
o
Can undergo saturation or inhibition
(Competitive inhibition)
o
The activity can be regulated or mediated using
chemical agents usually a ligand (hormones)
Primary Active Transport
o
Agents are moving all against their
electrochemical gradient.
o
Can progress on their own without any
simultaneous transport happening.
1.
Uniport
Ø
Carrier transports one agent at a time.
Ø
Hydrogen pump
2.
Antiport
Ø
Exchange transport
Ø
One is transported in and another one
is transported out
Ø
E.g. Na-K exchange pump, H-K
exchange pump
Ø
Na-K exchange pump is an
electrogenic transport that happens
continuously in an excited cell like cell
of the muscles and neurons.
Ø
PISO directions cannot be changed.
Escoto, Kelvin C.E.
2PISO: 2 Potassium In. 3 Sodium Out
Influx – Transport of ions inside the cell
Efflux – transport of ions outside the cell
•
•
•
Note! Some Active Transport are non-electrogenic. It
means that the exchange of ions is in equal amounts. E.g.
the Hydrogen-Potassium Exchange pump. 2H ions in
exchange of 2K ions would still have an exchange
mechanism but will not create an electrical change in the
cell. Making it a non-electrogenic active transport or an
Electro-Neutral Pump.
Secondary Active Transport
o
Some agents are transported against their
gradient while other agents are transported
along their gradient.
o
Only occur when another active transport is
simultaneously happening.
o
Antiport-dependent
o
Mechanism will be effective when there is Na-K
exchange pump.
1.
o
2.
Similar to uniport
Hydrogen pump
ATP-Binding Cassette Transporters
o
A type of transport associated with
Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR)
•
•
Carrier independent
Do not utilize carriers but the cell membrane acts
as a whole that forms vesicles.
1.
Endocytosis – membrane of the cell takes in the
agent. Exemplified by:
Phagocytosis – ingestion of large
agents.
o
Pinocytosis – intake of agents in fluid
form.
o
Involves a “docking” process wherein
there is binding with a specific
membrane protein receptor that will
form a vesicle in the cell membrane
coated by clathrin.
o
The vesicle is initially part of the
membrane. They are coated with
clathrin. Vesicles are then separated
from the cell membrane and referred
to as vacuoles. After the vesicles
separate they will be surrounded with
lysosomes and agents will be digested.
The clathrin will separate from the
vesicle after digestion and the clathrin
will be recycled and allow the
membrane to perform another
endocytosis.
o
Once the vesicles trapped a certain
agent it will also need other accessory
proteins like adaptin and dynamin.
There is also involvement of
microtubules and the dynein protein.
o
Portions without clathrin are not
involved in endocytosis
o
Absorption can be regulated:
Ø
Fluid phase
Unregulated Absorption;
nonspecific
E.g. absorption in the GIT
Ø
Adsorptive Endocytosis
Regulated Absorption
Requires a chemical agent
or ligands which will react
with the receptors to start
the activity
Receptor mediated or
adsorptive endocytosis
Transcytosis or Cytopempsis
o
Rapid transport of substance
o
Endocytosis at the apical portion of the
cell followed by exocytosis at the basal
part of the cell.
o
Counter Transport
o
Exchange transport
o
E.g. Sodium Calcium Counter transport
that is dependent on the Na gradient
provided by the Na-K exchange pump:
Na transported inward. Ca efflux
happens simultaneously.
o
Digoxins – cardiac glycosides that
inhibits the Na-K ATPase activity that
decreases the activity of the
symporters and counter transporters.
ATP-Dependent Transporters or ATPase Ion
Transporters
o
P-Type
Ø
Similar to antiport
V-Type
Ø
Ø
Na-K exchange pump, H-K
exchange pump
VESICULAR TRANSPORT
Depends its activity with the normal NaK pump activity.
E.g. Sodium – Glucose cotransport,
Sodium-amino acid cotransport (2
substances), Na-K Chloride cotransport (3 substances)
Other Carrier-mediated Transport from Berne and Levy:
Active Transport also have another type of carriermediated active transport and this are the:
1.
o
Symport
o
Also known as Co-transport/Coupled
Transport.
o
Carries several agents at a time.
o
Usually transports 2 agents at a time
but can also transport 3 agents
simultaneously in one direction.
o
2.
Ø
2.
3.
Exocytosis/Emeiocytosis – moves the agent
outward.
o
Reverse phagocytosis and pinocytosis
Escoto, Kelvin C.E.
o
o
o
1.
2.
Also needs clathrin
In the movement of the vesicle, it
needs the protein Kinesin
Secretory vs. Excretory Activities of the Cell
Similar to the direction of transport: out of the
cell.
Secretion – releasing of agents that are need by
the body and can affect the activity of other
cells.
Excretion – excreted agents are considered
waste products and released from the body.
Renal System: major excretory system
of the body that excretes almost all
waste products of the body except
carbon dioxide that are excreted by
the respiratory system.
o
Note: Secretion and Excretion can also be
regulated, partially-regulated or non-regulated.
o
2 Pathways Involved in Exocytosis
1.
Constitutive Pathway
Ø
Continuous partially
Ø
E.g. of non-regulated
secretory activity is the
secretion of the mucus,
secretion of mucus cannot
be control or can be
controlled at least partially.
2.
Non-Constitutive Pathway
Ø
Fully regulated pathway
using a ligand that will initiate
the transport.
Passive Transport
Osmosis
Diffusion
•
•
Simple
Facilitated
Filtration
Bulk Flow
Solvent Drag
Active Transport
Carrier Mediated:
•
Uniport (Primary)
•
Symport
(Secondary)
•
Antiport (Primary)
Transcytosis
Pinocytosis
Phagocytosis
Factors that Affect the Transport of the Cell
1.
2.
3.
4.
5.
Nature of the Substance
o
Lipid soluble agents easily penetrates the
membrane since there is no need for them
to look for channels as they can directly
penetrate the lipid bilayer membrane.
Size of the Agent/Molecular Weight
o
It should be very small (>2nm or 20
Ångström) and it should be very light (69,000
MW) to easily pass through the membrane.
Membrane Thickness
o
The thicker the membrane the lesser the
rate of transport whether active or passive
transport.
Surface Area
o
The greater the area the greater the
transport; the lesser the area the lesser the
transport.
Number of Channels/Pores
o
In passive transport: the greater the
channels, the faster the rate.
Permeability coefficient –permeability of the
membrane is dependent on the number
and size of channels.
6.
Number of Carriers
o
The greater the carriers in number, the faster
the rate of transport.
7.
Membrane Permeability
o
Semi-permeable membrane can only
transport water.
8.
Exposure
o
The longer the agents are exposed to the
membrane, the greater the rate of
transport.
o
Lesser time the agent is exposed; lesser
amount of agent is being transported.
9.
Energy Gradient
o
Passive transport with greater energy
gradient = grater the force = greater the
rate
o
Active Transport with greater energy
gradient = greater force needed = the rate
of the transport is lesser
Gradient Time Limitation – combined length of exposure
and energy gradient.
o
o
o
o
Cell Signaling or Cell Communication
Also known as signal transduction
Gap junction – part of the membrane used for cell
communication by adjacent cells or cells in direct
contact with one another.
Connexons – are chemical agents made up of smaller
proteins called connexins and are used for
communication by distant cells or nearby cells that
are not directly in contact with another cell.
Communication using Chemical agents:
Ø
Synaptic communication using
neurotransmitter can be used in adjacent
cell communication.
Ø
Hormones are used during distant cellcommunication.
o
Autocrine - cells communicating with another
identical cell within the area and are not directly in
contact with one another.
Ø
Released to interstitial fluid
Ø
E.g. communication happening in the islets
of Langerhans: a group of cells present in
the pancreas. Beta cells communicating
with another beta cells.
o
Paracrine - cells communicating with another nonidentical cell within the area and are not directly in
contact with one another.
Ø
E.g. Beta cells communicating with another
alpha cells in the islets of Langerhans in the
pancreas.
For the Communication to Happen:
1.
Change must be created in the extracellular region
that will eventually affect the cell. Extracellular
change will be transformed by the affected cell into
intracellular changes or also known as intracellular
messages. Intracellular agents will be affected by the
changes allowing to produce an activity that will be
directed to extracellular change.
2.
For it to react to extracellular change affecting the
cell, ligand-receptor interaction is needed. Receptors
can be present in the cytoplasm or the nucleus
(intracellular receptors).
3.
Interaction of Ligand and receptor will produce
Ligand-receptor complex that will now activate
certain enzymes present in the intracellular surface of
Escoto, Kelvin C.E.
4.
the cell. These enzymes are known as the second
messengers.
Once these second messengers are activated, they
will affect certain type of protein or an enzyme in the
cytoplasm. Then it will create a response directed to
the extracellular change affecting the cell.
STEPS IN CELLULAR COMMUNICATION WITH CHEMICAL
AGENT USE
1.
2.
3.
4.
Synthesis of the Agent
•
Ligand is needed to activate the cell.
Release of the Agent
•
E.g. In the synapse the NTA are normally
produced in the pre-synaptic.
Transport of Agents Towards the Target Cell
•
The agents from the pre-synaptic are
released to the post-synaptic once the
agents are needed.
Interaction with the Cellular Receptor
•
The cell should have the receptor for
effective communication.
Intracellular Receptors:
Nucleus
Cytoplasm
Cell Surface (membrane) Receptors:
Ion channel linked
Cytokine linked
Catalytic linked (receptor tyrosine
kinase)
G-Protein linked – also activates ion
channels
{
Second
Messengers
7.
Adenyl Cyclase (CAMP)
Phospholipase A2
Transducin Pathway
Phospholipase C (IP3)
Agents from the pre-synaptic will interact
with the receptors of the post-synaptic.
Formation of Ligand-Receptor Complex
Activation of the Second Messengers
•
In this part the ligand-receptor complex
activates certain group of enzymes in the
intracellular surface of the cell membrane.
Cellular Change Activity
•
The activation of the 2nd messengers will
make a response or reaction on the ligand
directed towards the change affecting the
cell.
•
5.
6.
1.
2.
3.
4.
8.
Termination of Agent’s Effects
•
The effect of the agent is non-continuous.
Thus, it is terminated once the effect of the
agent is seen on the targeted cell receptor.
Common Types of Termination:
•
Reuptake
Termination of the neurotransmitter in
the neural communication.
After termination in the post-synaptic,
the agent is taken back by the presynaptic to be reutilized for another
communication.
•
Destruction of the Agent
Enzymes terminate the effects of the
agent.
The effect is delayed since the effect of
the ligand (Neurotransmitter) must be
allowed to interact with target cell first
(post-synaptic) before it is activated.
Usually happens in the target cell.
Enzymes that usually deactivate the
Agents:
1.
Acetylcholine esterase destroy the
acetylcholine
2.
Monoamino Oxidase (MAO) and
Catechol-O-methyltransferase (COMT)
destroys epinephrine and
norepinephrine
3.
Insulinase – Insulin
4.
ADH – Vasopressin
Other Communication Termination: In certain cases,
termination is made by decreasing the activity of the
target cell secreting the ligand to reduce the amount of
ligand in the area. Change in the conformation of the
receptor protein can be a mean to stop the
communication process since the ligand will not be able to
activate the receptor.
Ligand or the Chemical Agents
§
Classified base on size and solubility:
§
Small and lipophilic molecules usually affect the
target cells by interacting with receptors present
inside the cell; affects intracellular receptors since
they easily penetrate the membrane.
§
Large and lipophilic molecules – although they
are lipophilic, they still cannot penetrate the lipid
bilayer because of their large size. To affect the
activity of the cell, they interact with membrane
receptors which are seen in all hydrophilic
agents.
§
Hydrophilic molecules – affect membrane
receptors
Receptors
§
Effect of ligands is dependent on the presence
and number of receptors.
§
Located in the cytoplasm, nucleus or cell
membrane.
§
Made mostly of proteins
§
Exhibits high degree of specificity
§
High affinity to a specific signaling activity
§
§
Down regulation or desensitization
Ø
Decreases the sensitivity and increases the
threshold or stimulation.
Up regulation or super sensitization
Ø
Increases the sensitivity and decreases the
threshold or stimulation.
Escoto, Kelvin C.E.
Apoptosis
§
Programmed death of a cell
§
Rate of destruction is equal to the rate of
production.
§
Characterized by overall compaction of a cell
and its nucleus and the orderly dissection of
the chromatin by endonucleases.
§
Mediated by proteolytic enzymes called
caspases.
§
Two Phases:
Ø Activation phase
-Self destruction/suicide
Ø Execution phase “eat me”
-Markers for phagocytes
(macrophages, from monocytes)
§ Two Distinct Pathways:
Ø Extracellular pathway
-Involves a death ligand (TNF)
Ø
Intracellular Pathway
-Decreased function of the
mitochondria will release the
caspases that will cause death of
the cell.
Ø Whether extra- or intra- cellular, it
uses caspses.
Ø Erythrocytes are not included since it
is anucleated.
Escoto, Kelvin C.E.
FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology
June 2, 2014 Section 1D
Homeostasis – maintenance of the constancy of the
internal environment; observed changes are controlled
by positive & negative feedback regulation
Regulating Systems – responsible for bringing
conditions back to normal whenever there is an
alteration
a. Nervous/Neuronial
- make use of nerve impulses (action potential)
produced by effectively simulated neurons
- immediate onset: usually muscles & secretory
cells
- can be voluntary & involuntary
- short duration
- localized
b. Endocrine/Humoral/Hormonal
- make use of agents (hormones) produced by
activated endocrine cells
- delayed response: cells involved in metabolism
like reproductive ability
- involuntary
- usually long duration
- diffuse
Cell/Plasma Membrane – made up of lipids &
proteins; involved in transport activities
*Outer layers: hydrophilic, lipophobic
*Central region: hydrophobic, lipophilic
- differentially/semi-permeable: capable of
allowing transport of only solvent particles
- selectively permeable: allows transport of
solvent & solute molecules but there is a
selection in the transport of solutes
DULAY, Arman Carl
**Aquaporins – water channels
**permeability of the cell can be altered
**Osmosis – water molecules move towards
an area having greater amount of osmotically
active agents
Cell Membrane Fxns:
- regulate transport
- maintain composition of ICF & ECF
- cell identification using surface
antigens
- signal transduction/cell
communication
- provides cellular stability; anchor for
structural proteins
- anchoring to neighboring cells &
basal lamina
- determination of cell shape
Activities of the Cell Membrane
*Apical Region – absorption and secretion;
protection
*Lateral Region – cell contact, adhesion,
communication
- Tight jxns = zonula occludens
- Desmosomes = zonula adherens(anchoring)
- Gap jxns = connexons(communication)
*Basal Region – cell-substratum contact; ion
gradient generation
- Hemidesmosomes & focal adhesions
1 of 3 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology
June 2, 2014 Section 1D
Composition of the Cell Membrane
Lipids: 50-60%
Proteins: 40-50%
Carbohydrates: negligible amount; usually coupled
with a lipid or protein
**The presence of carbohydrates in the cell
membranes of bacteria allow for recognition as
non-self antigen by the immune system
A.
Lipids
- Phospholipids: amphipathic
- Cholesterol: “moderator molecule”, provides
mechanical stability and flexibility, makes
membrane more permeable to lipid particles and
less permeable to water & prevents lipid
crystallization (fluidity)
- Glycolipids
B.
Proteins
- Integral/Transmembrane: amphipathic, utilized
as channels, pores or fenestrations
- Peripheral: present on the surfaces and does not
traverse the membrane
*act as channels/carriers
*antigenic markers
*receptors for hormones/NTA
*source of enzymes
*skeletal framework
*cell stability
*transport of water soluble particles needed by
the cell
DULAY, Arman Carl
C. Carbohydrates – present on extracellular
surface and never a pure carbohydrate
*cell identity markers
*agent for communication
*some are channels (rare)
Cell Membrane Transport
*Passive Transport – involves kinetic energy;
without energy prod’n from the cell
*Active Transport – involves energy produced
by the cell
Passive
Active
Not coupled with
Coupled with ATP
ATP
“Downhill”
“Uphill”
Along the gradient
Against the gradient
(High to low)
(Low to high)
Faster
Slower
No inhibition/nonUndergoes
specific
inhibition/always
specific
Bidirectional
Unidirectional
Stops at equilibrium
Continuous but leads
to saturation:
condition at which
carriers are
exhausted and rate
of transport stops
at maximum and no
add’l increase
Lipid soluble
Water soluble
partivcles
particles
Channels
Carriers & pumps
Channels do not
Conformational
change
change of carriers
conformations but
can be gated
Common energy gradients: concentration,
electrical, pressure
**In electrical gradients, you have to consider
the charge ion present and the electrical
charge of the area to which the ion will be
transported
Like charges repel; unlike charges attract
2 of 3 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology
June 2, 2014 Section 1D
Factors Affecting Transport
1. Nature of Substances (Solubility)
- lipid soluble substances=faster transport
2. Size (Molecular Weight of the Substance
- Lighter ones are easily transported
- Less than 69,000 molecular weight
3. Membrane Thickness
- the thicker the membrane, the harder
the transport
- the thinner the membrane, the faster
the transport
4. Area of Transport
- the greater the area the greater the
trasport
5. Presence of Pores/Channels
- the greater the number of pores, the
greater the transport
6. Electrical Charge
- Opposite charge have easier transport
7. Membrane Permeability
- membrane should be permeable to be
able to transport
- you can change the membrane
permeability
8. Time (Duration)/ Length of Exposure
- the longer the agent is exposed to the
agent, the more the transport.
9. Energy Gradient
- Passive = Direct Effect (greater
gradient=greater movement)
- Active = Indirect Effect (Lesser
gradient=lesser effect)
10. Concentration Gradient
*Permeability Coefficient – rate of
transport/permeability of the membrane is
dependent upon the size of the pores
*Gradient Time Limitation – combined length of
exposure and energy gradient
DULAY, Arman Carl
3 of 3 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 2
June 3, 2014 Section 1D
Membrane Transport Processes
PASSIVE TRANSPORT
1. Osmosis: move’t of H2O from less to greater
solute conc’n across a semi-permeable
membrane
: movement of H2O from higher to less
H2O conc’n across a semi-permeable membrane
*Isotonic/isosmotic – no net mov’t of H2O;
amount of solute is identical to the amount of
solutes present in body fluids/plasma (0.850.9% NaCl; 5% glucose)
- 280-300 milliosmol/L
*Hypertonic/hyeperosotic – greater than
isotonic; cells will shrink (plasmolysis)
*Hypotonic/hypoosmotic – less than isotonic;
cells will swell; cell may burst (osmotic lysis)
**There are regulatory mechanisms in the human
body that preserve cell volume/amt of H20 in cells
- Regulatory volume increase – when cells are
exposed in slightly hypertonic solutions; cells
attract/allow osmolytes to move in
- Regulatory volume decrease – when cells are
exposed in conditions where the plasma becomes
slightly hypotonic; osmolytes are transported out of
the cell
Osmolytes: Myoinositol, sorbitol, some electrolytes
(Na+, K+]
**Osmotically active agents are responsible for the
movement of water
Osmotic Pressure - force that attracts H2O that
attracts water towards an area with greater amt
of osmotically active agents
Van Koft’s Law/Eq’n - osmotic pressure is
dependent on th concentration of the sol’n
2. Diffusion: concerned with move’t of both solute
and solvent molceules
a. Simple – lipid particles; simple penetration
of lipid bilayer
DULAY, Arman Carl
b. Facilitated – water-soluble particles;
involves carrier molecules/proteins
c.
Restricted – water-soluble particles; protein
channels are utilized
3. Filtration – transport of solute and solvents
involving presence of greater number of pores in
the membrane; normally happens in capillaries
- selective, depending on the size of the
pores
*Albuminuria; proteinuria – caused by problems
in kidneys
Hydrostatic Pressure – force causing filtration of
different agents
4. Bulk Flow – move’t of large amount of
substances in bulk from higher pressure to lower
pressure
Left ventricle – highest pressure
Right ventricle – lowest pressure
Right atrial pressure = central venous pressure
5. Solvent Drag – whatever solutes dissolved/
suspended in the flowing solvent is dragged by
the solvent
Laminar flow – stream-like, silent, unidirectional
flow of blood
ACTIVE TRANSPORT
A. Carrier-mediated – binding of the agent with a
carrier protein
1. Primary – cells produce energy to transport a
molecule against its gradient; has its own
enzyme to hydrolyse ATP
a. Uniport – single agent; single direction
(Na+ pump}
b. Antiport – exchange transport (Na+-K+
pump)
2. Secondary – one agent is actively transported,
the other is transported along its gradient;
shares energy with another active transport
1 of 3 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 2
June 3, 2014 Section 1D
a. Symport – more than one agent in a single
direction (Na-glucose co-transport)
b. Counter-transport – exchange transport (Na+Ca2+ exchange)
**Decreased activity of antiport = decreased activity
of symport & counter-transport
B. Vesicular – involves the activity of the whole cell;
creation of vesicles
1. Phagocytosis
Monocytes – most phagocytic WBC
2. Pinocytosis
3. Transcytosis – transport of substances traveling
all throughout the cell
3 Steps in Active Transport
1. Association – binding of agent to carrier >
conformational changes in carrier
2. Translocation – mov’t towards area where the
agent is needed
3. Dissociation – separation of carrier from agent
Electrogenic Pump – creates electrical charge due to
unequal exchange of charged particles ex. Na+-K+
pump: 3Na outward - 2K inward
Non-electrogenic/Electroneutral Pump – equal
exchange, ergot no electrical activity/charge is
created ex. HCO3-Cl- exchange
DULAY, Arman Carl
Differences Between Carriers and Channels
CARRIERS (Active)
Slower (hundreds/sec)
Can be regulated
(gated channels)
Coupled with ATP
Uphill Transport
Undergo
conformational
change
CHANNELS (Passive)
Faster (>10,000/sec)
Not coupled with ATP
Downhill transport
No conformational
change
(Open and close quickly)
Properties of Channels
1. Selectivity – pore size & electrical charge
2. Gating property – regulation/control
a. Voltage gated – change in electrical
acitivity
b. Ligand gated – chemically activated;
involves protein activity (guanosine/Gprotein)
Excitatory –open
Inhibitory - close
c. Mechanically gated – stretching of cells
d. G-protein mediated
3. Continuously open (partial or complete) – no
regulation; passive/leaky channels as in the
small intestines
**Digitalis – inhibits heart activity; inhibits Na-K
pump/ATPase = traps calcium, inotropic activity
of heart increases
C. Bulk Transport
1. Endocytosis – into the cell
a. Phagocytosis – cell eating
b. Pinocytosis – cell drinking; fluids
2. Exocytosis/Emeiocytosis – out of the cell
3. Transcytosis – endocytosis coupled immediately
with exocytosis happening in different regions of
the cell (from apex to base) as in the proximal
convoluted tubules of nephrons and intestine
2 of 3 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 2
June 3, 2014 Section 1D
Endocytosis
- ‘docking’/binding of agent to be transported to
the cell membrane
- vesicle formation by cell membrane coated by
CLATHRIN
- allows cell to absorb/take in the agent
- Clathrin separates from vacuole and returns to
cell membrane (recycling)
- Can also involve proteins adaptine & tyramine
Endocytic Pathways
1. Fluid-phase
- non-specific
- non-regulated/uncontrolled
2. Receptor Mediated (Absorptive Endocytosis)
- chemically regulated usually a hormone that will
initiate the transport
- no receptor, no transport
*cholinergic receptors – muscatinic and nicotinic
receptors
*adrenergic receptors – alpha and beta receptors
DULAY, Arman Carl
3 of 3 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
Exocytosis
- similar to endocytosis but transports substances
out of the cell
- explains the ability of cells to secrete or excrete
substances
Exocytotic Patchway
1. Constitutive Pathway
- continuous partially regulated pathway
2. Non-constitutive Pathway
- fully regulated pathway using a ligand that will
initiate the transport
Cell Surface (Membrane) Receptors
- affect membrane permeability
- common ligands are protein in nature e.g. insulin
–alter membrane permeability to glucose, ADH –
permeability to water, aldosterone – permeability
to sodium
1. Ion channel linked
2. Cytokine linked
3. Catalytic linked (receptor tyrosine kinase)
4. G-protein linked
- adenyl cyclase
- (camp)phospholipase A2
Second messengers
- Transucin pathway
- Phospholipase C (IP3)
- Can also activate ion channels
Intracellular Receptors
- found in the cytoplasm and nucelus
- ligands are usually lipid-soluble agents ex.
Steroid hormones such as
cortisone/glucocorticoid,
aldosterone/mineralocorticoid (cytoplasmic),
estrogen, progesterone, testosterone (nuclear)
*Steroid ring - cyclopentanoperhydrophenanthene
ring
- since the membrane is permeable to lipid-soluble
agents, these agents act upon the receptors
found inside the cell
- alteration due to the effects of these hormones
are seen mostly on the nucleus such as the sex
hormones [GENE ACTIVATORS]
- common changes seen affect nuclear activity
and transcription, translation & regulation of
gene expression
*Thyroid hormone – non-steroid but can exert its
effect on nuclear receptors; made up of biogenic
amine; tyrosine for the production of the T3 or T4
hormone
Effects of the ligands are very dependent on the
presence and number of active receptors and are
usually direct
*Type I Diaabetes Mellitus (insulin Dependent) – no
insulin but with receptors
*Type II Diabetes Mellitus (Non-insulin Dependent:
they have insulin but the insulin receptors are not
responsive
*Nephrogenic Diabetes Insipidus: there are no
receptors for ADH in the kidneys
*Diabetes Insipidus: no ADH but no problem with
receptors
Down-regulation/desensitization – when a ligand is
present in excess, the number of active receptors
generally decreases.
DULAY, Arman Carl
Up-regulation – when there is deficiency of a ligand,
there is an increase in the number of active
receptors
*Prolongation of the condition {excess/deficiency of
ligands) will cause problems from the effects of the
hormone; body cannot maintain the regulation of
the condition
1 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
Cell Communication/Cell-Signaling/Signal Transduction
Transduction – conversion of one form of energy to
another
1. Cell to cell – gap junctions; known as nexus in
neurons; functional units are connexons
2. Chemical agents – with nearby or distant cells; uses
ligands
a. Synapses – utilizes neurotransmitters produced by
the pre-synaptic nerves; receptor are found in the
post-synaptic nerve
b. Endocrine – uses hormones; distant cells
Ex. Pituitary gland – controls different parts of the
body by producing tropic hormones ex. Growth
hormone, FSH, LH
c. Autocrine – communication with nearby cells of the
same cell type exx. Communication between insulin
secreting beta cells of the islets of Langerhans in the
pancreas
d. Paracrine – communication with nearby cells of
different cell type ex. Communication of beta cells with
gulacogon-secreting alpha cells
Steps involved in communication using chemical agents
1. Synthesis of the agent
2. Release
3. Transport towards target cell
4. Interaction with a cellular receptor
5. Change in cellular receptor
6. Change in cellular activity
7. Termination of effects
Re-uptake or decomposition of the chemical agents
by enzymes; recycling /re-utilizing
Acetylcholine – acetylcholine esterase
Epinephrine/norepinephrine – monoamine oxidase &
catechol-O-methyltransferase
Dopamine – dopaminase
DULAY, Arman Carl
Signal Transduction
Extracellular changes are transformed into
intracellular messages causing alteration in cellular
activity.
Initiated by molecules (ligands) interacting with
membrane receptors or intracellular receptors
activating second messengers and eventually cellular
response.
Classification of Signaling Molecules
1. Small lipophilic molecules – affect intracellular
receptors ex. Steroid hormones
2. Large lipophilic molecules – affect membrane
receptors
3. Hydrophilic molecules – affect membrane
receptors
Characteristics of receptors
1. located in the cytoplasm, nucleus or cell
membrane
2. made up mostly of proteins (integral)
3. exhibits high degree of specificity
4. high affinity to a specific signaling molecule
*nicotinic receptors – present on all autonomic
ganglia; myoneural junction of skeletal muscle
*muscatinic receptors – found in parasympathetic
neuroeffector junction & sympathetic cholinergic
neuroeffector junction
*alpha & beta receptors – sympathetic adrenergic
neuroeffector junctions
*insulin receptors – found in skeletal muscles and
adipose tissue
2 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
APOPTOSIS: programmed death of a cell
RBC – though unnucleated, it is able to survive because it
carries enough energy and nutrients that will last about
120 days
- characterized by overall compaction of a cell and
its nucleus and the orderly dissection of the
chromatin by endonucleases
- mediated by proteolytic enzymes called caspases
Local potential/local response
- Hypopolarizing change/local depolarizing change:
electrical change that does not allow a cell to
depolarize
- local excitatory state of the cell
- acute subthreshold potential
- negativity of the change becomes less than
normal
Two Phases
1. Activation phase: self-destruction
2. Execution phase: “eat me” markers for phagocytes
Local potentials in the different parts of the body:
Receptor potential
- local potential developed in sensory receptors
- generator potential
End plate potential
- muscles
Excitatory/inhibitory pos-synaptic potential
- post-synaptic portion of the neuron
Two distinct pathways:
1. Receptor mediated pathway(TNF) – extracellular
2. Mitochondria mediated pathway – intracellular
**Whatever amount of cells are destroyed, the same
number of new cells are produced by the body.
Reticulocytes - youngest red blood cells in circulation
Low reticulocytes = developing anemia
The presence of the ff. ions in the intracellular and
extracellular compartments of the cell are
responsible for the electrical activity of the cell:
ELECTROPHYSIOLOGY
Excitable cells – able to produce electrical activity
*Ions are responsible for cell electrical activity.
Resting membrane potential (RMP)
- negative electrical activity recorded on the inner
surface of the membrane
- steady potential: constant electrical activity, nonchanging
- transmembrane voltage potential: recorded on the
membrane
Action potential
- nerve impulse; arises from effectively stimulated cells
- response of excitable cells to threshold intensity
- results from depolarization of the cell
Threshold – lowest effective stimulus intensity
DULAY, Arman Carl
Electrochemical balance/equilibrium
- achieved by the Gibbs-Donnan effect
- due to the presence of ions that are not capable
of penetrating the membrane
Conductance
- membrane permeability to charged particles
- when the cell is resting, it has higher
conductance to K+ and Cl- and lower
conductance for Na+ and no conductance to
negatively charged proteins
3 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
Leaky or passive channels: continuously open, non-gated
channels
Nernst Equation
- single ion
Goldman-Hodgkin-Katz Equation
- expresses the same rel’ship as Nernst
Equation,but for ALL IONS INVOLVED according to
their permeability
Effect of concentration gradient
K+ will normally move outside the cell, Cl- will tend to
move in, Na+ has a tendency to move into the cell
Effect of electrical gradient
Inside negative condition attracts Na+ to move in via
sodium leakage, detains K+ inside the cell (but
concentration gradient has greater effect; K= moves
out), repels Cl= entry (balanced effect from
concentration and electrical gradient; no net flow)
Ergo, when the cell is resting, it has a tendency to
make the inside more negative, but this never happens
because it is always balanced by the Na-K exchange
pump. Remember PISO = maintains constant electrical
activity.
Electrogenic Na-K pump
– non-selective ion channel
– K is 100x more permeable than Na
The higher permeability of K= contributes about
67mV to the magnitude of the RMP. The Na-K
pump produces about 3mV.
Passive and Active Forces that Establish and
Maintain RMP
1. Nature of the cell membrane
2. Unequal distribution of ions
3. Operation of the Na-K pump
*Polarized cell = correct term to describe a
resting/inactive cell
When you effectively stimulate a cell, there is an
involvement of other channels other than leak
channels like:
Voltage gated channels: regulated by the electrical
activity of the cell; specific
1. Voltage-gated sodium channels: have 2 gates,
inactivation & activation gate
The electrical activity of the membrane is more
dependent on the permeability of the membrane to K+.
Resting electrical activity in the
muscle = -90mV
nerves = -70mV (smaller diameter); -90mV
(bigger diameter)
DULAY, Arman Carl
4 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
2. Voltage-gated potassium channels – has activation
gate only
This gives the cell the tendency to hyperpolarize or
to become more negative than normal. The closure
of the activation gates of VG K channels follows
coupled by the closure of the activation gates and
opening of the inactivation gates of VG Na
channels to prepare the cell for another activity.
The Na-K exchange pump’s activity increases.
Critical Firing Level: also known as the threshold
voltage; allows the membrane potential to reach the
threshold potential
If the cell is resting, there is no activity of the VGC
since they are all closed, only leaky channels and
carriers are active.
In the resting state, the inactivation gates of VG Na
channels are open. Upon effective stimulation, the cell
will immediately depolarize and the VG Na channel is
initially affected causing the opening of the activation
gates. Conductance to sodium therefore is increased
causing rapid and massive Na influx. This is NOT a
continuous change because it will eventually reach
equilibrium. This results to the closure VG Na channels
by the inactivation gates.
VG K channels are used to repolarize the cell. There
occurs a fast K+ efflux. Even if the cell reaches the
normal (-70mV), it will immediately stop the
repolarization. The equilibrium potential for K must
also be reached.
DULAY, Arman Carl
5 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
Exocytosis
- similar to endocytosis but transports substances
out of the cell
- explains the ability of cells to secrete or excrete
substances
Exocytotic Patchway
1. Constitutive Pathway
- continuous partially regulated pathway
2. Non-constitutive Pathway
- fully regulated pathway using a ligand that will
initiate the transport
Cell Surface (Membrane) Receptors
- affect membrane permeability
- common ligands are protein in nature e.g. insulin
–alter membrane permeability to glucose, ADH –
permeability to water, aldosterone – permeability
to sodium
1. Ion channel linked
2. Cytokine linked
3. Catalytic linked (receptor tyrosine kinase)
4. G-protein linked
- adenyl cyclase
- (camp)phospholipase A2
Second messengers
- Transucin pathway
- Phospholipase C (IP3)
- Can also activate ion channels
Intracellular Receptors
- found in the cytoplasm and nucelus
- ligands are usually lipid-soluble agents ex.
Steroid hormones such as
cortisone/glucocorticoid,
aldosterone/mineralocorticoid (cytoplasmic),
estrogen, progesterone, testosterone (nuclear)
*Steroid ring - cyclopentanoperhydrophenanthene
ring
- since the membrane is permeable to lipid-soluble
agents, these agents act upon the receptors
found inside the cell
- alteration due to the effects of these hormones
are seen mostly on the nucleus such as the sex
hormones [GENE ACTIVATORS]
- common changes seen affect nuclear activity
and transcription, translation & regulation of
gene expression
*Thyroid hormone – non-steroid but can exert its
effect on nuclear receptors; made up of biogenic
amine; tyrosine for the production of the T3 or T4
hormone
Effects of the ligands are very dependent on the
presence and number of active receptors and are
usually direct
*Type I Diaabetes Mellitus (insulin Dependent) – no
insulin but with receptors
*Type II Diabetes Mellitus (Non-insulin Dependent:
they have insulin but the insulin receptors are not
responsive
*Nephrogenic Diabetes Insipidus: there are no
receptors for ADH in the kidneys
*Diabetes Insipidus: no ADH but no problem with
receptors
Down-regulation/desensitization – when a ligand is
present in excess, the number of active receptors
generally decreases.
DULAY, Arman Carl
Up-regulation – when there is deficiency of a ligand,
there is an increase in the number of active
receptors
*Prolongation of the condition {excess/deficiency of
ligands) will cause problems from the effects of the
hormone; body cannot maintain the regulation of
the condition
1 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
Cell Communication/Cell-Signaling/Signal Transduction
Transduction – conversion of one form of energy to
another
1. Cell to cell – gap junctions; known as nexus in
neurons; functional units are connexons
2. Chemical agents – with nearby or distant cells; uses
ligands
a. Synapses – utilizes neurotransmitters produced by
the pre-synaptic nerves; receptor are found in the
post-synaptic nerve
b. Endocrine – uses hormones; distant cells
Ex. Pituitary gland – controls different parts of the
body by producing tropic hormones ex. Growth
hormone, FSH, LH
c. Autocrine – communication with nearby cells of the
same cell type exx. Communication between insulin
secreting beta cells of the islets of Langerhans in the
pancreas
d. Paracrine – communication with nearby cells of
different cell type ex. Communication of beta cells with
gulacogon-secreting alpha cells
Steps involved in communication using chemical agents
1. Synthesis of the agent
2. Release
3. Transport towards target cell
4. Interaction with a cellular receptor
5. Change in cellular receptor
6. Change in cellular activity
7. Termination of effects
Re-uptake or decomposition of the chemical agents
by enzymes; recycling /re-utilizing
Acetylcholine – acetylcholine esterase
Epinephrine/norepinephrine – monoamine oxidase &
catechol-O-methyltransferase
Dopamine – dopaminase
DULAY, Arman Carl
Signal Transduction
Extracellular changes are transformed into
intracellular messages causing alteration in cellular
activity.
Initiated by molecules (ligands) interacting with
membrane receptors or intracellular receptors
activating second messengers and eventually cellular
response.
Classification of Signaling Molecules
1. Small lipophilic molecules – affect intracellular
receptors ex. Steroid hormones
2. Large lipophilic molecules – affect membrane
receptors
3. Hydrophilic molecules – affect membrane
receptors
Characteristics of receptors
1. located in the cytoplasm, nucleus or cell
membrane
2. made up mostly of proteins (integral)
3. exhibits high degree of specificity
4. high affinity to a specific signaling molecule
*nicotinic receptors – present on all autonomic
ganglia; myoneural junction of skeletal muscle
*muscatinic receptors – found in parasympathetic
neuroeffector junction & sympathetic cholinergic
neuroeffector junction
*alpha & beta receptors – sympathetic adrenergic
neuroeffector junctions
*insulin receptors – found in skeletal muscles and
adipose tissue
2 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
APOPTOSIS: programmed death of a cell
RBC – though unnucleated, it is able to survive because it
carries enough energy and nutrients that will last about
120 days
- characterized by overall compaction of a cell and
its nucleus and the orderly dissection of the
chromatin by endonucleases
- mediated by proteolytic enzymes called caspases
Local potential/local response
- Hypopolarizing change/local depolarizing change:
electrical change that does not allow a cell to
depolarize
- local excitatory state of the cell
- acute subthreshold potential
- negativity of the change becomes less than
normal
Two Phases
1. Activation phase: self-destruction
2. Execution phase: “eat me” markers for phagocytes
Local potentials in the different parts of the body:
Receptor potential
- local potential developed in sensory receptors
- generator potential
End plate potential
- muscles
Excitatory/inhibitory pos-synaptic potential
- post-synaptic portion of the neuron
Two distinct pathways:
1. Receptor mediated pathway(TNF) – extracellular
2. Mitochondria mediated pathway – intracellular
**Whatever amount of cells are destroyed, the same
number of new cells are produced by the body.
Reticulocytes - youngest red blood cells in circulation
Low reticulocytes = developing anemia
The presence of the ff. ions in the intracellular and
extracellular compartments of the cell are
responsible for the electrical activity of the cell:
ELECTROPHYSIOLOGY
Excitable cells – able to produce electrical activity
*Ions are responsible for cell electrical activity.
Resting membrane potential (RMP)
- negative electrical activity recorded on the inner
surface of the membrane
- steady potential: constant electrical activity, nonchanging
- transmembrane voltage potential: recorded on the
membrane
Action potential
- nerve impulse; arises from effectively stimulated cells
- response of excitable cells to threshold intensity
- results from depolarization of the cell
Threshold – lowest effective stimulus intensity
DULAY, Arman Carl
Electrochemical balance/equilibrium
- achieved by the Gibbs-Donnan effect
- due to the presence of ions that are not capable
of penetrating the membrane
Conductance
- membrane permeability to charged particles
- when the cell is resting, it has higher
conductance to K+ and Cl- and lower
conductance for Na+ and no conductance to
negatively charged proteins
3 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
Leaky or passive channels: continuously open, non-gated
channels
Nernst Equation
- single ion
Goldman-Hodgkin-Katz Equation
- expresses the same rel’ship as Nernst
Equation,but for ALL IONS INVOLVED according to
their permeability
Effect of concentration gradient
K+ will normally move outside the cell, Cl- will tend to
move in, Na+ has a tendency to move into the cell
Effect of electrical gradient
Inside negative condition attracts Na+ to move in via
sodium leakage, detains K+ inside the cell (but
concentration gradient has greater effect; K= moves
out), repels Cl= entry (balanced effect from
concentration and electrical gradient; no net flow)
Ergo, when the cell is resting, it has a tendency to
make the inside more negative, but this never happens
because it is always balanced by the Na-K exchange
pump. Remember PISO = maintains constant electrical
activity.
Electrogenic Na-K pump
– non-selective ion channel
– K is 100x more permeable than Na
The higher permeability of K= contributes about
67mV to the magnitude of the RMP. The Na-K
pump produces about 3mV.
Passive and Active Forces that Establish and
Maintain RMP
1. Nature of the cell membrane
2. Unequal distribution of ions
3. Operation of the Na-K pump
*Polarized cell = correct term to describe a
resting/inactive cell
When you effectively stimulate a cell, there is an
involvement of other channels other than leak
channels like:
Voltage gated channels: regulated by the electrical
activity of the cell; specific
1. Voltage-gated sodium channels: have 2 gates,
inactivation & activation gate
The electrical activity of the membrane is more
dependent on the permeability of the membrane to K+.
Resting electrical activity in the
muscle = -90mV
nerves = -70mV (smaller diameter); -90mV
(bigger diameter)
DULAY, Arman Carl
4 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Cellular Physiology Part 3 & Electrophysiology
June 8, 2014 Section 1D
2. Voltage-gated potassium channels – has activation
gate only
This gives the cell the tendency to hyperpolarize or
to become more negative than normal. The closure
of the activation gates of VG K channels follows
coupled by the closure of the activation gates and
opening of the inactivation gates of VG Na
channels to prepare the cell for another activity.
The Na-K exchange pump’s activity increases.
Critical Firing Level: also known as the threshold
voltage; allows the membrane potential to reach the
threshold potential
If the cell is resting, there is no activity of the VGC
since they are all closed, only leaky channels and
carriers are active.
In the resting state, the inactivation gates of VG Na
channels are open. Upon effective stimulation, the cell
will immediately depolarize and the VG Na channel is
initially affected causing the opening of the activation
gates. Conductance to sodium therefore is increased
causing rapid and massive Na influx. This is NOT a
continuous change because it will eventually reach
equilibrium. This results to the closure VG Na channels
by the inactivation gates.
VG K channels are used to repolarize the cell. There
occurs a fast K+ efflux. Even if the cell reaches the
normal (-70mV), it will immediately stop the
repolarization. The equilibrium potential for K must
also be reached.
DULAY, Arman Carl
5 of 5 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION
INSTITUTE OF MEDICINE
DOCTOR OF MEDICINE
PHYSIO B
1.1 RENAL PHYSIOLOGY I
Dr. RA Cruz
12-2-2015
1.1.1
Excretory System
The excretory system is important for
maintaining homeostasis, maintenance of internal
environment. We can drink and eat as many food and
drinks as we want since the excretory system will
function to maintain homeostasis. The excretory system
includes the Kidneys, Lungs, GIT, and the Skin. The
lungs (Respiratory system) will remove CO2 and water.
The GIT removes undigested materials. The skin
excretes electrolytes and water.
The figure shows the kidney and its parts
(Refer to the figure). The renal cortex is the outer
region which is isotonic. At the inner region will be the
renal medulla which is hypertonic. Within the
medulla, the renal pyramids and Renal columns of
Bertin are found. The columns of bertin are found in
between the pyramids.
Found in the renal pyramids are the renal
papilla that will give rise to the minor calyces,
forming the major calyces. The major calyces forms
the renal pelvis connected to the ureter.
of these organs in
The most important
homeostasis is the kidneys. The function of the kidneys
includes:
 Excretion of metabolic wastes and foreign
chemicals
 Regulation of extracellular H2O, body fluid
osmolality, and electrolyte concentrations
 Regulation of arterial pressure (via RAAS)
 Regulation of acid-base balance
 Secretion, metabolism, excretion of hormones
 Endocrine function (Hormones include: Renin,
Erythropoeitin, Vitamin D)
Good to know: There is a debate whether Renin
should be considered a hormone or not since it does
not target an organ, instead, it targets a substance,
angiotensinogen.
 Gluconeogenesis – production of carbohydrates
from non-carbohydrate sources.
The kidneys are retroperitoneal organs. The
basic unit of the kidneys will be the nephron formed by
the blood vessels, renal corpuscles and renal tubules.
Blood is filtered in the nephron. The filtrate will form
the urine excreted from the body via the urethra.
1.1.2
1.1.3
Functional Anatomy of the Kidneys
The kidneys will regulate extracellular
osmolarity and volume. Extracellular fluids are
regulated where as when the ECF changes, the
Intracellular fluid will adjust accordingly.
Blood supply
The flow below shows the flow of blood from
the abdominal aorta to and out of the kidneys back to
the Inferior vena cava.
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1.1.4
Nerve Control
The kidneys will only have Sympathetic
innervation. Norepinephrine is released resulting to
vasoconstriction reducing renal blood flow. The
reduction may be as low as <200 ml/min. there are two
important conditions to remember, Oliguria and
Anuria. In Oliguria, the urine output is 300-500ml/day.
In Anuria, usually experienced when a person
experiences shock, the urine output is <50ml/day. The
normal amount of urine excreted by a person per day is
1 to 1.5L.
Another neurotransmitter important in the
kidneys will be dopamine which is a vasodilator.
Renalase
degrades
cathecolamine,
specificially
Norepinephrine and dopamine in the kidneys.
1.1.5
Nephrons (Blood Vessels)
the peritubular capillaries and/or vasa recta, both of
which are low pressure areas (13-15mmHg). This
allows for reabsorption.
Good to know: The blood supply in the kidney is unique in a
sense that it is the only organ with two arteriolar system,
and with two capillary beds.
The afferent and efferent arterioles controls the
pressure in the glomerulus since they are able to
vasoconstrict or vasodilate. This controls hydrostatic
pressure in glomerulus. On the other hand, the pressure
in the peritubular capillary is controlled by the efferent
arteriole only.
1.1.6
Nephron (Tubular cells)
The filtrate is collected from the glomerulus to
the bowman’s space (bowman’s capsule). It will flow
to the PCT (Proximal Convoluted tubule) where
majority of the filtered substances are reabsorbed,
or majority of wastes substances are secreted. Then
the filtrate goes to the loop of henle.
This is the nephron. In terms of the blood
vessels, this consists of the Afferent arteriole, efferent
arteriole, Glomerulus (Capillaries), Peritubular
capillaries, and vasa recta.
The afferent arterioles is closely associated with
the JG cells and Granular cells. The JG cells produce
Renin while the Granular cells produce Renin and
Erythropoeitin. These two type of cells are part of the
Juxtaglomerular complex, which will be discussed later.
This complex is important for activation of RAAS.
Filtration occurs in the Glomerulus. The
hydrostatic pressure in here is three times higher (60100mmHg) than the normal capillary bed (2030mmHg). Since this is a high pressure capillary bed,
filtration occurs. The blood filtered from the
glomerulus goes now to the efferent arteriole, then to
•
•
The loop of henle has the following parts:
Descending limb – where H2O is reabsorbed
Ascending limb – solutes are reabsorbed
- Further divided to Thick and thin
ascending limb.
- In the thin ascending limb, solutes are
reabsorbed passively.
- In the thick ascending limb, solutes are
reabsorbed actively.
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In the late portion of the thick ascending limb,
the macula densa is found (this is according to Berne
and Levy. According to Guyton and Hall, it is in the
early part of the DCT). The Macula densa serves as
Na+ concentration sensor. It detects the concentration
of sodium in the filtrate. This is important in the
activation of RAAS.
From the loop of henle, the filtrate then flows to
the DCT (Distal convoluted tubules), then to the
cortical collecting ducts, and the medullary
collecting ducts. The distal convoluted tubule and
collecting ducts are composed of principal cells and
intercalated cells. These are both sensitive to
aldosterone. When aldosterone is present, the kidneys
wil reabsorb sodium and/or water in exchange for
potassium and/or hydrogen. The principal cells handle
secretion of potassium, while the intercalated cells will
handle secretion of Hydrogen and bicarbonate.
1.1.7
Primary Cilia
All tubular cells has primary cilia except for
intercalated cells.
Polycystic kidney disease
There is a defect in the genes encoding for
the polycystin 1 and 2 which results to
defective primary cilia, resulting to
abnormal development of tubular cells
resulting into cysts. This results to renal
failure.
1.1.8
Juxtaglomerular apparatus
This is composed of the Macula densa, granular
cells, and mesangium. The Macula densa acts as
Sodium sensor such that when Na+ is low, it will signal
granular cells to release rennin activating RAAS. Once
RAAS is activated, blood pressure increases. The
mesangium is composed of mesangial cells and matrix.
The apparatus regulates the calibre of the
afferent and efferent arterioles affecting blood flow.
MD =Macula Densa, EGM = Extraglomerular
mesangial cells, G = granular cells
The electomicrogram above shows the primary
cilia (C). They are primarily composed of Polycystin1
and 2, encoded by pkd1 and pkd2 genes. The cilia acts
for sensor for tubular flow. When the fluid flows, the
cilia will bend. Calcium channels are opened allowing
for calcium influx which then results to secretion of
potassium. When calcium is taken in, the cell will
initiate calcium dependent pathways including
proliferation, differentiation, and apoptosis of
tubular cells.
1.1.9
Two types of Nephrons
The two types include the superficial /
cortical nephron and the juxtamedullary nephron.
The cortical nephrons are found in the cortex,
surrounded by an isotonic medium. The juxtamedullary
nephron’s loop of henle is found in the renal medulla (all
other parts are in the cortex), surrounded by a
hypertonic medium. Population wise, in every 7 cortical
nephrons, there is 1 juxtamedullary nephron. In terms
of function, more water is reabsorbed in the
juxtamedullary nephron’s loop of henle since it is in a
SDF Lindo
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hypertonic medium. Therefore, it has a higher
concentrating capability.
V – urine vol/time
P – plasma concentration
In addition, the JM nephron is associated with
vasa recta while the cortical nephron is associated with
the peritubular capillaries.


For example:
Given:
1.1.10 Renal Blood Flow
In terms of the amount of blood flowing in the
kidneys, its 20-25% of the Cardiac output (5L/min)
which is approximately 1.25L/min. With this amount
of blood flowing normaly, the normal urine output is
0.5-1ml/kg/hr (Pedia: 1-2 ml/kg/hr), or 30cc/hr.
This results to 1-1.5L/day.
CNa = ?
UNa =700 mEq/L
PNa =140 mEq/L
V = 1 ml/min
Computation: C = UV/P
C = (700 x 1)/140
C = 5 ml/min
Blood flow is guided by these two laws:
Ohm’s law: F = ∆P/R
Where F is Flow, ∆P is pressure gradient, R is
resistance. Such that:
↑ ∆𝐏 = ↑ 𝐅
↑𝐑 =↓𝐅
Poiuselle’s law (governing resistance):
R = 8lη/∏r4
Where R is resistance, l is length of vessel, η is
viscosity of blood, r is the radius of the vessel. Such
that:
↑ 𝐥 𝐨𝐫 𝐧 = ↑ 𝐑
↑ 𝐫 =↓ 𝐑
There are two methods for measuring Renal
Blood flow: the direct method (magnetic flow meters)
and the indirect method (clearance principle).
Therefore, in one minute, there is 5mL of plasma
devoid of Sodium.
In clearance principle in computing Renal blood
flow, PAH (Paramino hippuric acid) clearance is
utilized. The subject is infused with PAH and after a
while, blood sample is taken and concentration of PAH
in urine and blood is determined. The Renal Plasma
Flow is equal to the clearance of PAH.
CPAH = UPAHV/PPAH
With the CPAH given, the RBF (Renal blood
flow may be computed by
RPF / (1-hct)
Take note:
RBF through the vasa recta is very minimal
making it sluggish.
 <2% of RBF
▪ 0.7% of RBF
Other formulae you need to remember:


F = ∆P/R
F = (Parterial – Pvenous) / renal vascular resistance
In the direct method, renal blood vessels are
surgically isolated. This is not experimentally practiced
since this is too invasive. In the indirect blood and urine
sample is collected to determine clearance of a
substance. For example in the clearance of Na, Na
concentration is determined to compute for the other
parameters:
(Parterial – Pvenous) is governed by Blood pressure:
BP = (SV x HR) x TPR
where SV is Stroke volume, HR is heart rate,
TPR is Total Peripheral Resistance.
C = UV / P
C – clearance
U – urine concentration
Renal Vascular resistance is governed by Pouiselle’ law:
 R = 8lη/∏r4


↑ 𝐒𝐕, 𝐇𝐑, 𝐨𝐫 𝐓𝐏𝐑 = ↑ ∆P = ↑ 𝐅,
SDF Lindo
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Renal vascular resistanceis affected by:
 Interlobular arteries, afferent and
efferent arterioles
 Sympathetic
activity,
hormones
(angiotensin
for
constriction,
vasopressin for constriction, endothelin
for constriction, NO for dilatation,
Prostaglandin for dilatation)
 Renal autoregulation
 Blood viscosity
For blood viscosity, this does not change blood flow
that much. Patients who are chronically anemic will
have dilute blood, therefore resistance is low, blood flow
is high. Those with chronic polycythemia vera,
viscosity is high, resistance is high, then blood flow is
low. There are other conditions that drastically affect
blood flow. In dengue, the blood is so viscous due to
increased hemtocrit so resistance is increased and blood
flow decreased.
1.1.11 Renal Autoregulation
Renal autoregulation affects resistance. The
kidneys have intrinsic ability to control blood flow and
filtration rate. There is a constant blood flow and
filtration rate despite of fluctuations in arterial pressure.
The renal autoregulation pressure ranges in 90180mmHg. This means that for as long as arterial
blood pressure is within the range, renal blood flow and
filtration rate are kept constant; once below 90, renal
blood flow decreases, once higher that 180, renal blood
flow increases—filtration rate then adjusts accordingly.
▪ UO : 1.5L/day
Without Autoregulation
BP : 125 mmHg
▪ GFR : 225L/day
▪ Reabsorption : 178.5L/day
▪ UO : 46.5L/day
1.1.12 Tubuloglomerular feedback mechanism
Tubular cells will pick up as many Na as
possible. When the BP is high, blood flow and filtration
rate is also high, therefore, the amount of Na reabsorbed
is low due to the increase in speed of flow. Therefore
the NaCl concentration in the tubular fluid increases
which is then sensed by the Macula densa. Macula
densa secretes ATP and adenosine targeting the
afferent arteriole increasing it resistance by
constriction. The hydrostatic pressure in the
glomerules then decreases and filtration also decrease.
This offsets the original condition.
In order to keep renal blood flow constant,
resistance will adjust. Now this phenomenon is
governed by the tubuloglomerular feedback and the
myogenic mechanism. Renal autoregulation is
important since it makes sure that the amount of urine
ouput is kept 1.5L/day. In the absence if regulation, say
blood pressure is increased to 125 mmHg without,
using the computation for urine output, it will result to
46.5L /day which is definitely impossible since blood
available is only 5 liters!
With Autoregulation:
BP : 100 mmHg
▪ GFR : 180L/day
▪ Reabsorption : 178.5L/day
Now, when the BP goes down, RBF goes down
and GFR also goes down. Flow is slower so more Na is
reabsorbed. There will be decreased NaCl sensed by the
Macula densa. No ATP and adenosine is release so the
afferent arterioles will vasodilate. Macula densa also
SDF Lindo
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signals JG cells to release renin activating RAAS.
Angiotensin II from RAAS signals the efferent arteriole
to vasoconstrict increasing resistance. The pressure in
the glomerulus then increases, so hydrostatic pressure
is increased which increases filtration, offsetting the
original condition. In addition, angiontensin II goes to
the circulation increasing blood pressure.
In myogenic mechanism, the increase in BP and
RBF will stretch the blood vessels. This mechanical
phenomenon will open mechanical-gated Ca channels
allowing for influx. Influx of Ca will then result to
constriction of smooth muscles (Reflex constriction),
therefore, increasing resistance. This will in turn result
to decreased filtration rate.
1.1.14 Vasoconstrictors and Vasodilators
The figure above shows how ATP and
adenosine interacts with the smooth muscles causing it
to vasoconstrict.
Increase in carbohydrate and protein intake
increases renal blood flow and filtration rate. When
intake of protein and carbohydrate increases, the plasma
glucose and amino acid levels will increase and are
filtered in the glomerulus. The task of the tubular cells
is to reabsorb 100% glucose and 100% amino acids.
Everytime glucose or amino acids are absorbed, Na is
reabsorbed via co-transport. The NaCl level then goes
down, sensed by the Macula densa. It activates the
tubuloglomerular feedback.
Take note: ANP (Atrial Natriuretic Peptide—from the
atrium) and BNP (Brain Natriuretic Peptide—from the
ventricles) act as constrictors efferent arterioles but
dilators in the afferent arteriole.
1.1.13 Myogenic Mechanism
The figure shows that PGI1 and PGE2 (prostaglandins)
are cause dilation. When we drink pain relievers,
Prostaglandin synthesis is decreased affecting renal
vasoconst. and dil. When this occurs, chronic
constriction occurs, resulting to ischemia, then kidney
failure.
SDF Lindo
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1.1.15 Micturition
Is micturition a voluntary or involuntary
act? Some say both. Some say partial.
Apparently, impulses are also sent to the higher
center, the pons and the cortex. This allows for the
assessment of whether it is convenient to urinate or not.
The higher centers will modulate the reflex arc.
Is the micturition reflex voluntary or
involuntary? Involuntary.
When reflex is concerned, the micturition act is
involuntary. Therefore the following are present:






S: stretch receptors
AN: pelvic nerves
C: S2-3
EN: pelvic nerves
E: detrusor muscle, internal urethral sphincter
Higher C: pons, cortex
The stretch receptors are stimulated when the
bladder is distended. Signals are sent via the AN pelvic
nerves to center (s1 and s2). The center will send a
response to the EN pelvic nerves. Excitatory stimuli are
sent to the detrussor muscles so it contracts, while
inhibitory stimuli are sent to the internal urethral
sphincter for it to relax. This will induce urination.
In the figure above, the dotted line represent
pressure due to contraction of detrussor muscles.
Meanwhile, the solid line represents pressure increase
due to increase in volume.
The higher centers will modulate the reflex arc
so the the detrussor muscle is inhibited now, and the
internal urethral sphincter as well. This will allow for
the relaxation of the detrussor; the internal urethral
sphincter will contract. The pressure then drops. Thru
time, the urine volume increases, the bladder is then
again distended sending signals again. This will result
to micturition reflex, but the higher center will then
again modulate. Through time, the intensity for the
urge to urinate will increase until a maximum limit.
Good to know: Guyton refer to the micturition reflex as selfregenerating. Therefore, the reflex increases thru time.
1.1.16 Clinical correlation
Say Patient A suffers from Tertiary Syphilis
which later causes destruction of the pelvic nerves, thus,
the reflex does not process. The patient does not know
when the bladder is full. The pressure is very high
resulting to overflow incontinence. Management
includes insertion of catheter.
Patient B on the other hand has transected
spinal cord above the sacral segment. The reflex arc is
intact but the higher center cannot control it. Therefore
there is still incontinence. For management, the
inguinal region’s dermatomal region may be stimulated
to allow for controlled micturition.
SDF Lindo
Page 7 of 7
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
N
eurons, aka nerve cells, are the basic unit involved in the Nervous System (NS). NS does not utilize a single
nerve only. It needs to activate a certain structure that is initially affected by changes in the body, that is, the
sensory nerves (aka afferent neurons).
Figure 1. REFLEX ARC (The Functional Working Unit of the NS)
(1) If the problem is in the Reflex Arc  no response; otherwise, there is sensation – effective stimulation of
receptors.
(2) If the problem is in the SENSORY ARM  no sensation  no response
(3) If the problem is in the EFFECTOR ARM (and sensory arm is normal)  with sensation  no response in
the effector arm.
*Motor Neuron – aka motor nerve/ efferent nerve/ visceral nerve
e.g. visceral tissues such as skeletal muscle, smooth muscle, secretory glands.
Parts of a neuron
Dendrites – tapering and branching extensions of the soma
and generally convey information toward the cell body.
Axon – extension of the cell that conveys the output of the cell
to the next neuron or, in the case of a motor neuron, to a
muscle. In general, each neuron has only one axon.
Axon Hillock – usually the site where action potentials are
generated because it has a high concentration of the
necessary channels.
Soma – (perikaryon/ cell body) contains the nucleus and
nucleolus of the cell and also possesses a well-developed
biosynthetic apparatus for manufacturing membrane
constituents, synthetic enzymes, and other chemical
substance needed for the specialized functions of nerve cells.
(Koeppen and Stanton 2010, ebook)
CAYCO

Page 1 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
AXON TERMINAL makes use of NTA; some are connected to the cell body, but most are connected to
the dendrites of the next neuron
If stimulated here, transmission would be bidirectional a) towards the axon terminal, and b) towards the
dendrites/cell body. But since only a) can produce NTs, impulse transmitted to the cell body will just
eventually die out.
The Postsynaptic terminal contain receptors (e.g. muscarinic, nicotinic)
Orthodromic/ Anterograde = unidirectional transmission
Antidromic/ Retrograde = bidirectional; produces local current flow
CAYCO

Page 2 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
Speed of Impulse Transmission
1. Type A neurons – fast transmitting sensory neurons; all type A are myelinated
a. α – fastest; large diameter myelinated; >100 m/s to a max of 130m/s
b. β
c. γ
d. δ – slowest; small diameter myelinated; 15m/s
2. Type C neurons – slow transmitting sensory neurons; small diameter, unmyelinated; 0.3 to 0.5 m/s
Factors affecting speed of neurons/neuronal activity
The following may increase neuronal activity:
1. Slightly increased body temperature
 less than 1oC or 2o to 3oF
 lowers activation threshold of neuron
 results in hypopolarized nerves (more excitable)
2. Neurons with lower threshold
 results in hypopolarized nerves
3. Increased diameter of neurons – lesser resistance to impulse
flow
4. Myelinated neurons
 SALTATORY CONDUCTION – myelin is an
insulator and current flowing through it is negligible
so depolarization in myelinated axons jumps from
one node to the next node of Ranvier thereby
enhancing neural transmission or neural
conduction.
Why?
There is faster transmission with saltatory
conduction making use of the NoR because
most of Na+ channels are at the NoR.
Production of Myelin Sheath:
In the PNS  Schwann cells
In the CNS  Oligodendroglias
Number of Na+ channels per square micrometer of membrane in myelinated nerves:
Cell body
50 to 100
Axon hillock
350 to 500 (initial generation of action potential)
Surface of myelin
Less than 25
Node of Ranvier
2,000 to 12,000
Axon terminal
20 to 75
Axons of unmyelinated nerve
110
Myelination of nerves
Autonomic
Somatic (muscle nerves)
CAYCO

Preganglionic  myelinated
Postganglionic  unmyelinated
Both myelinated
Page 3 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
Synapses
Types of Synapses:
1. Chemical – most common; uses neurotransmitters
 Unlike electrical synapses, there is no direct
Best known NTs:
communication between the cytoplasm of the two cells
acetylcholine, norepinephrine,
here in chemical synapses. Instead, the cell membranes
epinephrine, histamine, gammaare separated by a synaptic cleft of some 20 µm, and
aminobutyric acid (GABA),
the interaction between the cells occurs via chemical
glycine, serotonin, and glutamate
intermediaries known as neurotransmitters (Koeppen
(Hall 2011, p. 559)
and Stanton 2010, ebook)
2. Electrical – uncommon; simply transmit, traversing the synapse,
from the pre- to the post- synaptic terminal since sometimes, the space at the cleft is so small it is already
negligible.
 Characterized by direct open fluid channels that conduct electricity from one cell to the next. Most
of these consist of small protein tubular structures called gap junctions that allow free movement of
ions from the interior of one cell to the interior of the next (Hall 2011, p. 559).
3. Conjoint – uncommon; can do both chemical electrical
4. Axosomatic – axon terminal is connected to the cell body
5. Axodendritic – most common; axon terminal is connected to the dendrites
6. Axo-axonal – axon to axon connection
 Serial synapses – axoaxonic synapse is made onto the axon terminal and influences the efficacy of
that terminal’s synapse with yet a third element.
 Reciprocal synapses – both cells can release transmitter to influence the other (Koeppen and
Stanton 2010, ebook).
*Note: according to Koeppen and Stanton (2010), chemical synapses occur between different parts of the neurons,
and that, types 4, 5 and 6 mentioned above are actually subtypes of chemical synapses. Aside from these, there are
additional types of synapses mentioned in the book that are also under chemical synapses: dendrodendritic (dendrite
to dendrite) and dendrosomatic (dendrite to soma).
CAYCO

Page 4 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
COMMUNICATION THROUGH DENDRITES
Classes of Neurotransmitters
TRANSMITTER
Acetylcholine
Serotonin
(5-hydroxytryptamine or 5-HT)
GABA
Glutamate
Aspartate
Glycine
Histamine
Epinephrine
Norepinephrine
Dopamine
Adenosine
Nitric oxide (NO)
Neurotransmitter and its receptor
TRANSMITTER
Acetylcholine
Norepinephrine
Dopamine
GABA
Serotonin
Adenosine
CAYCO

MOLECULE
Choline
Tryptophan
SITE OF SYNTHESIS
CNS, parasympathetic nerves
CNS, chromaffin cells of the gut, enteric cells
Glutamate
CNS
CNS
CNS
Spinal cord
Hypothalamus
Adrenal medulla, some CNS cells
CNS, sympathetic nerves
CNS
CNS, peripheral nerves
CNS, gastrointestinal tract
Histidine
Tyrosine
Tyrosine
Tyrosine
ATP
RECEPTOR
Cholinergic
Adrenergic
Dopaminergic
GABA
Serotonergic
Adenosine
Page 5 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
Synthesis and Degradation of Catecholamines
Criteria for Neurotransmitters (NTA)
1. Synthesized in a NEURON.
2. Present in the PRE-SYNAPTIC NERVE (stored in vesicles = 5,000 to 10,000 NTs per vesicle) and is
released on depolarization in physiologically significant amounts (200 to 300 vesicles per depolarization) 
total: 1 million to 5 million NTs
 If you release less than 1 million NTs  ineffective stimulation  will produce local potential
ONLY.
3. Has immediate and short-lived effects on the post-synaptic nerve
 Because NTs immediately move away from the receptor or there is immediate reuptake of the NTs
back to the presynaptic nerve.
4. A mechanism exists in the neuron or synaptic cleft for the removal of NTA at the receptors.
S
ignal Transmission at the Synapse
1. Transmitter is synthesized and then stored in vesicles.
2. An action potential invades the presynaptic terminal.
3. Depolarization of presynaptic terminal causes opening of Voltage-gated Ca2+ channels.
4. Influx of Ca2+ through channels
 Involves activity of attachment of
Synaptotagmin
5. Ca2+ causes vesicles to fuse with
presynaptic membrane
CAYCO

Synaptotagmin = Ca++ sensor that triggers the actual
fusion event. Local high Ca++ concentration allows the rapid
binding of Ca++ to protein synaptotagmin, and binding
causes conformational change in synaptotagmin triggering
the fusion of a docked vesicle (Koeppen and Stanton 2010).
Page 6 of 12
Physiology A [SY 2013-2014]


NERVE PHYSIOLOGY
Involves SNARE proteins:
o One Synaptobrevin = v-SNARES or VAMP (vesicle associated membrane protein)
o Two Syntaxin = t-SNARES or SNAP-25 (found on the target or presynaptic plasma
membrane)
Synaptic vesicle docking and fusion in nerve endings:
When this happens, it will
signal to release NTAs
towards synaptic cleft.
6. NTA is released into synaptic cleft via exocytosis
 Botulinum toxin can prevent release of NTA
CAYCO

Page 7 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
7. Transmitter binds to receptor molecules at the postsynaptic membrane  causes electrical changes at the
post synaptic nerve.
A chemical, such as the neurotransmitter
Acetylcholine (Ach), triggers a conformational
change in the channel protein which allows Na+
ions to enter the cell, causing depolarization.
An Ion-Linked Channel Receptor
Some NT molucules bind to receptors on ion
channels. When a neurotransmitter molecule
binds to an ion-channel linked receptor, the
channel opens (as in this case) or closes, thereby
altering the flow of ions into or out of the neuron.
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Page 8 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
8. Postsynaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the
postsynaptic cell
 NTAs acting as ligand activates Na+channels (ligand-gated Na+ channels) at the post synaptic
nerve  initially develop excitatory potential  initial local depolarizing change  will eventually
open the voltage-gated Na+channels
 If inhibitory, either K+ or Cl- channels will be activated  causing hyperpolarization. Inhibitory NTs:
GABA, glycine, enkephalins,
9. Summation of EPSPs (Excitatory post-synaptic potentials) to generate action potential at the postsynaptic
cleft.
Why?
ORTHRODROMIC TRANSMISSION at the SYNAPSES

NTs are present only in the pre-synaptic nerve.

Post-synaptic area is devoid of NTs.

The absolute refractory period
Mechanism of NTA deactivation
1. Re-uptake (by presynaptic terminal)
2. Enzymatic deactivation
e.g.
Acetylcholine Acetylcholinesterase
Epinephrine, Norepinephrine, Dopamine  Cathecol-o-methyltransferase (COMT)
Monoamine oxidase (MAO)
3. Diffusion of NTs away from the receptor
Desensitization of receptors
1. Homologous desensitization – loss of responsiveness to one transmitter agent
2. Heterologous desensitization – loss of responsiveness to almost all transmitter agents
Mechanism of drug effects
Agonistic effects (increase NTA effects)
 Increase synthesis of NTA
 Destroy deactivating enzymes
 Increase release of NTA from pre-synaptic cell
 Blocking the inhibitors on NTA release
 Increasing the sensitivity of receptors (to NTA)
 Stimulating the receptors by mimicking the NTA
 Decreasing deactivation/reuptake of NTA
CAYCO

Antagonistic effects (decrease NTA effects)
 Decrease synthesis of NTA
 Destroying NTA inside the pre-synaptic cell
 Blocking the release of NTA from the
presynaptic-cell
 Stimulating inhibitors on NTA release
 Decreasing the sensitivity of receptors (to NTA)
 Blocking the receptors
Page 9 of 12
Physiology A [SY 2013-2014]
Characteristics of Synapses
NERVE PHYSIOLOGY
Possible Combinations of Temporal Summation
1. Temporal summation (see
electrophysiology notes)
2. Spatial summation (see
electrophysiology notes)
3. Convergence
 several presynaptic neurons
transmitting impulses to a
SINGLE postsynaptic nerve
 produces localized potential
because it only affects a
SINGLE group of cells
4. Divergence
 Single presynaptic nerve to
several postsynaptic neurons
 Diffused impulses 
widespread effect in the body
 activity at the sympathetic
nervous system
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Page 10 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
Possible Combinations of spatial summation
5. Facilitation – occurs when neuronal activation is frequent/prolonged/repetitive; repetitive stimulation of
neurons result to enhancement of neuronal activity (e.g. training of athletes)
6. Potentiation – Sustained activity  keep on releasing neurotransmitter  activity increases
7. Occlusion
 Response of two neurons simultaneously stimulated is lesser when the two neurons are stimulated
separately. Instead of getting a response, impulses cancel out producing no activity (e.g. activation
of an inhibitory nerve in the area)
 Note: Renshaw cell inhibition
8. Delay – there is normal delay because of the several steps involved before finally releasing NTA into the
synaptic cleft (ie. activation first of synaptogramin  synaptobrevin and syntaxin connection)
9. Excitation
Integration of the synapse
10. Inhibition
Summary of Synaptic transmission
Excitatory  EPSP
1. Activation of Ligand-gated Na+channels causing: Hypopolarization  Depolarization
2. Activation of Voltage-gated Na+channels
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Page 11 of 12
Physiology A [SY 2013-2014]
NERVE PHYSIOLOGY
Inhibitory IPSP
1. Activation of Ligand-gated K+ or Cl- channels causing: Hyperpolarization (pre/postsynaptic inhibition)
2. Cl- influx and/or K+ efflux
3. Inactivation of Na+ channels
*Seen mostly in the brain: explains our distinction from animals acting only on instinct.
Once aware of the presence of stimulus, one can also know the:
1. Quality/nature of the stimulus
2. Intensity of the stimulus
Greater intensity (e.g. pressure)  greater firing of action potential, Lower intensity (e.g. touch)
3. Location of the stimulus
 In the cortex (at the parietal lobe), there are parts representing different parts of the body except for
internal organs. The FACE and HANDS are well represented. There are specific receptors for
particular area/part of body
o Baroreceptor (pressure), photoreceptor (eyes), auditory receptor
 eyes  rods and cones  optic nerve  visual cortex of brain at the
occipital visual cortex (Brodmann area 17)
 Ears  organ of Corti  cochlear nerve
4. Timing of stimulus application – timing the stimulus was applied and was removed
Additional Vocabulary:
Stereognosis – identification of 3D objects via touch
Topognosis – identification of localization of stimulus
Adaptation of sensory stimulation – exposed to certain type of stimulus for prolonged time
Renshaw cell - an inhibitory interneuron in the ventral horn of gray matter of the spinal
cord that is held to be reciprocally innervated with a motor neuron so that nerve
impulses received by way of processes of the motor neuron stimulate inhibitory
impulses back to the motor neuron along an axon of the internuncial cell (MerriamWebster 2013).
Renshaw Cell Inhibitory System. Also located in the anterior horns of the spinal
cord, in close association with the motor neurons, are a large number of small neurons
called Renshaw cells. Almost immediately after the anterior motor neuron axon leaves
the body of the neuron, collateral branches from the axon pass to adjacent Renshaw
cells. These are inhibitory cells that transmit inhibitory signals to the surrounding motor
neurons. Thus, stimulation of each motor neuron tends to inhibit adjacent motor
neurons, an effect called lateral inhibition. This effect is important for the following
major reason: The motor system uses this lateral inhibition to focus, or sharpen, its
signals in the same way that the sensory system uses the same principle—that is, to
allow unabated transmission of the primary signal in the desired direction while
suppressing (Hall 2011, p. 675).
Sources:
Lecture of Sir Felipe C. Barbon, M.D.
JE HALL, PhD (2011). Guyton and Hall Textbook of Medical Physiology. 12th Edition. Philadelphia: Saunders, Elsevier
KOEPPEN, BM and BA STANTON (2010). Berne & Levy Physiology. 6th Edition [Ebook].
CAYCO
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Page 12 of 12
Renal Physiology II: Filtration, Reabsorption and Secretion
(Ronald Allan Cruz, MD)

Gibbs-Donnan effect
o
Filtrate is similar to plasma except for CHON
Nephron



Glomerular filtration
Tubular reabsorption
Tubular secretion

Urinary excretion = F – R + S
As far as secretion is concerned, this is the sum of the three different
processes done by the nephrons, so here you have filtration, reabsorption
and secretion. Excretion is equal to filtration minus reabsorption plus
secretion, so that’s your net excretion.
So looking at the diagram, you have your afferent arteriole,
glomerulus and efferent arteriole. Magnifying it, you have your filtration
barrier composed of three layers from the blood going to the filtrate: the
capillary endothelium which is fenestrated and next, you have your
glomerular basement membrane then you have your Bowman’s
epithelium and then after that, you have your filtrate already.
Now your filtering membrane is said to be 100x more
permeable to capillaries and it will exhibit the Gibbs-Donnan effect
which will be discussed more later.

Looking at the diagram, you have your glomerulus then your
peritubular capillaries, Bowman’s capsule/space, and tubule.
In diagram A, this depicts filtration only, such that the substance is
filtered, not secreted, not reabsorbed. A typical example would be inulin.
For diagram B, the substance is filtered and partially reabsorbed, so
some of substance X will go back to the circulation. If you get a urine
sample, substance X is still present in the urine sample. A typical
substance would be electrolytes: sodium, potassium etc.
Filtration barrier
o
Bowman’s epithelium

Podocytes, filtration slits

Sialoglycoproteins
o
Basement membrane

Lamina rara externa

Lamina densa

Lamina rara interna

Trimer of α1-6 collagen IV, laminin,
polyanionic proteoglycan, entactin,
heparan-SO4, fibronectin
o
Capillary endothelium

Sialoglycoproteins
In diagram C, the substance is filtered and completely reabsorbed
such that if you get urine sample, substance X should be absent. A typical
example would be proteins, amino acids and glucose.
In diagram D, the substance is filtered, but somehow, some of it
passes through the efferent arteriole into the peritubular capillaries and
this substance is secreted. So this substance is brought to the peritubular
cells and then it goes out into the filtrate. A typical example would be
creatinine.
Glomerular Filtration
Filtration barrier

Bowman’s epithelium

Basement membrane

Capillary endothelium

100x more permeable than capillaries
1
Shannen Kaye B. Apolinario, RMT
Looking at your filtration barrier more closely, this is your
electron micrograph of your filtering membrane. So again from the blood
to the filtrate, you have your capillary endothelium, the basement
membrane and you have your Bowman’s epithelium.
First, you have your capillary endothelium. As what we have
said earlier, it is fenestrated. One important characteristic of your
capillary endothelium is that it contains sialoglycoproteins which are
negatively charged.
From there, we go to the glomerular basement membrane,
again, our direction is from the blood to the filtrate. So the first layer is
your lamina rara interna. Next you have your lamina densa and then
lastly you have your lamina rara externa. So your glomerular basement
membrane would contain important negatively charged proteins like
your type 4 collagen, laminin, polyanionic proteoglycan entactin, heparan
sulphate and fibronectin. All of them will impart a highly negative
basement membrane.
Going now to your Bowman’s epithelium, it has slit pores and
they will also have foot processes or podocytes. The podocytes
interdigitate such that when you look at the top view, it has slit pores.
Take note also that the Bowman’s epithelium will also have
sialoglycoproteins imparting a negative charge. Because of your negative
charge, it will repel negatively charged particles. Because of your slit
pores and fenestration, it can allow the easy passage of larger molecules
compared to your regular capillary beds found in the systemic circulation.

barrier is completely permeable to water. If you increase the molecular
weight, looking at sodium, glucose and inulin so that is 23, 180 and 5,500
respectively, all of which will have the same filterability which is 1.0.
Meaning to say, looking at inulin, inulin is completely filtered. If you
increase the molecular weight further, you have your myoglobin which is
17,000 having a filterability of 0.75, this simply means that 75% of
myoglobin is filtered. However, with albumin with a larger molecular
weight of 69,000, it has a filterability of 0.005. Meaning to say, 0.5% is
filtered - there is very little amount of albumin which is filtered. In this
table, the larger the molecule, permeability or filterability decreases due
to the slit pores and fenestrations.
Mesangial cell
o
Contractile, phagocytic, produces matrix and collagen,
biologically active mediators
Another important structure within the glomerulus is the
mesangial cell. So you have your afferent arteriole, glomerulus, efferent
arteriole, and the dark structures are termed as the mesangial cells.
These are mesenchymal in origin and they have important functions.
They may have contractile properties or phagocytic properties and they
produce the matrix that will support the basement membrane. So it
produces important proteins like your collagen, entactin, proteoglycan
etc. The mesangial cells now will support the filtrate barrier. Also, your
mesangial cells are able to produce active mediators like prostaglandin.
So you will note that because of prostaglandin which is a vasodilator and
because of your contractile elements, the mesangial cell can actually
control the blood flow going into the glomerulus.
As what was said earlier, one of the important mediators is
prostaglandin which is a vasodilator. If you dilate your vessel, blood will
flow and long term use of NSAIDs will create renal problems.
Looking at this graph, here you have your molecular radius or
size of molecule and filterability. What they did is that they utilized
dextran: negatively charged polyanionic dextran, neutral and polycationic
or positively charged dextran. Given a molecular weight of let’s say 30,
you will note that the negatively charged dextran has a low filterability
compared to the neutral one having the same size more so with a
positively charged dextran. So of the three, the positively charged has the
highest filterability. A negatively charged particle will not easily pass
through however, in positively charged particle, it can easily pass
through. So the filtering barrier permits the passage of small and
positively charged molecules.
Because of the slit pores and fenestrations, the permeability is
said to be 100x more permeable than your regular capillary bed.
Because of negatively charged proteins found in your filtering
membrane you can observe the Gibbs-Donnan effect. What is Gibbs
Donnan effect? Recall that the membrane is highly negative. We said that
it will allow the passage of small positively charged molecules. What is
left in the blood would be negatively charged particles - large negatively
charged particles like albumin. When your plasma is filtered, you
concentrate now your albumin so the concentration of albumin goes up
and the negative charge of your plasma increases because of albumin.
Because of this, if you have let’s say a small positively charged molecule
passing along with plasma, it will not be filtered as readily as before
because it will now be attracted to the negatively charged albumin. So
that s your Gibbs Donnan effect. It is not a general statement that when it
a molecule is small and positively charged, it can easily pass through or
filtered. It is not as simple as that, it depends on the concentration of
albumin. So here you have the filtrate having similar characteristics with
plasma except that it will not have plasma proteins.
Effective Filtering Pressure
Looking at this table, here you have your different substances
that are filtered. Water with a molecular weight of 18 will have a
filterability of 1.0, meaning to say, it is 100% filtered or the filtering
2
Shannen Kaye B. Apolinario, RMT


PG: 60-70 mmHg
ΠG: 32 mmHg

Effective filtering pressure
o
(PG + ΠB) – (PB + ΠG)

PG – glomerular hydrostatic pressure

ΠB – Bowman’s oncotic pressure

PB – Bowman’s hydrostatic pressure

ΠG – glomerular oncotic pressure
As far as filtration is concerned, just like what you had the
lecture in microcirculation, the Starling forces will come into play. Here
you have your glomerular hydrostatic pressure of 60-70 mmHg and your
glomerular oncotic pressure of around 32 mmHg. These forces will come
into play as far as filtration is concerned.
So first we need to understand effective filtering pressure or
what the net pressure for filtration is. Here you have your Starling’s
forces, just like what was discussed before during your cardio lecture, for
filtration to occur, you need to get your pro-filtering factors minus your
anti-filtering factors. So for the pro-filtering factors, you have
glomerular hydrostatic pressure generated by the pumping action of
the heart. For ΠB, that is Bowman’s oncotic pressure due to the
presence of proteins inside the Bowman’s capsule which is normally 0 in
value because proteins are not filtered. However, in certain pathologic
conditions like nephrotic syndrome or glomerulonephritis, proteins can
pass through increasing the Bowman’s oncotic pressure. The antifiltering factors are Bowman’s hydrostatic pressure due to the
presence of fluid inside the Bowman’s space and that is your ultrafiltrate.
And lastly, you have glomerular oncotic pressure so that’s the plasma
proteins present in the glomerulus.

Effective filtering pressure = 10 mmHg
o
(PG + ΠB) – (PB + ΠG)

PG – glomerular hydrostatic pressure = 60 mmHg

ΠB – Bowman’s oncotic pressure = 0 mmHg

PB – Bowman’s hydrostatic pressure = 18 mmHg

ΠG – glomerular oncotic pressure = 32 mmHg
Getting now their values, you will have an effective filtering
pressure of 10 mmHg.
Filtration Coefficient



Quantification of Glomerular Filtration




GFR = C inulin
C inulin = (U inulin x V) / P inulin
C inulin = (120 mg/mL x 1 mL/hr) / 1mg/mL
C inulin = 120 mL/min

BUN, creatinine estimates GFR
In the laboratory, to experimentally measure GFR we utilize
the clearance of inulin. How do we do this? The subject is infused with
inulin, after achieving steady-state, we utilize the clearance principle. We
simply get a urine sample and a blood sample, send it to the laboratory,
and know the inulin concentration of both. Let’s say that the inulin
concentration of inulin is 120 mg/mL, in plasma is 1mg/mL at steady
state. Of course urine flow rate is more or less constant - 1mL. Simply
plug in the values and you will get 120 mL/min. It is almost the same with
125 mL/min, so inulin is said to be the gold standard in measuring GFR
because the renal handling of inulin is only via filtration, it is neither
secreted nor reabsorbed. Filtration is the only one that happens and is the
gold standard as far as measuring GFR is concerned. However, in the
clinics, not all patients are given inulin because it is expensive and it is
not readily available so what we utilize are BUN and creatinine.
However, BUN and creatinine will only estimate GFR so it is
not an accurate measurement. It will only estimate GFR because BUN
(Blood Urea Nitrogen) is from protein metabolism (amino acid
metabolism). The problem with BUN is that it is filtered and reabsorbed
so BUN underestimates GFR. As far as creatinine is concerned, this is
from creatine phosphate. The problem with creatinine is that it is filtered
and secreted so that overestimates GFR. Now, you have a range, one that
underestimates and the other one overestimates GFR so more or less you
know where you will get the values.

GFR = Kf x EFP
o
Kf: Filtration coefficient

Permeability

Surface area

Mesangial cell activity
o
EFP: Effective Filtering Pressure
PG
o
o
o
GFR = 12.5 mL/min/mmHg x 10 mmHg
GFR = 125 mL/min
Now to get your glomerular filtration rate, your effective
filtering pressure is multiplied with Kf. Kf is your filtration coefficient and
the filtration coefficient is dependent on 3 factors: permeability of the
membrane, surface area and mesangial cell activity.
Let’s look at it one by one. Looking at the permeability of the
filtration barrier, of course if you increase the permeability you increase
Kf, GFR increases. For example, if the subject or patient has
glomerulonephritis meaning to say, that the glomerulus is inflamed or the
filtering membrane is thickened, the Kf will go down or decreases, GFR
decreases. That’s why patients with glomerulonephritis present with
oliguria.
As far as surface area is concerned, of course if you increase
the surface area, Kf increases, GFR increases. Example, if a patient
undergoes partial nephrectomy (a certain portion of the kidney is
removed), the surface area goes down, consequently, the GFR will go
down.
Mesangial cell activity will also alter the Kf. Recall that your
mesangial cells will have important functions: contractile properties,
produces prostaglandins etc. and all of these will affect Kf.
So getting now your Kf of around 12.5 mL/min/mmHg
multiply that will effective filtering pressure of 10mmHg, so your GFR
now is around 125 mL/min.
3
Shannen Kaye B. Apolinario, RMT




Arterial pressure

↓ pressure: ? GFR

↑ pressure: ? GFR
Afferent arteriole resistance

↑ resistance: ? GFR
Efferent arteriole resistance

↑ resistance: ? GFR

↑↑↑ resistance: ? GFR
As far as glomerular hydrostatic pressure is concerned:
What will happen with glomerular filtration if arterial pressure
drops? What will happen with glomerular filtration if arterial
pressure goes up?
What will happen to GFR if your afferent arterioles constrict?
What will happen to GFR if you moderately constrict your efferent
arteriole?
What will happen to GFR if you severely constrict your efferent
arteriole?

PG
o
o
o
Arterial pressure

Renal autoregulation: 80-160 mmHg

↑ pressure: ↑GFR
Afferent arteriole resistance

↑ resistance: ↓ GFR
Efferent arteriole resistance

↑ resistance: ↑ GFR

↑↑↑ resistance: ↓ GFR
What will happen with glomerular filtration if arterial pressure
drops? The question is how high or how low? If you will recall your
previous lecture, within autoregulatory range, GFR is constant. Below 80,
GFR goes down, above 160, GFR will go up.
What will happen to GFR if your afferent arterioles constrict?
GFR will go down because the hydrostatic pressure in the glomerulus
drops.
Filtration is non-selective, if a molecule is small and positively
charged, it will be filtered indiscriminately most of the time. However, as
far as reabsorption is concerned, reabsorption is selective.
What will happen to GFR if you moderately constrict your
efferent arterioles? GFR increases because you increase the hydrostatic
pressure inside the glomerulus.
If we have a GFR of 125 mL without reabsorption, our urine
output would be 178 L per day which is physiologically impossible
because we only have 5 L of blood and 3 L of plasma. Because of
reabsorption, with a GFR of 125 mL/min, our average of urine output is
around 1-1.5 L/day and that’s the job of reabsorption – to bring back
essential substances into the body.
What will happen to GFR if you severely constrict your efferent
arteriole? GFR will go down because the blood flow will be curtailed.
Initially in the glomerulus, filtration will occur but the thing is, since you
severely constrict your efferent arterioles, plasma proteins will not pass
through so you will now concentrate your plasma proteins within the
glomerulus. Increasing plasma proteins increases oncotic pressure and
oncotic pressure will oppose filtration. If oncotic pressure increases,
filtration will decrease.
Filtration Fraction



Extent of fluid loss from plasma
Extent to which plasma CHOn is concentrated
FF = GFR/RPF
o
GFR / C PAH
o
% of plasma flowing through the kidneys that is filtered
o
0.16-0.2o
Going now to filtration fraction, this is the extent of fluid loss
from plasma or the extent to which plasma proteins are being
concentrated like severe constriction of the efferent arteriole. The
formula for your filtration fraction - GFR divided by renal plasma flow.
Take note that renal plasma flow is actually equal to the clearance of PAH.
That’s the percent of plasma flowing through the kidneys that is filtered.
In this table, here you have your commonly filtered,
reabsorbed and sometimes excreted substances. So you have your
amount filtered, amount reabsorbed and amount excreted as well as the
percent of the filtered load reabsorbed. Looking at it one by one, let’s say
if you have plasma glucose of 180 g/day – that’s the amount filtered, this
180 should be reabsorbed such that if you get a urine sample, you should
not be finding glucose there. Therefore, you have 100% reabsorption.
Looking at your electrolytes for example sodium. In sodium,
25,500 are filtered but the reabsorbed are 25,400 such that the percent
filtered is around 99.4% so a certain amount of sodium goes out into the
urine.
Mechanisms for Reabsorption

Active Transport
o
o
o

Looking at this diagram, you have the blood side and filtrate
side. As your blood passes through, plasma is filtered; plasma proteins
are left behind being concentrated. The higher the fraction, the higher the
concentration of your plasma proteins and normally, that’s around .16 to
.20. In this graph, you have the afferent end, glomerulus, and efferent end
(blood flows in this direction). This is plotted against osmotic/oncotic
pressure. Take note that as blood passes through from the afferent side to
the glomerulus to the efferent side, your oncotic pressure increases
slowly increasing now your filtration fraction.
Tubular Reabsorption



GFR = 125 mL/min
UO = 178 L/day
UO = 1-1.5 L/day

Reabsorption
o
Selective
4
Shannen Kaye B. Apolinario, RMT
Transport maxima

Carrier-dependent

Glucose, amino acids, PO4, SO4, Vitamin C, malate,
lactate, aceto-acetate, β-hydroxybutyrate
Gradient-time limitation

Depends on the gradient established and the time
the fluid is in contact with the epithelium
Pinocytosis

CHON
Passive transport
o
Depends on electrochemical and osmotic gradient
o
H20, urea, Cl-
Now let’s talk about the different mechanisms for
reabsorption. You have two general processes: active and passive. What’s
the difference between the two? The difference is the utilization of energy
and gradient: in active – uphill and in passive – downhill.
In passive transport, it depends on the electrochemical and
osmotic gradient. This is how water, urea and chloride are reabsorbed. It
does not utilize energy and goes downhill.
Looking at active transport, there are three processes:
transport maxima, gradient time limitation and pinocytosis.
Pinocytosis, this is how your filtered proteins are being
handled. So in the luminal side, you pinocytose your proteins and then it
goes to the lateral side then exocytosed going to the blood. So basically
that’s trancytosis. Sometimes you pinocytose your protein and within
your tubular cell this is digested breaking it into its component amino
acids and these amino acids will go into the blood via their respective
carriers or channels.
When you say transport maxima, this is carrier dependent. It
depends upon energy supply and carriers. With that, these are the
substances that will need carriers: Glucose, amino acids, PO4, SO4,
Vitamin C, malate, lactate, aceto-acetate, β-hydroxybutyrate. So your
transport maxima because of carriers, will exhibit saturation. These
substances will require carriers so when saturation is achieved, the rate
of transport will be constant. If you increase your substrate but you do not
saturate your carriers, it will go up. But if you saturate the carriers, it will
be constant. Look at glucose, imagine that the patient is diabetic. If you
have so much glucose in the filtrate, carriers will reabsorb only a certain
amount of glucose and beyond that, if you further increase glucose, it
spills out in the urine so if you get the urine sample, it would contain
glucose.
Gradient-time limitation depends on the gradient established
and the time the fluid is in contact with the epithelium and this is how
sodium and bicarbonate are being handled by the kidneys. Just like what
we have talked about tubule-glomerular feedback, it depends on the
gradient established so if the gradient is high, the rate of reabsorption is
faster. What about the time the fluid is in contact with the epithelium? For
as long as the filtrate is in contact with your tubular cells, tubular cells
will be able to reabsorb as much sodium as possible. If the flow of the
filtrate is slow, the fluid is in contact with the epithelium for a longer time
and it gives the tubular cells time to reabsorb your solutes.
Quantification of Tubular Reabsorption

Quantification of reabsorption
o
R = filtered – excreted
o
RX = (GFR x PX) – (UX x V)
For the quantification of reabsorption, reabsorption is the
amount filtered minus the amount excreted. So the font with the same
color will mean the same thing. The amount filtered is equal to GFR times
the concentration of that substance in plasma. For the amount excreted,
that’s your urine flow rate times the concentration of that substance in
the urine.

Factors affecting tubular reabsorption
o
Flow rate
o
Osmotic pressure of the filtrate
o
Hormone influence

ADH, aldosterone, ANP, angiotensin II

PTH, Vit. D, calcitonin
Here are the factors affecting tubular reabsorption, number
one is flow rate – if you increase flow rate, reabsorption rate will
decrease. Osmotic pressure of the filtrate – if the osmotic pressure of the
filtrate is increased, reabsorption will decrease because your oncotic
pressure will attract the fluid. Hormonal influences which can alter
reabsorption rate. For example, ADH for water reabsorption; aldosterone
for sodium; atrial natriuretic peptide (ANP) will decrease reabsorption;
Angiotensin II is said to have properties that will permit sodium
reabsorption and of course PTH – vitamin D and calcitonin will control
calcium and phosphate handling.

Quantification of reabsorption
o
R = filtered – excreted
o
RX = (GFR x PX) – (UX x V)

If the filtered load > excretion rate, net reabsorption has
occurred

Reabsorption = Kf x NRF
o
Kf – filtration coefficient

Permeability

Surface area
o
NRF = (PI + ∏C) – (PC + ∏ I)

PI : interstitial hydrostatic pressure

∏C: peritubular capillary oncotic pressure

PC : peritubular capillary hydrostatic pressure

∏I: interstital oncotic pressure
5
Shannen Kaye B. Apolinario, RMT
So the filtered load is greater than your excretion rate, net
reabsorption has occurred. So just like glomerular filtration, your Starling
forces will also play a role. So this is your Net Reabsorptive Force. At
first glance, it looks the same with effective filtering pressure but it is not.
Your net reabsorptive force is pro-reabsorptive factors minus your antireabsorptive force so the font with the same color would mean the same
thing. For pro-reabsorptive factors, you have your interstitial
hydrostatic pressure and peritubular capillary oncotic pressure so they
will promote reabsorption. For anti-reabsorptive factors you have your
peritubular capillary hydrostatic pressure and interstitial oncotic
pressure. Starling’s forces will comprise your net reabsorptive force. You
multiply that with Kf, Kf is also the concentration coefficient as far as
reabsorption is concerned, you only have permeability and surface area
to come into play, mesangial cells are not included because we are now in
tubular cells not in the filtering barrier.

Reabsorption = Kf x NRF
o
Kf – filtration coefficient = 12.4 ml/min/mmHg
o
NRF = (PI + ∏C) – (PC + ∏I) = 10 mmHg

PI : interstitial hydrostatic pressure = 6mmHg

∏C: peritubular capillary oncotic pressure =
32mmHg

PC : peritubular capillary hydrostatic pressure = 13
mmHg

∏I: interstital oncotic pressure = 15 mmHg




Reabsorption = 12.4 ml/min/mmHg x 10 mmHg
Reabsorption = 124 ml/min
GFR = 125 mL/min
UO = 1 mL/min
Plugging in the values, your filtration co-efficient is around
12.4 and your net reabsorptive force is also 10. To get reabsorption rate,
12.4 x 10 = 124 mL/min. If you will recall your GFR, GFR is 125,
reabsorption is 124, to get your urine output, you simply subtract so you
now have 1 mL/min and that is now your urine flow rate.

Reabsorption
o
Powered by pumps
o
Back-leak
This diagram will show the basic mechanism for reabsorption.
You have your filtrate, tubular cell, interstitium or blood. There are two
processes: active and passive. Everything starts with the Na-K pump. NaK pump will remove sodium so Na goes into the blood. The concentration
of Na inside the cell decreases and you now have a concentration gradient
between your filtrate and your tubular cell and that will now power your
secondary pump. Na from your filtrate goes into cell via secondary pump,
secondary pump is able to transport another substance – substance X
such that for every transport of Na, substance X will also be reabsorbed.
Your Na will go out into the blood via Na-K pump but substance X will go
into the blood via other means.
Let’s look at substance Y. Let’s say substance Y is an anion like
chloride. Na enters, your tubular cell becomes positive because of Na,
your filtrate becomes negative because of substance Y causing an
electrochemical gradient powering now the passive transport or
reabsorption of substance Y. Na goes into the other side and the anion
will also go together with it.
Substance X, Na and substance Y are solutes, all of them will go
into the blood, all of them are reabsorbed and water also goes along.
Solutes will now act as osmotic attractants and water will go through
aquaporins and is now reabsorbed.
Some substances may pass through paracellular route or in
between cells. Some substances when reabsorbed may go back into the
filtrate and this is your back-leak and it commonly happens with
potassium.
Segments of the Nephron

Reabsorbs 67% of filtered H2O, Na, Cl, K

Early PCT
o
Na-H antiport
o
Na-glucose symport
o
Na-amino acid symport
o
Na-P symport
o
Na-lactate symport
o
H2O reabsorption
o
Pinocytosis of CHON
That’s how you reabsorb certain substances. Although not all
transport mechanisms are shown, the mechanism is the same for
reabsorption to all of them.
You reabsorb now solutes; of course water will be reabsorbed
as well. Whatever amount of solute is reabsorbed, the amount of water
that will be reabsorbed is the same. Also in early portions of PCT,
pinocytosis of proteins is evident but was not shown. So in here, there is
reabsorption of filtered proteins.

Late PCT
o
Na-H antiport
o
Paracellular NaCl reabsorption
o
H2O reabsorption
In the late PCT, this is where further reabsorption of water and
reabsorption of chloride will occur.
Now let’s go the different segments of the nephron. First, you
have your proximal convoluted tubule, PCT is divided into two segments:
the early PCT and late PCT.
In the proximal convoluted tubule, this is where obligatory
reabsorption of substances occurs so the filtered water, electrolytes,
proteins, amino acids etc. all of them will be reabsorbed in the PCT. In the
early PCT, these are the transport mechanisms present: Na-H antiport,
Na-glucose symport, Na-amino acid symport, Na-P symport, Na-lactate
symport, H2O reabsorption and Pinocytosis of CHON
In this diagram, you have filtrate, cell and blood. Everything
starts with Na-K pump powering secondary pump which in this case is
the Na-H antiport. Na enters, H exits. H will combine with a filtered anion
in the filtrate; your H anion complex can easily enter the tubular cell.
Once inside the cell, they will dissociate, H will go back out via antiport
whereas your anion will go back into the filtrate via another transport
mechanism – your chloride anion antiport. Essentially, H will just go
round and round. The anion will also go round and round. The net effect,
Cl enters together with Na and you now have a net reabsorption of NaCl.
Just like what was mentioned earlier, Na can go into the blood via the
pump whereas Cl will go out via other means and in this case, you have
your K-Cl cotransport and this is a passive process. Because Cl goes
downhill, K will also go on downhill mechanism. Also, NaCl can be
reabsorbed via paracellular routes or in between cells.
A. In this diagram, here you have filtrate, tubular cell and
blood. You have your Na-H antiport. Everything begins with Na-K pump
creating a gradient for Na that will power the secondary pump which in
this case is the Na-H antiport. Na is reabsorbed in exchange for H.
B. In this diagram, here you have your Na-glucose cotransport
or SGLT 2. Again it starts with Na-K pump powering the secondary active
transport. As Na enters, glucose enters. Na exits via primary glucose
whereas glucose will exit via other transport mechanism and this is now
your GLUT 2.
6
Shannen Kaye B. Apolinario, RMT

PCT
o
H2O reabsorption

67% of filtered H2O
o
Solvent drag

Changes in Na reabsorption influence H2O and solute
reabsorption
So you reabsorb now solutes in the PCT, of course water will
follow. So basically in the PCT, 67% of the filtered water is reabsorbed
and here you have aquaporins – water channels. Some solutes are
reabsorbed via solvent drag specially via paracellular route. For
example, the water that passed through via paracellular route, it can
bring with it solutes and changes in solute reabsorption will influence
water and solute absorption. You will note that in order for us to
reabsorb amino acids, glucose, chloride etc., we need to reabsorb sodium
with them. So if the sodium concentration in the filtrate is low, the
reabsorption rate of other substances would also be low.
So you will note your PCT is the site for obligatory
reabsorption so it is not influenced by external factors. PCT will require
tons of mitochondria because it needs energy. Take note also that as far
as solute reabsorption is concerned in the PCT, there is commensurate
reabsorption of water – the amount of solutes reabsorbed is also equal to
the amount of water that is reabsorbed. Therefore, what is the tonicity of
the filtrate when it exits the PCT? It is isotonic.




 Thin: passive reabsorption
 Thick: active reabsorption
NKCC2 transporter
Na-H antiport
Claudin-16
Transcellular, paracellular NaCl reabsorption
Ascending limb on the other hand, solutes are reabsorbed.
Ascending limb is divided into two segments: thin ascending and thick
ascending lim. In the thin ascending limb, passive reabsorption of solutes
occurs whereas in the thick ascending limb, active reabsorption of solutes
occur. So how does that happen?
Looking at the diagram, you have the descending, thin and
thick ascending limb. In the thin descending limb, water is reabsorbed
and the concentration of the filtrate increases or it becomes concentrated.
The solutes now being more concentrated will have a concentration
gradient. In the thin ascending limb, NaCl are passively reabsorbed.
Renal tubular acidosis – defect in sodium-bicarbonate
transport. One of its manifestation is acidosis because bicarbonate is not
reabsorbed.
Cystinuria – defect in basic amino acid transport therefore
there is aminoaciduria.

Loop of Henle
o
Reabsorption

Thin descending limb
 15% of the filtered H2O
 AQP1
Now we go to the loop of Henle. The loop of Henle is divided
into three segments or two main segments: the descending and ascending
limb.
In the thick ascending limb, you have your filtrate, cell and
blood. Everything begins in the Na-K pump that will power the secondary
active transport and one important transport protein is the Na-K to Cl
cotransport. It will transport 4 ions: 1 Na, 1 K and 2 Cl molecules. These
four molecules are now reabsorbed, Na goes into the blood via the pump,
Cl will go into the blood via some other means or it can go with K. Take
note that K back-leaks into the filtrate. When K leaks out into the filtrate,
the filtrate is imparted with a positive charge. This positive charge will
drive other positively charged ions to be reabsorbed via paracelluar
routes through Claudin 16 – a tight junction capable of permitting the
passage of Mg or Ca. So other cations are now reabsorbed. Take note that
in the ascending limb, water is NOT reabsorbed.
To emphasize, in the descending limb, water is the only one
that is reabsorbed and in the ascending limb, solutes are the only ones
that are reabsorbed. So when the filtrate exits the loop of Henle, the
tonicity of the filtrate is hypotonic because in the ascending limb, solutes
are removed and the one that is left is water making the filtrate hypotonic
so the ascending limb of loop of Henle is said to be a diluting segment
because it dilutes the filtrate.
Descending limb. Specially in the juxtamedullary nephron,
when the loop of Henle enters the renal medulla, it is exposed to a
hypertonic medium. In the descending limb of the loop of Henle, water
reabsorption occurs. Just like in the diagram, water is the only one that is
reabsorbed, there is no solute reabsorption.

7
Ascending limb
 25% of the filtered NaCl
Shannen Kaye B. Apolinario, RMT
Looking at an example of a disorder, you have Barter’s
syndrome and you have defects like Na-K-Cl symport that is defective.
The manifestations are hypokalemia, hyperaldosteronism and metabolic
alkalosis. There is hypokalemia because K is not reabsorbed. Because the
Na-K-Cl transport is defective, Na is also not reabsorbed so the Na state in
the body decreases. When the Na state of the body is low, the effective
circulating volume is also decreased and that activates RAAS. There is
alkalosis because aldosterone will reabsorb Na in exchange for H so H
spills out in the urine and what is left in the body is bicarbonate.

Early DCT
o
Reabsorption

8% of filtered NaCl

Na-Cl symport
We will now go to the DCT. Just like in the PCT, DCT is divided
into two segments: the early and the late DCT.
In the early DCT, 8% of the filtered NaCl is reabsorbed so again
everything starts with the Na-K pump powering the secondary pump.
Taken note also that in the early portions of DCT, water is NOT
reabsorbed therefore in the early segments of DCT, there is also dilute
urine so this is also a diluting segment because water is not reabsorbed.

Late DCT and Collecting Ducts
o
ADH

8-17% of filtered H2O
o
Aldosterone
o
Principal cells

Na-K pump-ENaC

Paracellular Cl reabsorption

AQP2, AQP3, AQP4
o
Intercallated cells

K-H pump
Going now to the late DCT and collecting ducts, the DCT and
collecting ducts will be influenced by hormones. As far as antidiuretic
hormone (ADH) is concerned, it varies. Without ADH, 8% of the filtered
water is reabsorbed and with ADH, 17% of the filtered water is
reabsorbed. ADH now will permit the formation of aquaporins. As far as
aldosterone is concerned, it will target two types of cell present in the
DCT and collecting ducts: the principal cells and the intercalated cells.
The action of aldosterone is that it will permit or it will increase the
activity of Na-K pump. Increasing the activity of Na-K pump permits
faster reabsorption of Na and consequently, K is secreted.
What happens to K? Looking at the intercalated cells, there is
K-H pump so K exits and enters the intercalated cells via K-H pump in
exchange for H. And that’s why if a person has hyperaldosteronism,
alkalosis occurs because H spills out.
So the late DCT and collecting duct is where facultative
reabsorption of water occurs because it is influenced by ADH unlike in
the PCT. In PCT, it is obligatory, with or without ADH, 67% of water will
always be reabsorbed.
In distal renal tubular acidosis, there are different defective
transport mechanisms. The manifestations include metabolic acidosis,
hypokalemia, hypercalciuria and nephrolithiasis.
For Liddle’s syndrome, amiloride-sensitive Na channels. The
problem with this is there is decrease in Na excretion so Na stays in the
body and consequently, there will be hypertension.
For example, if there is defect in DCT, will you expect amino
acids in the urine? NO, because amino acids are reabsorbed in the PCT.
Take note that as far as mitochondria concentration is
concerned, the one that needs the greatest amount of mitochondria is the
PCT (not so much with the ascending loop of Henle, DCT and collecting
tubules) because in the PCT, there is obligatory reabsorption of
substances.
Tubular Secretion
Tubular secretion is a lot like reabsorption, the only difference
is the direction of the substance.

Any substance ↑ concentration to a greater extent than does
inulin is secreted
Any substance increasing concentration to a greater extent
than inulin is excreted. As what was mentioned earlier, inulin is filtered,
not secreted and reabsorbed. For example, if you have 100 units of inulin
8
Shannen Kaye B. Apolinario, RMT
excreted and if you have a substance X with a urine concentration of 50,
what happened was filtration and reabsorption. If substance X is also 100
units, the substance was filtered, not secreted and not reabsorbed. If
substance X is 150, it was filtered and secreted.
The same is true for a weak base. You have an uncharged base,
it goes into the tubular cell and into the filtrate, H ions are secreted by the
tubular cell and H ions will interact with the base so the base now
becomes positively charged thereby it cannot go back anymore. So these
acids and bases are excreted.
Mechanisms for Tubular Secretion
One practical application for this is salicylic acid (aspirin)
poisoning. In salicylic acid poisoning, the urine has to be alkalinized by
giving sodium bicarbonate because when salicylic acid goes into the
filtrate, the H ion will interact with the filtered bicarbonate and the
salicylate now becomes charged and excreted.

Active secretion
o
o

Transport maxima

Carboxylic, sulfonic acids, hippurate, creatinine,
penicillin, thiazide, glucoronides, urological contrast

Organic bases, guanidine, thiamine, choline,
histamine
Gradient-time limited

H, K
Segments of the Nephron

PCT
o
Na-H antiport
Passive secretion
o
Diffusion trapping

Weak bases, quinine, quinacrine,
chloroquine, NH3

Weak acids, salicylic acid, phenobarbital
procaine,
Just like in reabsorption, there are also two basic processes:
active and passive transport. Active transport utilizes energy and against
a gradient and on the other hand, passive transport is downhill and
doesn’t utilize energy.
In active secretion, just like in reabsorption, there is also
transport maxima and gradient-time limited transport. For transport
maxima, it also utilizes carriers and the mechanism is the same. The
substances that are being handled by transport maxima are listed above.
For gradient-time limitation, just like in reabsorption, the principle is
the same. It is also dependent on the time and the gradient and this is
how H and K are being handled.
For passive secretion, there is diffusion trapping this is how
qeak bases, quinine, quinacrine, procaine, chloroquine, NH3, weak acids,
salicylic acid, and phenobarbital being handled. So how will diffusion
trapping work? We will talk about it in a little while.
Looking at the different segments of the nephron, in the PCT,
you have your Na-H antiport, Na-K pump powering the secondary active
transport, H goes out. H is now secreted.
o
Secretion of organic anions

cAMP, cGMP, hippirates, urates, bile salts, oxalate,
PGE, PGF, ascorbate, folate

Anionic drugs, toxins
This diagram shows the basic mechanism for secretion. You
have the filtrate, the cell and the interstitium or the blood. Everything
starts with the Na-K pump that creates Na gradient powering the
secondary pumps. Secondary pumps more often are antiports, so for
every Na that is reabsorbed from the filtrate, substance X goes out into
the filtrate – Na exchanges with substance X, and the mechanism is the
same.
Weak acids and weak bases in the blood are uncharged so they
are unionized. Because they are unionized, they can easily pass through
cell membranes and they go the tubular cell and they go into the filtrate.
Once in the filtrate, they will return to their ionic form. For example, you
have a weak acid that is unionized; it goes into the tubular cell then to the
filtrate. Once in the filtrate, this acid will interact with filtered
bicarbonate. The H ion will associate itself with the bicarbonate and the
acid now becomes negatively charged. Once the acid becomes negatively
charged, it now cannot pass through the cell membrane. This is diffusion
trapping – the acid now is trapped in the filtrate.
9
Shannen Kaye B. Apolinario, RMT
For organic anions, this diagram shows how organic anions are
secreted. Na-K pump is activated so Na exits. With the exit of Na, Na
inside the cell decreases powering a secondary pump, the NaDC found in
the basolateral membrane which permits the re-entry of Na. The entry of
Na is coupled with the entry a-ketoglutarate and that will power another
transport mechanism: OAT 1,3. a-ketoglutarate inside the cell increases
powering OAT4, a-ketoglutarate goes out. OAT 1,3 is able to pump in
organic ion. As far as Na and a-ketoglutarate is concerned, both will just
go round. The net effect is the entry of organic anion. This organic ion will
go to the filtrate via MRP 2 and OAT 4 which is another transport carrier.
This is how organic anions are being handled and listed above are the
substances that are handled that way.
o

Late DCT and Collecting Ducts
o
Aldosterone
o
Principal cells

Na-K pump-ENaC
o
Intercallated cells

K-H pump

H pump
Secretion of organic cations

Creatinine, dopamine, epinephrine, norepinephrine

Cationic drugs, toxins
Let’s now go to cations. The principle is almost the same with
cations. Everything starts with the Na-K pump. Because of the primary
pump, the inner surface of the cell membrane becomes negatively
charged. That negative charge will permit the entry of a cation. Cation will
enter via diffusion or through a channel or carrier like OCT. When that
happens, concentration of cations inside the cell increases and it goes out
into the filtrate via MDR1 or OCTN. OCTN is a hydrogen exchanger and a
secondary pump so as the cation exits, H enters. The substances that are
handled that way are listed above.

starts with the Na-K pump powering the secondary pump and H is
secreted.
Loop of Henle
o
Thick ascending limb

Na-H transport
In the late DCT and collecting ducts, aldosterone will exert its
influence. Aldosterone will target the principal cells and intercalated cells.
With that, aldosterone increases the activity of Na-K pump. Looking at the
principal cell, it will handle K and the intercalated cell will handle H. If the
activity of primary pump is increased, principal cells will secrete K. with
the influence of aldosterone, as far as intercalated cell is concerned, it will
secrete H. That’s the influence of aldosterone and here you have the
different transport mechanisms responsible.
Quantification of Secretion

Quantification of secretion
o
S = excreted – filtered
o
SX = (UX x V) - (GFR x PX)

If the filtered load < excretion rate, net secretion has occurred
For the quantification of secretion, amount secreted is equal to
the amount excreted minus amount filtered. Excreted is equal to urine
flow rate times the concentration of substance in the urine. Filtered is
GFR times the concentration of substance in plasma. If the filtered load is
less that the excretion rate, therefore net secretion has occurred.
Glomerulotubular Balance

In the loop of Henle, secretion does not happen in the
descending limb because the only thing that happens is water
reabsorption. In the ascending limb, we have Na-H antiport. Everything
10
Shannen Kaye B. Apolinario, RMT
↑ reabsorption rate in respone to ↑ tubular load
o
Prevents overloading of the distal segments with an ↑ GFR
o
Prevents large changes in fluid flow in the distal tubules
brought about by:

Changes in arterial pressure

Disturbances that would create problems in the
maintenance of Na and vol homeostasis
Tubuloglomerular balance, this is an increase in
reabsorption rate in response to an increase in tubular load – if substance
X is increased in the filtrate, reabsorption rate will also increase. For
example eating a high carbohydrate meal will increase glucose in the
plasma and that consequently increases glucose in the filtrate. So that
should cause an increase in the reabsorption rate. This prevents the
overloading of the distal segments with an increase in glomerular
filtration and prevents large changes in fluid flow in the distal tubules
brought about by changes in arterial pressure and disturbances that
would create problems in the maintenance of Na and volume
homeostasis.
Calculation of Reabsorption and Secretion Rates




Filtered load = GFR x PX
Excretion rate = V x UX
R = filtered – excreted
S = excreted – filtered
For the calculation of reabsorption and secretion rates: filtered load
is GFR times the concentration of X in plasma; excretion rate is urine flow
rate times the concentration of X in urine; reabsorption is filtered minus
excreted and secretion is excreted minus filtered.
“ Not only so, but we also rejoice in our sufferings, because we know
that suffering produces perseverance; perseverance, character; and
character, hope. And hope does not disappoint us, because God has
poured out his love into our hearts by the Holy Spirit, whom he has
given us.”
-Romans 5:3-5
GOD BLESS YOU 
11
Shannen Kaye B. Apolinario, RMT
Far Eastern University
Nicanor Reyes Medical Foundation
Institute of Medicine
1D – Batch 2020
Renal Physiology II
Urine Formation:
Filtration, Reabsorption & Secretion
Dr. Ronald Allan Cruz – January 10, 2017
NEPHRON
Basic Processes of Urine Formation:

Glomerular filtration

Tubular reabsorption

Tubular secretion
w
Excretion = Filtration – Reabsorption + Secretion
AA
EA
reabsorption rate. This is typical for many of the
electrolytes of the body such as Na, Cl- & etc..
The substance in C is FILTERED but COMPLETELY
REABSORBED from the tubules back into the blood.
When a urine sample is obtained, substance C should be
absent. This pattern occur for some of the nutritional
substances such as amino acids and glucose, allowing
them to be conserved in the body fluids.
The substance in D is FILTERED, however, some
remains in the blood so this will have to be
SECRETED. It goes out from the peritubular capillaries
to go to the renal tubule to be excreted. When a urine
sample is obtained, substance D should be present. This
pattern is true for organic acids and bases, permitting
them to be rapidly cleared from the blood and excreted
in large amounts in the urine. Example is creatinine.
GLOMERULAR FILTRATION
 Non-selective as long as small and not
negativley charged molecule
FILTRATION BARRIER
Bowman’s
Capsule
Peritubular
capillaries
AA
Renal
Tubule
Filtrate side
The substance in A is FILTERED ONLY by the
glomerular capillaries, it is not secreted and reabsorbed.
When a urine sample is obtained, SUBSTANCE A is
present. The excretion rate will be same as the one
filtered. A classic example is inulin.
The substance in B is FILTERED and PARTIALLY
REABSORBED from the tubules back into the blood but
notice that substance B is also excreted so when a urine
sample is obtained, it will be present. In this case, the
excretion rate is calculated as filtration rate –
Blood side
Filtration Barrier consists of:
1. Capillary endothelium
 First layer from the blood side
 Has fenestrations (butas butas)
 Contains sialoglycoproteins
2. Basement membrane
 Has several layers
o Lamina Rara Interna – 1st
layer from the blood side
o Lamina densa
Escoto, KC // Gloriani, KP
1 of 13
o Lamina Rara Externa
The proteins present in the basement
membrane are: Trimer of α1-6
collagen IV, laminin, polyanionic
proteoglycan, agrin, perlecan,
entactin, heparan-SO4, fibronectin
Bowman’s Epithelium
 Has podocytes
o Finger like projections
o Interdigitate to form slits so
there will be slit pores in
between
 Has slit pores/ slit diaphragms
 It also has sialoglycoproteins
Clinical Application

3.
When the proteins are destroyed, example during
glomerulonephritis such that immune complex will
destroy the protein present in the filtration barrier,
negative charges is lost
 Since negative particles are lost, proteins
easily leak out.
 Patients with glomerulonephritis will present
with proteinuria.
Figure: An electron micrograph of the filtration barrier
Characteristics of the Filtration Barrier
A. Because of the slit pores and the fenestrations,
the
filtration
barrier
has
a
HIGH
PERMAEBILITY, greater than the average
capillary bed so the substances can easily pass
through.

100x more permeable than a regular
capillaries
B. It has A LOT of NEGATIVE CHARGES

Negative charge proteins present in the
filtration barrier.

Because of this, plasma proteins that
are typically negatively charged are not
allowed to pass through the filtration
barrier
C. GIBBS-DONNAD EFFECT

Since the plasma proteins are not able
to pass through, some positively ions
will be attracted to the negative charge
of the plasma protiens.

Some negatively charge small particles
like anions are repelled by the plasma
proteins
At the end of the day, the filtrate is said similar to the
plasma, except that it will not contain plasma protein.
 If plasma Na concentration is 145 mEq/L, the
amount of Na present in the Bowman’s space
would be the same
 If the plasma glucose level is 200 mg/dL, the
amount of glucose present in the Bowman’s
space is 200 mg/dL.
This table will show the filterability of several
substances present in the plasma.
 Notice that water, Na, Glucose and inulin
will have a filterability of one so they are
EASILY FILTERED.
 As the size of the molecule increases, the
filterability decreases simply because of the
fenestrations and slit pores that they can’t fit
through.
In the figure above, molar radius or molecular size is
plotted against relative filterabilty.
Black line = negatively charged particles
Blue line = neutral particles
Red line = positive particles
Given a specific size (30):
 A molecule with negatively charge at 30 will
have low filterability compared to a molecule
that is neutral
 It also has less filterability compared to
positively charged molecule with the same
Negatively charged particles are not readily filtered because
of the charge of the filtration barrier.
Escoto, KC // Gloriani, KP
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TWO DETERMINANTS AFFECTING FILTERABILITY
1. Size of the particle
2. Charge of the particle
MESANGIAL CELL
 Mesangial cells can affect filtration rate by
regulating the RBF because it can alter the
capillary surface size.
 Has contractile properties
o Has cytoskeleton elements that
allows them to contract and relax
o If they contract, they affect the
surface area of the glomerulus,
affecting also filtration.
 Has phagocytic properties
 Produce matrix and collagen
 Produce biologically active mediators – affects
blood flow to the glomerulus
o Vasodilators
o Vasoconstrictors
PHYSICAL PROPERTIES AFFECTING FILTRATION

STARLING FORCES – necessary for the
computation of effective filtering pressure:
Green texts = Pro
filtering factors
Red texts = Anti
filtering factors
NORMAL VALUES:
PG: 60-70 mmHg
∏G: 32 mmHg
(PG + ∏B) – (PB + ∏G)




PG: glomerular hydrostatic pressure

Presence of fluids present
in the glomerulus

Driven by the pumping
action of the heart
∏B: Bowman’s oncotic pressure

Proteins present in the
Bowman’s space

They will attract fluid thus
facilitating filtration

Said to be ZERO mmHg
because proteins are not
normally filtered.
PB: Bowman’s hydrostatic pressure

Presence of fluid present in
the Bowman’s space
∏G: glomerular oncotic pressure

Plasma proteins in the
glomerulus
Effective filtering pressure = 10 mmHg
EFP = (PG + ∏B) – (PB + ∏G) = 60 – 50 = 10




PG: glomerular hydrostatic pressure = 60
mmHg
∏B: Bowman’s oncotic pressure = 0 mmHg
PB: Bowman’s hydrostatic pressure = 18
mmHg
∏G: glomerular oncotic pressure = 32 mmHg
By entering the values, you’ll get an effective filling
pressure of 10mmHg.
Clinical Application
Some diseases can alter or change the Starling Forces

Glomerulonephritis – can increase Bowman’s
Oncotic Pressure (∏B).

Kidney Stones
 Urine can’t flow to the ureters
 Bowman’s Hydrostatic pressure (PB)
can increase
GLOMERULAR FILTRATION RATE
There are two formulas discussed by Dr. Cruz and I
don’t know which one will be used 
1st formula
According to Berne and Levy,
there is a different effective
filtering pressure between
the arterial side and the venous
side. Look at the figure on the
right for the values of the efferent
and afferent side.
To get the GFR according to Berne
and Levy:
GFR = Kf[(PG-PB) – σ(πG-πB)]
σ – reflection coefficient of CHON
– this is equal to one so it does
not do anything
Albumin – most important plasma protein
2nd Formula – I think this is the one that will be used
because it is simpler and this the one used in the
previous trans but be reminded that this formula is
from Guyton and Hall.
GFR = Kf x EFP
EFP = Effective filtering pressure
Kf = Filtration coefficient = Property of the membrane
due to:

Permeability
 Glomerulus is 100x more permeable
than regular capillary bed due to the
fenestrations
Glomerulonephritis can affect permeability. Due to the
inflammation, the filtering barrier thickens so the
permeability decreases, Kf goes down, GFR also goes
down. So patients with glomerulonephritis also have
oliguria.
Escoto, KC // Gloriani, KP
3 of 13

Surface area
 The more number of nephrons, the
greater the surface area, the greater
the Kf, the greater the filtration rate.
Patients that undergone Partial Nephrectomy, a
portion of kidney is removed. Some nephrons are also
removed, decreasing the surface area, decreasing
the Kf, GFR decreases.

Mesangial cell activity
 The mesangial cell can either relax or
contract affecting the surface area
 It
can
elaborate
vasoactive
substances that can alter Starling
Forces
2.
IMPORTANCE OF DETERMINING GFR
 Because GFR reflects renal function, we can
know if the patient will have renal failure
o If GFR is 25% or below, there is a
renal failure
o So if we have a normal GFR of
120ml/min, then the patient has 30
ml/min GFR, then he has a renal
failure and you are a candidate for
dialysis

Application:
Kf = 12.5ml/min/mmHg
EFP = 10 mmHg
 GFR = 12.5ml/min/mmHg x 10 mmHg
 GFR = 125 ml/min
NORMAL
VALUES:
 M: 90-140 ml/min
 F: 80-125 ml/min
TWO METHODS FOR QUANTIFICATION
GLOMERULAR FILTRATION RATE
1.
Creatinine estimation

This is the one normally used in the
clinics

Serum Creatinine will estimate GFR
Glomerular Hydrostatic Pressure (PG)
 Arterial pressure
o ↓ pressure: ? GFR
o ↑ pressure: ? GFR
 Afferent arteriole resistance
o ↑ resistance: ? GFR
 Efferent arteriole resistance
o ↑ resistance: ? GFR
o ↑↑↑ resistance: ? GFR
As far as glomerular hydrostatic pressure is concerned:
OF
Use of Inulin

The gold standard in determining
filtration rate

This is done by getting the clearance
of inulin because it is equal to the
GFR
 INULIN
IS
FILTERED
ONLY, not secreted nor
reabsorbed

Infuse the subject with inulin and
allow him to be in steady state
HOW IT IS DONE:
1. Remember the clearance method:
C=UV/P
2. Get a blood and urine sample, determine the
plasma and urine concentration of inulin.
3. Plot the values then compute.
Example:
Cinulin = (120mg/ml x 1ml/min)/1mg/ml
Cinulin = 120ml/min
4. If the clearance of Inulin is 120 ml/min, then it
is equal to the GFR
Inulin is not normally used in the clinic because of its
availability and cost.
NOTE: BEFORE ANSWERING BE MINDFUL OF THE
PREVIOUS TOPIC
1.
2.
What will happen to GFR if arterial pressure
decreases?
What will happen to GFR if arterial pressure
increases?
For nos. 1 and 2, remember the RENAL
AUTOREGULATORY RANGE: at BP of 90 – 180 mmHg,
there will be a constant RBF and GFR.
Even though you increase and decrease BP so as long as
you are within the auto-regulatory range, RBF will be
constant or unchanged so as the GFR.
So the answer for nos. 1 & 2 is it depends on the BP.
So when you are within the range, GFR is constant.
BUT IF BEYOND THE RANGE, GFR IS DIRECTLY
PROPORTIONAL TO THE BP.
3.
What will happen to GFR if afferent arteriole
resistance increases?
If the afferent arteriole constrict, then GFR decreases
and vice versa.
4.
5.
What will happen to GFR if efferent arteriole
resistance slightly increases?
What will happen to GFR if efferent arteriole
resistance is maximally constricted?
Escoto, KC // Gloriani, KP
4 of 13
For the efferent arteriole, it has a peculiar phenomenon.

Slightly constricted efferent arteriole such
that blood can still flow through, GFR
increases because the hydrostatic pressure in
the glomerulus will go up.

Maximally constricted efferent arteriole
such that blood is not easily allowed to pass
through, GFR decreases.
 Plasma protein will increase in
glomerulus because blood can’t pass
through the glomerulus
 When Plasma Proteins increase in
the glomerulus, glomerular oncotic
pressure increases (remember, this
is an anti-filtering factor), this will
attract fluid back to the glomerulus.
FILTRATION FRACTION

Extent of fluid loss from the plasma

The extent to which plasma proteins are being
concentrated

This is the percent of plasma going to the
kidney that is filtered

NORMAL VALUES: 0.15 – 0.22
FF = GFR/Renal Plasma Flow
Review of Renal 1:
GFR = clearance of inulin
RPF = clearance of PAH
C= U V / P
As blood flows from the afferent to efferent side,
GLOMERULAR ONCOTIC PRESSURE GRADUALLY
INCREASES.
TUBULAR REABSORPTION

Reabsorption is said to be selective unlike
filtration

Tubular cells will have to select certain
molecules to be brought back to the body.
To understand the concept of reabsorption:
Let’s have a GFR = 125 min/ml
 Without reabsorption, urine output (UO)
would be 178 L/day and this is physiologically
impossible
 NORMALLY, UO IS 1-1.5 L/day so this simply
means that substances have to be brought
back to the body.
The blood flows from afferent arteriole to efferent
arteriole and in the glomerulus, filtration will occur. As
blood flows through the blood vessels in the
glomerulus, blood or plasma is filtered some will remain
in the glomerulus to go to the efferent arteriole.
If filtration fraction is 0.2, this simply means that 20% of
plasma is filtered and the other 80% went through the
efferent arteriole.
The higher the Filtration Fraction, the more
concentrated the plasma proteins become.
EXAMPLE:
FF = 0.5 vs. FF = 0.2


If FF is 0.5, this simply means that 50% is
filtered and 50% went to the efferent arteriole.
Between 0.2 and 0.5, it is the blood with 0.5 FF
contains the higher amount of proteins
because there is a larger amount of water
removed.
Table shows the different substances commonly seen in
the plasma, the amount filtered, amount reabsorbed and
the percent of filtered load reabasorbed.


Glucose is 100% filtered and 100%
reabsorbed so in urine sample, GLUCOSE
SHOULD BE ABSENT
In electrolytes, they are not 100% reabsorbed.
Some will stay in the urine.
BASIC PROCESSES IN TUBULAR REABSOPRTION

Passive Transport
 Depends on electrical or
concentration gradient
 This is how H20, Chloride and urea
are being handled.
 Do not utilize energy
Escoto, KC // Gloriani, KP
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
Active Transport
 Needs ATP
 Involves three processes

QUANTIFICATION OF REABSOPRTION
THREE PROCESSES OF ACTIVE TRANSPORT
1.
Transport Maxima (TM)
 Carrier dependent transport modes
 Substances handled by transport
maxima:
i. Glucose (SGLT, GLUT)
ii. Amino acids (Na-Amino
acid transporters)
iii. Phosphate (PO4), Sulfate
(SO4)
iv. Vit. C
v. Malate, lactate, acetoacetate, β-hydroxybutarate
 Properties of carrier mediated
transport are exhibited:
i. Saturation – all of the active
sites are filled up by
substrate
ii. Competition/inhibition – an
inhibitor can decrease
transport rate
iii. Specificity – a transporter
can only transport specific
molecule
CLINCAL APPLICATION
When you have DM, blood sugar goes up as high as 300 500 mg/dL. Glucose transporters (SGLT and GLUT) are
saturated. If the carriers are saturated, the rate of
transport becomes constant at maximum rate. Even if
the concentration of glucose increases, transport rate
will still be the same because transport maxima is
reached.
Any excess glucose that is not accommodated by
carriers will go out in the urine = GLUCOSURIA
2.
Gradient-time limitation
 Depends on the gradient established
and the time the fluid is in contact
with the epithelium
 HCO3
and
Na
are
actively
transported this way.
High concentration gradient = Faster rate of transport
especially for HCO3 and Na.
When the flow of the filtrate is fast, rate of reabsorption
is low because there is less time for the fluid to be in
contact with the tubular cells. Slower flow means more
time for the tubular cells to pick up ions
3.
Pinocytosis
 Simplest
 This is how small polypeptides are
being handled
When polypeptides are filtered, they
are pinocytosed by the cells
R = filtered – excreted
RX = (GFR x PX) – (UX x V)
GFR = Glomerular Filtration Rate
Px = Plasma concentration of the substance
Ux = Urine concentration of the substance
V = urine flow rate.
FACTORS AFFECTING TUBULAR REABSORPTION
1.
2.
3.
Flow rate
 If flow rate is fast = reabsorption rate
is slow
Osmotic pressure
 If the osmotic pressure of the filtrate
is high = reabsorption rate decrease
o This is because fluid goes to
the filtrate
Hormonal influence
 There is a wide variety of hormones
that will affect handling wide variety
of substances
o ADH = water
o Aldosterone = Na and H20
and a little bit of K
o ANP & Angiotnestin II =
Na and H20
o PTH, Vit. D & Calcitonin =
Ca and PO4
If the filtered load > excretion rate, net reabsorption has
occurred:

For example, the filtered load if plasma
glucose level is 200 mg/dL = the amount of
glucose present in the Bowman’s space will be
200 mg / dL so when you get a urine sample,
glucose will be zero.
o In this FL = 200 and the ER = 0 so FL
is greater, therefore glucose is
reabsorbed.
COMPUTATION FOR REABSORPTION RATE
*this is NOT the same with GRF formula so don’t be
confused*
R = Kf x NRF
Kf = filtration coefficient
NRF = net reabsorptive force; this are the Starling
forces
NRF = (PI + ∏C) – (PC + ∏I)
PI : interstitial hydrostatic pressure
∏C: peritubular capillary oncotic pressure
PC : peritubular capillary hydrostatic pressure
∏I: interstital oncotic pressure
Green texts = Pro
reabsoprtion factors
Red texts = Anti
reabsoprtion factors
Escoto, KC // Gloriani, KP
6 of 13
PI : interstitial hydrostatic pressure

due to the fluid present in the interstitial space

the point of reference is the fluid going back to
the blood; FLUID SHOULD GO BACK TO THE
BLOOD

An increase in interstitial hydrostatic pressure
(fluid in interstitial space is large),
reabsorption increases.
∏C: peritubular capillary oncotic pressure

due to the plasma proteins present in the
blood vessels

this will attract fluid back in the blood vessels
PC : peritubular capillary hydrostatic pressure

pushes fluid out into the interstitium

decreases reabsorption
∏I: interstital oncotic pressure

proteins present in the interstitial space will
attract fluid, so fluid will be going to the
interstitial space

decreases reabsorption
PROCESS OF REABSORPTION
Filtrate
Diagram: Basic process of reabsorption; mechanism which absorption take place.
This will help you understand the concept of how do we reabsorb.
1.
NORMAL VALUES
Reabsorption = Kf x NRF


Kf – filtration coefficient = 12.4 ml/min/mmHg
NRF = (PI + ∏C) – (PC + ∏I) = 10 mmHg
 PI : interstitial hydrostatic pressure =
6mmHg
 ∏C: peritubular capillary oncotic
pressure = 32mmHg
 PC : peritubular capillary hydrostatic
pressure = 13 mmHg
 ∏I: interstital oncotic pressure = 15
mmHg
Reabsorption = 12.4 ml/min/mmHg x 10 mmHg
Reabsorption Rate = 124 ml/min
URINE OUTPUT
2.
3.
4.
5.
Recall that the previous computation for GFR is 125
ml/min.
Our Reabsorption rate was 124 ml/min
If we SUBTRACT THE REABSORPTION RATE FROM
THE GFR, WE WILL NOW GET THE URINE FLOW
RATE (V). This is the one used for clearance equation.
Everything begins here.
6.
V = 1 ml/min
7.
Everything begins in the Na-K pump (3 Na out
& 2 K in).
a. Located at the basolateral side, the
Na-K pump brings 3 Na back into the
blood and 2 K into the tubular cell.
b. Since Na is ACTIVELY being pumped
out, the amount of sodium inside the
tubular cell decreases.
In the filtrate, there are tons Na present (145
mEq/L).
By concentration gradient, Na from the filtrate
in the tubules will enter the cell via a
transporter.
a. This transporter, other than Na, it
also transports another substance.
Example is substance X
 if substance X is glucose,
then that transporter is
SGLT2
 if substance X is an amino
acid, the this is a Na-Amino
acid transporter.
Na enters and GOES TO THE BLOOD via the
Na-K pump
Substance X enters.
a. Inside the cell, its concentration
increases
b. In the blood, since it is flowing, X in
the blood is less in amount.
By concentration gradient, Substance X enters
the blood via another transporter.
a. This transporter will facilitate the
transfer of X in the blood.
 If substance X is glucose
then this is GLUT2
Y will represent an anion, an example is
Chloride.
a. Once Na is reabsorbed, it will impart
positive charge on the blood side and
a negative charge on the filtrate side.
 This will drive an anion to
diffuse
through
and
reabsorbed back in the
blood (Passive transport)
Escoto, KC // Gloriani, KP
7 of 13
8.
9.
Na, Chloride, Substance X is reabsorbed.
a. This molecules will exert OSMOTIC
POTENTIAL, attracting water
Water will now be reabsorbed via OSMOSIS
Back-Leak *will be discussed in detail later*
 Sometimes, after reabsorbing a substance, the
substance can go back to the filtrate
 This is exhibited by the yellow arrow in the
diagram
TUBULAR REABSORPTION IN DIFFERENT
SEGMENTS OF THE NEPHRON
A.
PROXIMAL CONVULUTED TUBULE (PCT)
This is where majority of reabsorption occurs – 67% of
filtered H2O, Na, Cl & K.
Na-K pump located in the basolateral membrane is the
key element in proximal tubule reabsorption.

Early segment of PCT
o SGLT2, GLUT2
o Na-H antiport
o Na-amino acid symport
o Na-P symport
o Na-lactate symport
o H2O reabsorption
o Pinocytosis of CHON
Diagram:
Everything begins at the Na-K
pump. Na goes out to the blood
forming a concentration gradient
between the filtrate and the cell.
This will power the entry of Na. If
glucose enters with it then it is the
SGLT transporter (as seen in B).
Na will go to the blood again via
Na-K pump and the glucose will go
via the GLUT2 transporter.
In the first half of the PCT, Na is
mostly reabsorbed together with
HCO3 and organic solutes than
Chloride. This will cause a lower
concentration of glucose and
amino acids when it enters the late
PCT.

Late segment of PCT
o This is where Chloride and H2O will
be reabsorbed.
o Na-H antiport, Cl-anion antiport
o Paracellular NaCl reabsorption
o H2O reabsorption

Reabsored solute exerts
osmotic potential attracting
water.
Paracellular reabsorption of NaCl
Diagram:
1. Everything begins with the Na-K
pump. As Na goes into the blood,
this will drive Na-H exchanger /
Na-H antiport (NHE3).
2. This NHE3 will allow Na to
enter the tubular cell in exchange
for H+ to go out to the apical
surface.
3. In the filtrate, H+ will complex
with an anion.
4. The H-anion complex has
neutral charge so it can easily
diffuse to the tubular cell due to
concentration gradient.
5. Inside the cell, H-anion complex
will dissociate ( H+ and anion)
6. The dissocitated H+ from the
complex will be acted again by the
NHE3 (H+ is recycled)
7. Anion will go out of the cell in exchange for a Cl via the Cl-anion
antiport to maintain electrical neutrality.
8. The net transport of H+ and anion is zero (paikot ikot lang)
9. At the end, Na is reabsorbed and goes back into the blood via Na-K
pump.
10. Chloride has been reabsorbed and it will go into the blood via the K-Cl
symporter / cotransporter.
Looking at H20 Reabsoprtion

Around 67% of filtered
water will be
reabsorbed
Transcellular reabsorption of H20
WATER REABSORPTION ROUTE:
1. Transcellular route
2. Paracellular route
SOLVENT DRAG – sometimes
passages are large enough such
that solute can be reabsorbed with
water
Changes in Na reabsorption
influence H2O and solute
reabsorption
TAKE NOTE:
Filtrate entering the Loop of Henle is ISOTONIC or ISOOSMOTIC
B.
LOOP OF HENLE

Descending limb of LOH
o Water reabsorption ONLY (15% of
filtered H2O)
o Via Aquaporin1 (AQP1) in the thin
descending limb
Escoto, KC // Gloriani, KP
8 of 13

Ascending limb of LOH
o Only Solutes are reabsorbed (25% of
filtered NaCl)
o There are two segments:

Thin ascending limb –
passive reabsorption

Thick ascending limb –
active reabsorption
Passive reabsorption in the thin ascending limb
 Recall that in the descending limb, water is
removed via osmosis
 The concentration of the filtrate increases
 As it progress in the loop, and as it ascends in
the thin ascending limb, there high
concentration of solute that will drive
passive reabsorption.
Active reabsorption in the thick ascending limb
 NKCC2 is the important transporter
o Na-K-2Cl symporter
 Na-H antiport
 Claudin-16
 Transcellular, paracellular NaCl
reabsorption
4.
5.
7.
Cl will go to the blood via K-Cl cotransporter.
K has two fate:
 It can go to the blood: K-Cl
cotransporter
 It can go to the filtrate: K leak
channel (back leak)
When K goes back to the filtrate, the filtrate
becomes positively charged
The positive charge in the filtrate will drive the
reabsorption of other cations through
CLAUDIN-16
 Remember that the positive charge of
the filtrate is the IMPORTANT
driving force for several cations (Na,
K, Ca++ & MG++) to be reabsorbed
through this channel.
 This is paracellular pathway
C.
DISTAL CONVULUTED TUBULE (DCT)

Early segment of DCT
o Reabsorption of Na, Cl and Ca
o 8% of filtered NaCl
o Na-Cl symport
o Water is not reabsorbed /
impermeable to water
6.
NKCC2
CLAUDIN-16
The Ascending limb of LOH and early segment of
DCT are the DILUTING SEGMENTS OF THE NEPHRON.
Through this segments solutes are only
reabsorbed
So if solutes are taken out, water is only left in
the filtrate so that is why the diluting segment.
Figure: transport mechanisms for reabsorption in the thick ascending limb of LOH
1.
2.
3.
Everything begins with the Na-K pump,
creating a Na gradient that will power the
NKCC2 transporter.
Na enters together with two Cl, and one K ions.
 Four ions are reabsorbed through
this transporter
Na again will go to the blood via that Na-K
pump

Late segment of DCT and Collecting Tubule
o Final modification of urine
o This segments are responsive to
hormones:

ADH – water reabsorption
in the DCT and CT increases
up to 8 -17%

Aldosterone – if present,
modification of K &
Escoto, KC // Gloriani, KP
9 of 13
o
o
handling of H and HCO3
happens
Facultative reabsorption in these
segments because it needs the
presence of ADH for H2O
reabsorption
This is also composed of two cells:

Principal cells
 Primarily handles
Potassium
 Affected by
aldosterone
 Na-K pump-ENaC
 Paracellular Cl
reabsorption
 AQP2, AQP3,
AQP4

Intercalated cells
 Affected by
aldosterone
 K-H pump /
antiporter
 H pump
5.
This concentration gradient is greater than the
amount of K in the filtrate so it goes now to the
filtrate.
Hyperaldosteronism will cause the patient to have
hypokalemia because K keeps on going out on the
urine.
How do intercalated cells work in the presence of
Aldosterone?
1.
2.
3.
4.
For every K that enters from the filtrate, H will
go out to the filtrate.
If aldosterone is present and the activity of the
Na-K pump increases, more K goes out.
And if more K is present in the filtrate, then
the K-H antiporter can reabsorb more K in
exchange for H+
H+ is excreted
Hyperaldosteronism will cause the patient to have
alkalosis because of the loss of H+.
So in summary, Hyperaldosteronism will manifest in
the patient as:
 Hypokalemia
 Alkalosis
TUBULAR SECRETION
This is similar to reabsorption BUT OPPOSITE IN
DIRECTION.

How do principal cells work in the presence of
Aldosterone?
1.
2.
3.
4.
Aldosterone increases the number and activity
of Na-K pump
If the pump activity increases, more Na is
reabsorbed and more K is pumped into the
cell.
Because of this, more Na is reabsorbed from
the filtrate then it goes into the blood
For K, its concentration gradient inside the cell
increases due to the increased activity of the
pump
Any substance ↑ concentration to a greater
extent than does inulin is secreted
o Example that if there is a particular
substance and a urine sample is
obtained, if its urine concentration is
greater than inulin but they have the
same plasma concentration, then this
substance is said to be excreted.
BASIC PROCESSES IN TUBULAR SECRETION
1. Active secretion

energy / ATP dependent
2. Passive secretion

Not energy / ATP dependent

Process is DIFFUSION TRAPPING
Two types of Active Secretion
1. Transport Maxima

Utilizes transporters / carriers

Substances handled by transport
maxima:
i. Carboxylic, sulfonic acids,
hippurate, creatinine,
penicillin, thiazide,
glucoronides, urological
contrast
ii. Organic bases, guanidine,
thiamine, choline, histamine
Escoto, KC // Gloriani, KP
10 of 13
2.
Gradient-time limitation

Depends on the concentration
gradient and flow rate

Substances handled:
i. H+
ii. K+
DIFFUSION TRAPPING

A passive secretion process

Substances handled:
i.
Weak bases, quinine, quinacrine,
procaine, chloroquine, NH3
ii.
Weak acids, salicylic acid,
phenobarbital
BASIC PROCESS OF SECRETION
6.
Charged particles can’t cross the cell
membrane so this negatively charged particles
can’t cross so it will be excreted.
a. this is DIFFUSION TRAPPING
For Weak Base:
1. If you have, NH3 (Ammonia)
2. The weak base can easily cross the membrane
because it is neutral
3. However, when it reaches the filtrate side, it
will encounter a H+
4. H+ binds to the weak base making the
molecule positively charge.
5. After binding to a molecule, it can’t cross the
membrane thus it is secreted and excreted
CLINICAL APPLICATION
Filtrate
Diagram: General mechanism for secretion
1.
2.
3.
4.
Everything begins with a pump
 It does not have to be the Na-K pump
At any case, Na is transported to the blood in
exchange of substance X
Substance X in the blood will increase in
concentration
Substance X can go into the filtrate via another
transporter
 A classic example is K. So when K is
secreted, a pump will bring K into the
cell (Na-K pump) then it goes out into
the filtrate.
Management of Salicylate toxicity: (too much aspirin
during failed suicide attempt)

Too much aspirin will make the patient
experience metabolic acidosis

If salicylates are high in the blood, intravenous
HCO3 is given.

By giving HCO3, it will be filtered

As salicylates diffuses through the cell
membrane going to the filtrate side, it will
encounter the HCO3

It will give off its H+ becoming negatively
charged then it can’t cross the membrane

Salicylates are now secreted then secreted.
TUBULAR SECRETION IN THE DIFFERENT
SEGMENTS OF THE NEPHRON
A.
PROXIMAL CONVULUTED TUBULE

Na – H antiporter
i. Everything begins with a
Na-K pump powering the
secondary active transport
PASSIVE SECRETION

Handling of weak acids, weak bases and some
anti-malarial drugs

Refer to the diagram above for discussion
For Weak Acid:
1. Acid in the blood is neutral and it can easily
cross the cell membrane and it will go out into
the filtrate
2. Once in the filtrate, the weak acid will
encounter a filtered HCO3 ion
3. Once HCO3 is present, the acid will give of its
H+
4. H+ will go the HCO3 to be buffered
5. Acid now becomes negatively charged and it
can no longer cross the cell membrane.
Escoto, KC // Gloriani, KP
11 of 13

Secretion of organic cations
i.
Creatinine, dopamine, epinephrine,
norepinephrine
ii.
Cationic drugs, toxins
1.
2.
3.
4.
5.
6.
7.
Diagram: How organic cations are secreted
1.
2.
3.
4.
5.

Everything begins with Na-K pump imparting
a negative charge within the cell
 This is because 3 positively charge
Na ions goes out compared to taking
in 2 positively charge K ions
The negative charge inside the cell will attract
a cation from the blood
A cation can easily diffuse through or be
transported via organic cation transporter
(OCT)
The number of organic cations in the cell
increases; fewer organic cations in the filtrate
making a concentration gradient empowering
the organic cations to go to the filtrate
The organic cations can now go into the
filtrate via two transporters:
 OCTN
 Multi drug resistant protein 1
(MDR1)
8.
Everything begins with Na-K pump.
 More Na out, less Na inside the cell
 This will empower Nadicarboxylate transporter
Na now a tendency to come inside the cell via
NaDC transporter
As Na enters, NaDC transports along αketoglutarate with it.
The amount of α-ketoglutarate increases
inside the cell and less in the blood
 This will power Organic Anion
transporter (OAT1,3)
This OAT1,3 will now transport αketoglutarate back into the blood in exchange
for an organic anion.
 So basically, α-ketoglutarate is just
going back and forth from blood to
cell
The net effect is that Na is reabsorbed and
organic anion enters the cell.
Inside the cell, the anion concentration
increases and less is present is in the filtrate
 Another concentration gradient
This will drive the anion to go into the filtrate
via:
 Organic anion transporter 4
(OAT4)
 Multi-drug resistant protein 2
(MRP2)
B.
LOOP OF HENLE

Secretion ONLY occurs at the thick
ascending limb

Na-H antiporter
C.
LATE DCT and COLLECTING DUCTS

Aldosterone

Principal cells
i. Na-K pump-ENaC

Intercalated cells
i. K-H pump
ii. H pump
Secretion of organic anions
i.
cAMP, cGMP, hippirates, urates, bile
salts, oxalate, PGE, PGF, ascorbate,
folate
ii.
Anionic drugs, toxins
Diagram: How Organic anions are secreted.
This is discussed on the part of reabsorption of DCT
so go back to it.
Escoto, KC // Gloriani, KP
12 of 13
QUANTIFICATION OF SECRETION
S = excreted – filtered
SX = (UX x V) - (GFR x PX)
So secretion is the amount secreted minus the amount
filtered. *binaligtad mo yung formula ng reabsorption*
If the filtered load < excretion rate, net secretion has
occurred
REVIEW:
If the filtered load > excretion rate, net reabsorption has
occurred and R = filtered – excreted
SUMMARY OF FORMULAS FOR REABSORTION AND
SECRETION RATES
Filtered load = GFR x PX
Excretion rate = V x UX
R = filtered – excreted
S = excreted – filtered
GFR = Kf x EFP(starling forces)
V = Filtration Rate – Reabsorption Rate
GLOMERULARTUBULAR BALANCE
 An increase in reabsorption rate with an
increase in filtered load
 If you increase the filtered load, reabsorption
rate is also increased BUT PERCENT
REABSORBED REMAINS THE SAME
 This will prevent the overloading of the distal
segments with an increase in GFR
o Most particularly for Na because if
GFR is increased, the filtered load of
Na also increases and in the late
portion of LOH, there is the macula
densa
o It is sensitive to Na concentration
and this glomerulartubular balance
will prevent large changes in fluid
flow going to the distal segments by:

BP

Disturbances that would
create problems in the
maintenance of Na and
volume homeostasis
Example:
Na is 99% reabsorbed.
Filtered load is 100 Na units (100 units of Na is filtered)
How much Na is reabsorbed?

99 units of Na
Base on glomerulartubular balance, if filtered load is
increased, reabsorption rate increases. This is
exemplified in this example:
Filtered load is 1000 Na units (1000 units of Na is
filtered)
How much Na is reabsorbed?

990 units of Na because 99% is still the %
reabsorbed.
IT IS ONLY THE REABSORPTION RATE THAT IS
CHANGING NOT THE PERCENT REABSORBED DESPITE
THE CHANGE IN FILTERED LOAD.
Escoto, KC // Gloriani, KP
13 of 13
FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Muscle Physiology
June 16, 2014 Section 1D
INJURY/DAMAGE TO THE NERVE
- Results to death or degeneration
- Some can undergo regeneration mostly
happening in the PNS (about 1mm per day)
o Growth factors
o Plasticity (in the CNS) – remodeling of
neurons but alters the behavior of the
neuron
**Problems in the reflex arc = problems w/
sensation and problems in the response of the body
to changes in the env’t
MUSCLE PHYSIOLOGY – physiology of effectors
particularly of the skeletal muscles
Motor neurons/somatic nerves: control the activity
of skeletal muscles
Neuromuscular/neuromyal/myoneural junctions:
terminal end of the motor nerve and the muscle; also
considered as a synapse
*Motor nerves originate from the
ANTERIOR/VENTRAL HORN of the spinal cord.
The anterior horn is responsible for generating the
impulses of action potentials transmitted by the
motor nerves towards the muscle, therefore
activating the muscle making it undergo
CONTRACTION.
*When the motor nerve is destroyed, the muscle
undergoes paralysis.
*Impulses activating the ventral horn come from
the cerebral cortex [primary motor cortex in the
frontal lobe: FRONTAL AREA IV/pre-central
gyrus] via the corticospinal tract. When motor
nerves are activated, entry of extracellular Ca++
ions is observed resulting to the release of
neurotransmitters towards the neuromyal
junction (REMEMBER NERVE PHYSIOLOGY).
•
Motor unit - motor neurons connected to the
muscles via the muscle fibers
MUSCLE TISSUE ORGANIZATION
1. Muscle bundle – made up of muscle fascicles
covered by the EPIMYSIUM
2. Fascicle – bundle of fibers covered by
PERIMYSIUM
3. Muscle fibers – muscle cell; bundle of myofibrils
covered by ENDOMYSIUM/SARCOLEMMA
4. Myofibrils – made up of sarcomeres
5. Sarcomere – made up of interdigitating
myofilaments; arranged IN SERIES
-
The muscle serves as the post-synaptic area. The
communication is mostly chemical.
- ACETYLCHOLINE: major neurotransmitter
- NICOTINIC RECEPTORS: predominant receptors
a. Nicotinic 1 [N1] – present in end-plate
b. Nicotinic 2 [N2]
•
End-plate potential – local potential in
muscles; happens when the muscle is exposed
to a subthreshold potential leading to muscle
contraction
DULAY, AC
1 of 4 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Muscle Physiology
June 16, 2014 Section 1D
MYOFILAMENTS
1. Actin – thin filament
- series of G actin molecules; directly attached to
the Z disc by actinin and cap Z
2. Myosin – thick filament
- series of light and heavy meromyosin
- held in position at the center of the sarcomere
by titin by firmly connecting the Z disc to the M
lines
Z disc – boundary of the sarcomere
M line – center line of the sarcomere
SLIDING FILAMENT MODEL OF CONTRACTION
shortening of the muscles as an effect of
muscle activation resulting from the ‘sliding’ motion of
the actin filaments
titin is a collapsible protein allowing actin to
slide towards the M line >> shortening of sarcomere
- during relaxation, actin moves back to its original
position
*The muscle does not lengthen when it relaxes, it only
returns to its RESTING LENGTH.
*When the muscle is inactive (polarized), it is
RELAXED. There is no interaction seen between actin
& myosin because the TROPONIN-TROPOMYOSIN
COMPLEX blocks the myosin-binding site present on
the actin filament.
*Intracellular Ca++ ions are required to expose the
myosin-binding sites
*Muscle activation causes the release of stored Ca++
ions and they will bind with the troponin molecule,
specifically Troponin C, moving the troponintropomyosin complex exposing the myosin-binding
sites.
DULAY, AC
*Myosin, utilizing the myosin heads, can now
interact with the actin filaments by pulling the
actin towards the center of the sarcomere
developing POWER STROKES or the swiveling
motion of the myosin heads requiring the
breakdown of ATP
IN NORMAL CONDITIONS…
Myosin filaments are normally surrounded by six
(6), regularly arranged actin filaments
There are about 600 myosin heads per thick
filament
One myosin head can interact with almost two (2)
actin molecules (1:1.8)
When the muscle is stimulated and there is
maximal stimulation, not all myosin heads are able
to interact with the myosin filaments; only 2040% of the total myosin heads interact with the
myosin filaments during maximal activity of the
muscle
TROPONIN-TROPOMYOSIN COMPLEX
Troponin
1. Troponin I – when the muscle is inactive, it
allows the troponin-tropomyosin complex to
stay on top of the myosin-binding sites
2. Troponin C – molecule that interacts with Ca++
ions
3. Troponin T – responsible for the firm
attachment of the tropomyosin to the actin
filament
If Ca++ ions are released from the muscle and
interacts with Troponin C, it decreases the
inhibitory function of Troponin I.
2 of 4 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Muscle Physiology
June 16, 2014 Section 1D
Ca++ sensing receptors present in the
sarcotubular system – control the activity
of voltage-gated Ca++ channels in the
cisterns
1. Dihydropyridine receptors – transverse tubules
2. Ryanodine receptors – sarcoplasmic cisternae
•
Muscle twitch: simplest response of a muscle
towards a single stimulation; contractionrelaxation of a muscle
MUSCLE CONTRACTION
•
Normal or healthy motor nerves control the
activity of the skeletal muscle. When the nerve is
activated, an action potential is generated that
activates the muscle. The end-plate of the sarcolemma
of the muscle fiber receives the activity.
•
Motor nerves release Ach, a chemical agent,
that interacts with the nicotinic receptors present on
the end plate. Ligand-gated Na+ channels are activated
upon muscle activation. End-plate potential, therefore,
is developed and this can undergo summation if there
is continuous transmission of Ach towards the endplate, eventually generating an action potential.
•
The TRANSVERSE TUBULES & the
SARCOPLASMIC RETICULUM (SARCOTUBULAR
SYSTEM) are the conducting structures of the muscles
used to transmit the action potentials from the endplate to the myofibrils.
•
T-tubules are connected to the sarcolemma.
The invaginations of the sarcolemma allow the action
potentials to enter the T-tubules. The T-tubules are
directly connected to the SR as well. The sarcotubular
system is directly in contact with the sarcomeres.
•
Upon entrance of the action potentials in the
T-tubules, the terminal end/CISTERN of the SR is
activated. Ca++ ions are found at the cisternae.
Interaction of myosin heads with actin filaments is
termed as CROSS-LINKAGE FORMATION. This allows
the myosin heads to develop power strokes. The
muscle develops tension therefore.
**When a muscle develops force, it also develops
tension.
DULAY, AC
STAGES
1. Latent Period – development of action
potential; corresponds to the absolute refractory
period of the action potential; muscle is not
excitable
Calsequestrin: protein responsible for holding onto
the Ca++ ions in the sarcoplasmic cisternae when
the muscle is inactive. Once action potentials reach
the terminal ends of the SR, calsequestrin activity
decreases causing them to let go of the Ca++ ions
that will initiate muscle activity. Effective
transmission of action potentials are made possible
by the TRIAD arrangement of the T-tubules and
SR, where one T-tubule is bound by two
sarcoplasmic cisternae.
Decreased activity of calsequestrin allows the Ca++
ions to move towards the actin filament where the
TropC is, thus removing the inhibitory effect of
TropI thereby developing power stroke. Note that
energy is required for this activity. ATP is normally
stored in the myosin heads in the muscles. The
myosin heads also possess the enzyme ATPase.
2. Contraction Period – muscle is at the relative
refractory period; muscle is back to normal
excitability in the later part of the contraction
period
• Tetanic contraction: muscle is stimulated
while it is still in the contraction period
• Incomplete tetanus: let the muscle undergo
relaxation before applying a second stimulus
3 of 4 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Muscle Physiology
June 16, 2014 Section 1D
3.
Relaxation Period
When muscles relax, they simply return to resting
length. The energy in the muscle is stored in the
myosin heads. The cessation of the action potential
will allow the calcium ions’ release to move away
from TropC. TropI activity increases that results to
the covering of the myosin-binding sites by the
troponin-tropomyosin complex, ending the myosinactin interaction. Ca++ ions return to the cisterns. This
requires energy since it is an active transport. They
are pumped backed to the terminal cisterns using the
Ca-Mg ATPase. The antiporter used is Sarcoplasmic
Endoplasmic Reticulum Calcium ATPase (SERCA).
DULAY, AC
4 of 4 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Muscle Physiology Part 2
June 22, 2014 Section 1D
SERCA: responsible for returning Ca ions back to the
terminal cisterns
- Ca++ pump, requires energy
SARCOMERE STRUCTURE
A band: dark bands; total length of the myosin
filament including the peripheral ends with actin
filaments
I band: light band; 2 adjacent sarcomeres devoid of
myosin
H zone: area not having actin, purely myosin
*It is the I band and the H zone that undergoes
shortening
**Mg+ is required for the immediate hydrolysis of
ATP during the development of power strokes/crossbridge formation.
**A resting muscle utilizes ATP to maintain RMP
(Na-K exchange pump).
Rigor mortis: Permanent formation of actin-myosin
complex after death
Continuous ATP expenditure = continuous production
of heat
1. Resting heat – generated at rest; Na-K exchange
pump
2. Initial heat – heat produced in excess of resting
heat during contraction
- Activation heat
- Heat of shortening
3. Recovery heat – generated by the metabolic
processes that restore the muscle to its
precontraction state
4. Relaxation heat – extra heat in addition to
recovery heat produced when a muscle returns
to its resting length
Heat production is greatest during muscle
contraction.
Latent period – ARP
Contraction period – RRP; muscle is excitable
Relaxation period – back to normal excitability
DULAY, Arman Carl
TETANUS: muscle responding while it is in the
period of contraction; a form of temporal
summation/wave summation/frequency
summation
- exposure of muscle to frequent stimulation
1. Incomplete – muscle is stimulated when it is
about to relax; periods of relaxation are
observed
- increasing frequency of stimulation
2. Complete – stimulating the muscle while in
the state of contraction; fused tetanus
- not allowing the muscle to relax
Tetanizing frequency: high frequency of
stimulation; frequent release of Ach = continuous
generation of end-plate potentials
QUANTAL SUMMATION: exposing muscles to
gradually increasing stimulus intensity >> gradual
increase in the magnitude of response
- graded response or multiple unit summation
- explained by recruitment of motor units
1 of 4 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Muscle Physiology Part 2
June 22, 2014 Section 1D
Size principle: recruitment starts with the slower,
weaker fibers and later on, the bigger, faster fibers
Maximum response = activation of all muscle fibers
TYPES of MUSCLE FIBERS
1.
Slow-twitch – initially activated; weaker,
small motor units
become more vascularized when frequently
stimulated
for stamina and endurance
The response of a slow-twitch fiber is already its
maximum response
2.
Fast-twitch – bigger, faster, stronger fibers
Hypertrophy: increase in size
Hyperplasia: increase in number of fibers
Angiogenesis: formation of blood vessels
Greater length-less tension…why?
Normally, an ideal space should be present in the
region of the myosin (M line) during rest. When
the sarcomere is stretched, actin filaments are
pulled away from each other (away from the
myosin filament). For the muscle to react, the
myosin heads should interact with the myosin
filamanets. Lesser myosin heads are able to
effectively interact with the actin filaments if
they are pulled away from each other. If there is
excessive stretch, actin filaments are really
moved away from myosin, the developed tension
is equal to zero.
Less length-less tension… why>
Overlapping of actin filaments is observed during
compression of the sarcomere. Some actin
filaments are covering other acting filaments.
The myosin heads are not able to interact with all
the available myosin-binding sites.
Maximal intensity: initial maximum response of a
muscle
Submaximal: summation is observed
Supramaximal: response is siimlar to maximal
LENGTH-TENSION RELATIONSHIP
Ideal length of the muscle = resting length
When muscle is stimulated at lesser ideal resting
length, there is less development of
tension/force/pressure
DULAY, Arman Carl
FORCE-VELOCITY RELATIONSHIP
As you increase the load, the velocity of muscle
response decreases.
Effect of increasing load to work performance:
A change in distance should be observed.
No load=no work
Lighter load=greater work
Increasing the load during maximum work will
result to decrease in muscle performance
2 of 4 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Muscle Physiology Part 2
June 22, 2014 Section 1D
Isometric: muscle contracting without load; no
change in length; static response; no work done; also
observed when trying to lift a very heavy load
Ex. Maintenance of posture
Isotonic: work performance during contraction with
a change in distance
a. Concentric: increasing work; lighter load
b. Eccentric: decreasing work heavier load
Isotonic contractions utilize more ATP but are more
efficient.
Isokinetic: constant rate of activity; essential in the
development of muscles
-
Dystropin: allow firm contact with intracellular
structures and extracellular components
present in the muscle fibers
maintains normal shape of muscle
loss of dystropin results to dystrophy: muscle
rupture
Fatigue: if there is continuous activation of the
muscle; muscle performance gradually decreases
- no change in frequency & intensity
Dev’t of Fatigue - Factors:
- there is a decrease of available energy source
- body’s protective response to limit muscle
activation and prevent injury
a. ATP
b. Creatin phosphate
c. Glycogen
- increase in body temperature
- increase of lactic acid concentration due to
anaerobic metabolism
- continuous activation of motor neurons
- TropC insensitivity
- Increase ADP
- Leaky channels: Ca & K out of the cell
- Lack of Ach
- Free radicals
*Treppe: increasing magnitude of
contraction with same intensity of stimulation;
pre-fatigue
Aerobic activities: utilizes glycogen and fats in the
presence of O2
Anaerobic activities: glycogen
DULAY, Arman Carl
3 of 4 FAR EASTERN UNIVERSITY – DR. NICANOR REYES MEDICAL FOUNDATION Physiology – Dr. F.C. Barbon
Muscle Physiology Part 2
June 22, 2014 Section 1D
DULAY, Arman Carl
4 of 4 Renal Physiology III: Regulation of Plasma and Water Volume, and
Osmotic Equilibrium and Optimal Ionic Balance in the Plasma
(Ronald Allan Cruz, MD)
Regulation of Plasma and Water Volume
Plasma and Water Volume
As what we’ve been discussing, the job of the excretory system is to
maintain homeostasis. This has a plasma osmolality of 282 mOsm/L. So
the job of the excretory system first and foremost is to maintain plasma
osmolality of 282 mOsm/L. With that, having a wide variety of intake in
the diet, it is now the job of the kidneys to conserve fluid and excretes
solutes. We’ve already mentioned that in the maintenance of homeostasis
what is more important is what we excrete, not what we take in so it is
the job of the kidneys is to excrete solutes.

Kidneys
o
Conserve fluids
o
Excrete solutes
o
50-1400 mOsm/L urine
o
Sp gr: 1.002-1.400
o
UO: 0.5-1 ml/kg/min

Blood: 5L
o
Plasma: 3L

282 mOsm/L
o
Formed elements: 2L
plasma osmolality is isotonic, but the blood volume is low, ADH will still
be released.
The job your ADH is for water reabsorption particularly in the
DCT and collecting ducts. It promotes the synthesis of aquaporins for
water reabsorption but other than aquaporins, there are also other
transport mechanisms that will increase. You have your UT-A1, UT-A3 so
these are your urea transporters, your NKCC2 (sodium-potassium to
chloride transporter), sodium-chloride symporter, and ENaC (epithelial
sodium channel). All of these will promote solute reabsorption and with
solute, water will go along with them.
In the antero-ventral portion of the 3rd ventricle, this is where
your osmoreceptors reside so they will indirectly detect plasma tonicity.
When plasma tonicity increases, it will affect the tonicity of the
cerebrospinal fluid such that water within the CSF will go out into the
vascular compartment so the tonicity of CSF increases. Your CSF
surrounds the omoreceptors so when its tonicity increases, water inside
the osmoreceptors will go out and the osmoreceptors will shrink. When
your osomoreceptors shrink, they will now stimulate your supraoptic and
paraventricular nuclei for the synthesis of ADH and they will stimulate
your posterior pituitary for the release of ADH.
Other important receptors found in within the vascular system,
you have your baroeceptors and your cardiopulmonary reflex whose job
is to detect blood volume or pressure. Other important structures in the
CNS, you have your subfornical region and organum vasculosum of
lamina terminalis and their primary function is to regulate thirst.
Here you have the range of urine osmolality, it could be as low
as 50 mOsm/L so that’s a dilute urine, having a specific gravity of 1.002 or
it can be concentrated having an osmolality of 1,200-1,400 mOsm/L and a
specific gravity of 1.400. With specific gravity, this is a comparison of the
solute concentration of a particular fluid with plasma so if the specific
gravity of a fluid is 1, it is identical with plasma.
This is your urine now and with the function of the kidney,
urine output averages to around 0.5-1 mL/kg/min. So the job of the
kidney is to conserve fluids and excrete solutes so that plasma osmolality
is maintained at 282 mOsm/L.
Antidiuretic Hormone




Produced in the supraoptic nuclei and paraventricular nuclei
Released by the posterior pituitary
o
↑ plasma tonicity
o
↓ blood vol
↑ H2O reabsorption
o
 AQP2
o
 UT-A1, UT-A3, NKCC2, Na-Cl symporter, ENaC
AV3V
o
Osmoreceptors
o
Median preoptic nucleus

Baroreceptors, cardiopulmonary reflexes
o
Subfornical region
o
Organum vasculosum of the lamina terminalis
One of the more important hormones that will control
osmolality or plasma osmolality is your ADH or antidiuretic hormone
produced in the supraoptic and paraventricular nuclei within the
hypothalamus. Your ADH now via your axonal transport will go to the
posterior pituitary for storage and release. So the site where ADH
synthesis occurs is within the hypothalamus but storage is in your
posterior pituitary and so is its release. The two stimuli that will trigger
release of ADH is at least 1 percent increase in plasma osmolality or a 10%
decrease in blood volume or blood pressure. On a day to day basis, plasma
osmolality supersedes blood volume. Just like now, under physiologic
conditions, the release of ADH is more sensitive with regard to increase in
plasma tonicity so if the plasma osmolality increases, ADH is released.
However during pathologic states like shock or haemorrhage, a drop in
blood volume supersedes plasma osmolality. Meaning to say, even if
1
Shannen Kaye B. Apolinario, RMT
So here you have your hypothalamus. When magnified, you
have your osmoreceptors. Once plasma tonicity increases, CSF tonicity
increases, osmoreceptors will detect tonicity. They will now stimulate
supraoptic and paraventricular nuclei for the synthesis of ADH and
subsequent release of ADH from posterior pituitary. ADH now is released
targeting DCT and collecting ducts for the reabsorption of water. Take
note also you have your baroreceptors and cardiopulmonary receptors
that will in turn stimulate your supraoptic and paraventricular nuclei.
In this table, you have here the stimuli that will either increase
or decrease ADH release. So for ADH release, 1% increase in plasma
osmolality or at least a 10% drop in blood volume or blood pressure. In
the decrease for ADH, it is the opposite. You also have various drugs that
will either increase or decrease ADH release.

ADH: regulates plasma osmolality
ADH promotes reabsorption of water, aldosterone promotes
reabsorption of sodium. This is a common misconception among medical
students that because ADH reabsorbs water, students would initially
think it will regulate volume. Since aldosterone reabsorbs solutes, it will
regulate tonicity. Actually, it is the opposite. The job of ADH is to regulate
tonicity and the job of aldosterone is to regulate volume. Why? The
primary stimuli for ADH is an increase in tonicity so we need to reabsorb
water in order to bring tonicity back to 282 mOsm/L, it is its only job. The
job of aldosterone is to reabsorb solutes but together with solutes, you
have corresponding reabsorption water so basically you are reabsorbing
isotonic fluid. So ADH regulates tonicity whereas aldosterone
regulates volume.
A. This is plasma osmolality plotted against plasma ADH. Take
note that when plasma osmolality is 280 or 282 mOsm/L less, release of
ADH is zero. However, beyond 280 or 282 mOsm/L, as you increase
plasma osmolality, ADH secretion increases.
In this diagram, here you will take note the action of ADH when
water intake is low. So when water intake is low, plasma tonicity
increases stimulating now the osmoreceptors. Your osmoreceptors will
then trigger ADH release and together with that, you have stimulation for
thirst. Your ADH will target the DCT and collecting ducts for the
production of aquaporins as well as production of other transport
mechanisms promoting reabsorption of urea and solutes like NaCl. You
now promote water reabsorption so with that; you have an increase in
urine osmolality and a decrease in urine volume. Water is retained in the
body therefore plasma osmolality goes back to normal offsetting the
initial condition.
Consequently, if you have increased water intake, plasma
osmolality goes down. Stimulation going to the osmoreceptors is cut off
therefore osmoreceptors are not stimulated, you do not release ADH, you
decrease the production of aquaporins therefore water is not reabsorbed;
it goes out into the urine. Urine therefore will have a decrease in
osmolality (dilute urine) and an increase in urine volume. Consequently,
plasma osmolality goes back up to normal offsetting the initial condition.
2
Shannen Kaye B. Apolinario, RMT
B. This is percent change in blood pressure/volume plotted
against ADH release. Take note that if you have zero change in pressure
or if pressure increases, ADH release is zero. However, if pressure or
volume drops, ADH release increases accordingly.
Looking at this graph, you have plasma osmolality and ADH
release. The green line is the same as this one (red line in the graph
above) and it is 280 or 282 mOsm. Above 280 or 282 mOsm, ADH release
increases. In this graph however, this will show to us the effect of chronic
changes in blood pressure. When we have chronic changes in blood
pressure, the set off point for ADH release adjusts. If you look at the red
line, here you have chronic 10% decrease in pressure or volume – chronic
hypotension. Take note that the set off point is from 280 to 270, it went
down. At 270 below, ADH release is zero but greater than 270, ADH
release increases. The same is true for chronic hypertension; here you
have a 10% chronic increase in volume or pressure. The set off point is
from 280 to 290, so it increased. Below 290, ADH release is zero, above
290, ADH release increases.
1
2
Looking at diabetes insipidus, you have two types: central
and nephrogenic. When you say central DI, there is a decrease in ADH.
The more common pathology would be a decrease in neurophysin.
Neurophysin shuttles the ADH from the hypothalamus to the pituitary
gland (its like a school bus) so if there is a decrease in neurophysin, ADH
will not be transported to the posterior pituitary therefore it will not be
released. For nephrogenic DI, ADH may be present, the receptors are
absent. Even if you have ADH but no receptors, still, water cannot be
reabsorbed. For your central and nephrogenic, symptomatology would be
similar – polydipsia and polyuria. Why is there polydipsia? Because
plasma tonicity is always high, stimulating the thirst center. Why is there
polyuria? Because you cannot reabsorb water and water will be excreted.
Thirst


In this diagram, this will show to us the action of ADH in the
tubular cell. So this you have your filtrate, tubular cell in the DCT or in the
collecting duct, interstitium or blood. 1. Here you have ADH, it will attach
to V2 receptor. When activated, it is coupled with G protein activating
now your adenylyl cyclase. That increases your cAMP, activating protein
kinase A. Protein kinase A will facilitate exocytosis of aquaporin 2 as
represented by the circles.
2. Here you have exocytosis of aquaporin; your AQP2 is now
incorporated on the luminal side of the membrane. It is not shown here
but in the basolateral surface, you have AQP 3 or 4 which are always
there. So your AQP 3 and 4, this is constitutively produced, meaning to
say, it is always there. But your aquaporin 2, they are regulated
depending on the presence of ADH. With that, water will be reabsorbed
going through aquaporin 2 from luminal side then it will go into the blood
via aquaporins 3 and 4. When ADH is absent, there is the endocytosis of
aquaporin channels on the luminal side. Aquaporins can either be
degraded or they may be recycled.
•
SIADH
o
 ADH

H2O retention

Hypoosmotic body fluids

Hyperosmotic urine
•
Nephrogenic syndrome of inapproriate antidiuresis
o
 V2 receptor activation
o
 ADH
•
Diabetic insipidus
o
 ADH: central

 neurophysin
o
 V2 receptors: nephrogenic

AQP2
o
Polydipsia, polyuria
Looking at several disorders, you have Syndrome of
Inappropriate Antidiuretic Hormone (SIADH). Here you have an increase
in ADH. Because of that, you have water retention therefore you have a
hypoosmotic body fluid – low tonicity and a hypertonic osmotic urine –
concentrated urine.
In nephrogenic syndrome of inappropriate antidiuresis,
this is where you have an increase in V2 receptors. So even though ADH is
absent, your receptors are always active resulting to continuous
stimulation of adenylyl cyclase producing aquaporins and continuous
reabsorption of water. You will note that for nephrogenic syndrome of
inappropriate diuresis, since you have continuous production of
aquaporins and continuous reabsorption of water, manifestation will be
similar as SIADH so the plasma is hypoosmotic and urine is hyperosmotic.
Take note both will have similar manifestations but their etiologies are
different.
3
Shannen Kaye B. Apolinario, RMT



2-3%  plasma osmolality
10-15%  bood vol or pressure
o
Thirst threshold > threshold for ADH secretion

Thirst: 295 mOsm/kg H2O

ADH: 285 mOsm/kg H2O
Angiotensin II:  thirst
+ oropharyngeal, upper GIT receptors:  thirst
Correction of plasma osmolality, blood vol and pressure: 
thirst
For your thirst mechanism, the thirst center is stimulated
when you have a 2-3% increase in plasma osmolality or a 10-15%
decrease in blood volume. So take note that the threshold for thirst is
higher than the threshold for ADH release. Here you have tonicity for
plasma that will stimulate thirst. This is the tonicity of plasma for ADH
release so if you could notice, thirst is higher compared to ADH release.
Practical application is that if you feel thirsty, this simply means that ADH
release has already occurred.
Other important stimuli for thirst, you have angiotensin II so
that increases thirst, stimulation of oropharyngeal and upper GIT
receptors will decrease thirst. Notice that if you feel thirsty and you drank
water, water is not yet absorbed by the gastrointestinal tract but you
don’t feel thirsty anymore and this is your oropharyngeal and GI
receptors.
Coke Story: this is where your soda will be
backing on its marketing strategy. If it is hot and you
feel thirsty, it very appetizing to drink an iced cold
coke. You drank Coke and you feel satisfied - you are
not thirsty anymore. But mind you that Coke
contains solutes. Later on you will notice that you
feel thirsty again and you will drink Coke again.
Because of this physiologic phenomenon, Coca-Cola
is getting richer and richer :D
Correction of plasma osmolality and blood volume and
pressure decreases thirst.
Reabsorption of Water





PCT - 65% of H2O is reabsorbed
LOH: descending limb – 20% of H2O is reabsorbed
LOH: ascending limb – solutes are reabsorbed
DCT – H2O permeability is ADH-dependent
CT – H2O permeability is ADH-dependent


Plasma: 282 mOsm/L
Urine: 50-1400 mOsm/L
Looking at the different segments of the nephron, in the PCT
here you have obligatory water reabsorption; next in descending limb,
only water is reabsorbed so that’s 20% of the filtered water; in the
ascending limb, solutes only are reabsorbed. Looking at DCT and
collecting ducts, the percentage of water reabsorbed varies depending on
the presence of ADH. Without ADH, water reabsorption is around 8% but
with the presence of ADH, it is as high as 13%. Of course, the job of the
nephron is to maintain plasma osmolality giving us a urine osmolality
that varies; it can either be concentrated or diluted.

Obligatory urine volume
o
Minimal vol of urine that must be excreted
o
Excretion: 600 mOsm/day
o
Concentrating ability : 1200 mOsm/L
o
600 mOsm/day / 1200 mOsm/L
o
0.5 L/day
Now let’s look at obligatory urine volume. This is the minimal
volume of urine that must be excreted. Remember that the job of the
kidney is to excrete solutes in order to maintain plasma tonicity. This
solute must be dissolved in some medium (or else you’ll be urinating rock
salt). It has to be suspended in a medium and this medium is your
minimal volume of urine so that’s your obligatory urine volume. How do
we get this? Let’s say you want to remove 600 mOsm from your body. The
concentrating ability of the kidney at maximum is around 1200 mOsm.
Why is it 1200 mOsm? Because it is the tonicity of the renal medulla. So to
get your obligatory urine volume, simply divide 1200 to 600 and you will
get 0.5 L. This simply means that within the day, if you want to remove
600 mOsm of solute, you need to remove 500 mL of fluid.
o
o
o
o
Sea water: 2400 mOsm/L
Concentrating ability : 1200 mOsm/L
2400 mOsm/day / 1200 mOsm/L
2L/day
Practical application: let’s say you quit medschool and have
decided to join Survivor. There’s no water and you decided to drink sea
water instead. You take in 1 L of sea water with a tonicity of 2,400 mOsm.
2,400 divided by 1,200 you will get 2 L. This simply means that to remove
your 2,400 mOsm, 2 L of fluid is excreted. Take note that you only took 1L
so this simply underlines the fact that if you drink hypertonic solutions,
you aggravate dehydration.

Countercurrent Mechanism
Concentrating the urine
o
ADH
o
Hypertonic renal medulla: 1200-1400 mOsm/L
 Countercurrent mechanism
 Recycling of urea
 Function of the vasa recta
Looking at the concentrating ability of the kidney, we’ve
already discussed ADH. With the action of ADH, water is reabsorbed
because via osmosis, the hypertonic medulla will attract water. The
question is: how does the medulla become hypertonic? The tonicity of the
medulla is around 1200-1400 mOsm. These are the mechanisms by which
we create a hypertonic medulla: your counter-current mechanism and
recycling of urea contributes to the tonicity of the medulla. Your countercurrent mechanism will add NaCl to the renal medulla contributing
around 600 mOsm. Urea which is a by-product of protein metabolism will
contribute another 600 mOsm in the renal medulla (600 + 600 =1,200).
These two mechanisms will create a hypertonic medulla. Your vasa recta
on the other hand will not create a hypertonic medulla but it will
maintain the tonicity of the medulla.
4
Shannen Kaye B. Apolinario, RMT
How do we create a hypertonic medulla? First you have
counter-current mechanism. This is your PCT, loop of Henle, DCT. Let’s
say everything is isotonic. Your filtrate will go from PCT to descending
limb. In the descending limb supposed to be, water will be reabsorbed but
water will NOT be reabsorbed because everything is isotonic. Then your
filtrate will go up into the ascending limb, in here you have active
reabsorption of solutes, you have your NKCC2 co-transport. Solutes are
reabsorbed. The tonicity of the medulla now increases. Batch 2 of filtrate
comes along. Since the tonicity of the medulla has increased, water is
reabsorbed. When water is reabsorbed, the tonicity of the filtrate goes up.
This batch, when it ascends the loop of Henle, since it is concentrated,
more solutes will be pumped into the interstitium. The first one to
increase will increase even further. Since the tonicity further increased,
when batch 3 comes along, more water will be reabsorbed, the tonicity of
the filtrate further increases, when it ascends more solutes will be
reabsorbed more than batch 2 and 1. You will notice that the tonicity of
renal medulla gradually increases until you established your osmotic
gradient.
Concentrating the Urine
Looking at this diagram, this is your loop of Henle, DCT,
collecting ducts. The blue background will represent renal interstitium
and you have the cortex which is isotonic and the medulla which is
hypertonic. The red structures will represent the vasa recta. Without ADH
water is simply excreted but with the presence of ADH as represented by
the yellow circles, water is reabsorbed, it goes into the interstitium and
then it will go into the vasa recta. You will note that water will not stay in
the renal medulla; it will go into the vasa recta. Why will it go to the vasa
recta? Because of plasma proteins. So water now exits your renal
interstitium, it goes back into the circulation via vasa recta maintaining
now the tonicity of the medulla. Take note the vasa recta will not
contribute solutes but it will maintain the tonicity of the medulla. Without
vasa recta, the water that has been reabsorbed will stay into the
interstitium diluting the renal medulla.
Recycling of Urea
like any capillary bed, this is where filtration will also occur such that
fluid will go from plasma it goes now into the interstitium because of
hydrostatic pressure and more so because of the tonicity of the medulla.
In your arterial side also, you have a small amount of solutes entering
your vasa recta. Now looking at the U-shaped configuration of vasa recta,
the amount of water that went out has the same amount of water that will
go back in. Why will it enter? Because of plasma proteins. When water
enters the venous side of vasa recta, that increases hydrostatic pressure
inside the vessel permitting the exit of solutes.



This is your loop of Henle, DCT, collecting ducts. The number in
front of you will represent concentration for urea. In the PCT and
descending limb of loop of Henle, water is reabsorbed therefore urea
concentration increases. Then it goes up in the ascending limb and into
the DCT. The DCT and the early portions of collecting ducts are
impermeable to urea as represented by the dark lines. It means that urea
is NOT able to permeate the cell membrane. It will just pass through and
the concentration is maintained. However, your ADH as represented by
yellow circles will promote reabsorption of water in DCT and collecting
ducts so water is reabsorbed and the concentration of urea increases.
Take note in the early portions of collecting tubule, it is impermeable but
once it reaches the medullary collecting ducts, your medullary collecting
ducts are now permeable now to urea so it can now pass through. Since
urea concentration has increased, you now have a gradient. Urea diffuses
out and it goes back into the ascending limb because of concentration
gradient. Then it goes up again going to DCT and collecting ducts. You will
notice that urea will just go around. Urea now contributes around 600
mOsm of solute in your renal medulla.
Practical application: patients with chronic protein
malnutrition have decreased urea production. Patients with protein
malnutrition will have weaker concentrating capability so their urine is
always diluted.


+ ADH
o
+ 600mOsm/L in the medulla
- ADH
o
Medulla < 1400 mOsm/L
The action of urea is mediated by ADH. Without ADH, you will
not be able to concentrate urea in the collecting ducts therefore you do
not have a gradient that will permit recycling of urea. So that’s the action
of ADH.
Vasa Recta
This is your arterial side and venous side. The numbers will
represent tonicity. when your vasa recta flows to the arterial side, just
5
Shannen Kaye B. Apolinario, RMT
U-shaped
Blood flow is low
Serves as countercurrent exchangers
o Minimizes solute loss
o ↑ medullary renal blood flow, ↑ solute washout, ↓
concentrating ability
Notice that the amount of solute that entered, the same amount
will exit. The amount of water that exited, the same amount of water will
enter. So that’s the importance of U-shaped vasa recta. If it were a straight
capillary bed, the water the water that went out cannot go back in so that
is why your vasa recta is U-shaped and it parallels the loop of Henle. This
serves as your counter current exchanger. It is called counter current
exchanger because when it acts in concert with your loop of Henle, they
are the only ones exchanging solutes. So your vasa recta now will
minimize solute loss in medullary interstitium. If you increase your
medullary renal blood flow, that increases solute wash out decreasing
now the concentrating ability of the kidney so you can just imagine if
blood flow is fast, solutes will be washed out faster so the tonicity of the
medulla decreases. If you will recall the very first lecture, it was
mentioned that the blood flow going to the renal medulla is sluggish.
Concentrating Ability of the Kidney

H2O diuresis
o
– ADH
o
Dilute urine
* Antidiuresis
- + ADH
- Concentrated urine
Looking at diuresis and anti-diuresis, this is a simplified
diagram. Your vasa recta here should superimpose your loop of Henle. In
the absence of ADH, we produce dilute urine, water stays in the tubules
and it exits. However with the presence of ADH we produce concentrated
urine. This will provoke water reabsorption and the water that went out
will go back into the vasa recta. It will go back into the circulation because
of plasma proteins. With that, you maintain the tonicity of the medulla
even if water is reabsorbed.



ADH
Corticopapillary osmotic gradient
o
Countercurrent mechanism
o
Recycling of urea
o
Role of the vasa recta
Hypertonic medulla
o
Active transport of solutes in the ascending limb of LOH
o
Active transport of ions form the CT
o
Urea
o
↓ osmosis from the medullary tubules into the
interstitium
Again, for the concentrating ability of the kidney: first is ADH
and it was already mentioned earlier, second is your corticopapillary
osmotic gradient. Your cortex will have a tonicity of 300. Your papilla or
medulla will have a tonicity of 1,200 so here you have your osmotic
gradient. This is due to your counter-current mechanism, recycling of
urea and the role of vasa recta. For your hypertonic medulla, take note
there is active transport of solutes in the ascending limb and active
transport of ions in the collecting ducts. You also have the role of urea and
a drop in osmosis from the medullary tubules into the interstitium.
Countercurrent Mechanism
down because there is solute wash off; there is increase in solute loss. If
the flow is very high, the flow is able to bring the solutes with it so the
medulla decreases its tonicity.
If you increase ADH, what will happen to the osmotic gradient?
ADH or vasopressin is a vasoconstrictor if you constrict your renal
arteries or arterioles, GFR decreases. If GFR decreases, filtrate formation
and filtrate flow is low. We are talking about solutes particularly NaCl and
renal handling of NaCl is via time gradient limitation. So if flow rate is
slow, it gives time for renal tubules to reabsorb solutes therefore solute
increases in the renal medulla so that increases osmotic gradient.
If you increase urea, what will happen to the osmotic gradient?
For urea, the more urea you have, the greater the osmotic gradient.
Free Water Clearance



Estimates the ability to concentrate or dilute the urine
Rate at which solute-free water is excreted
Free H2O
o
Produced in the diluting segments of the kidney
o
+CH2O: -ADH
o
-CH2O: +ADH
Now we’ll go to water clearance. So your free water clearance
estimates the ability to concentrate or dilute the urine or the rate at
which solute free water is excreted. Free water is being produced in the
diluting segments of the kidney such that if you have positive water
clearance, water is excreted, so ADH is absent. If you have a negative
water clearance, ADH is present, water is conserved.

CH2O = V – Cosm
o
CH2O – free H2O clearance
o
V – urine flow rate
o
Cosm – osmolar clearance

Uosm x V / Posm

Anatomy (Question)
o
↑ length of LOH: ? osmotic gradient
o
↑ juxtamedullary nephrons: ? osmotic gradient

Anatomy (Answer)
o
↑ length of LOH, ↑ osmotic gradient
o
↑ juxtamedullary nephrons, ↑ osmotic gradient



V: 1 ml/min
Uosm: 600 mOsm/L
Posm: 300 mOsm/L
If you increase the length of the loop of Henle, what will happen
to the osmotic gradient? When the length of the loop of Henle increases,
osmotic gradient increases. If you have a long loop of Henle, more solutes
are pumped into the interstitium. If you look at the loop of Henle of
dessert animals like camel and Meer cat, they have longer loops of Henle
so that they will be able to conserve water more.



CH2O = V – Cosm
CH2O = 1 – [(600 x 1)/300]
-1 ml/min
o
+ADH
o
H2O is conserved
If the juxtamedullary nephrons increased in number, what will
happen to the osmotic gradient? If you increase the number of
juxtamedullary nephrons, more solutes will be entering the renal
medulla.

Physiology (Question)
o
↑ flow rate in the LOH: ? osmotic gradient
o
↑ flow rate in the vasa recta: ? osmotic gradient
o
↑ ADH: ? osmotic gradient
o
↑ urea: ? osmotic gradient

Physiology (Answer)
o
↑ flow rate in the LOH: ↓ osmotic gradient

↑ solute loss
o
↑ flow rate in the vasa recta: ↓ osmotic gradient

↑ solute loss
o
↑ ADH: ↑ osmotic gradient

Vasoconstrictor, ↓ blood flow, ↓ solute loss
o
↑ urea: ↑ osmotic gradient

+600 mOsm/L to the medulla
If you increase the flow rate in the loop of Henle, what will
happen to the osmotic gradient? If you increase the flow rate in the vasa
recta, what will happen to the osmotic gradient? Osmotic gradient goes
6
Shannen Kaye B. Apolinario, RMT
To get your free water clearance, it is equal to urine flow rate
minus osmolar clearance. You will take note that your osmolar clearance
is actually your clearance principle. So how do we use this? Urine flow rate
is around 1mL/min so that’s more or less constant. You get urine
osmolality – get a urine sample and send it to the lab and the result is 600
mOsm. You get your plasma osmolality – get a blood sample and send it to
the lab and the result is 300 mOsm. With this plasma osmolality, is the
patient dehydrated or has plasma tonicity increased? It increased because
the normal is 282 mOsm, So what would you expect? There is ADH release.
Having your values now, plug them in so 1 minus 600 x 1 / 300, you’ll get
negative 1 mL/min therefore you stimulate ADH release which actually
supports a hypertonic plasma. Take note that an increase in the negativity
this simply means an increase in ADH release meaning to say, the more
the negative your value is, the higher the amount of ADH released. Water
now is conserved. So we have mentioned earlier that the more negative
your water clearance is, the greater the amount of ADH; the more positive
your water clearance is, more water is excreted.



+ CH2O: -ADH
- CH2O: +ADH
0 CH2O: +loop diuretic
o
Urine is not diluted: the diluting segment is inhibited
o
Urine is not concentrated: the corticopapillary osmotic
gradient is abolished
What if the free water clearance is zero? This happens when we
use loop diuretics. Diuretics like furosemide etc. The action of loop
diuretic is to inhibit the NKCC2 pump in the thick ascending limb. If you
inhibit your NKCC2 pump in the loop of Henle, what happens to the
tonicity of the medulla is that it will decrease. Rigorous use of loop
diuretics will produce and isotonic medulla because the solutes are not
pumped into the interstitium so when your filtrate flows, water will stay
in the tubules. So urine is neither concentrated nor diluted. That’s your
zero free water clearance.
Water Reabsorption
So here you have your PCT, the site for obligatory water
reabsorption so that’s 65-67% reabsorbed and take note that your
hormones will not be influencing reabsorption rate for PCT. However, for
your DCT and collecting ducts where facultative water reabsorption
occurs, reabsorption of water is influenced by hormones particularly
ADH. They are also influenced by hydration status of the individual so
without ADH, we’ve mentioned that water reabsorption is around 8% and
in the presence of ADH, it is around 13%.
Segment
Percentage of
Filtrate
Reabsorbed
Mechanism of
Water
Reabsorption
Proximal
tubule
67%
Passive
Loop of Henle
15%
Descending
thin limb only,
passive
None
Distal tubule
0%
No water
reabsorption
None
Late distal
tubule and
collecting duct
≈8%-17%
Passive
ADH, ANP, BNP`
Regulation of Osmotic Equlibrium and Ionic Balance in the Plasma
As far Na and K handling are concerned, aldosterone will play
an important role but the role of aldosterone will be more extensive on
the adrenal lecture. As far as Ca and phosphate are concerned, this will be
handled more extensively in PTH, vit.D and calcitonin or the endocrine
lecture.
Shannen Kaye B. Apolinario, RMT



Most abundant extracellular cation
Determines the ECF vol
DCT and CT reabsorption is concerned with acid-base balance
Na is the most abundant extracellular cation and it will
determine your extracellular fluid volume. Together with Na, you have
your corresponding anions like bicarbonate and Cl, so all of these will
determine ECF volume. Take note in the DCT and collecting tubules,
reabsorption of Na goes hand in hand with acid base balance.
In this diagram, this will show the percentage of solute or Na
being reabsorbed in the different segments of the nephron.
Hormones
That Regulate
Water
Permeability
None
In this table, you have the different segments of your nephron.
You have the percentage of filtrate being reabsorbed and of course the
hormones that will regulate reabsorption rate. Take note that only in the
late DCT and collecting ducts wherein your hormones will exert their
effects. The other segments are not influenced by hormones. So that’s
regulation of water.
7
Sodium
In this graph, you have your Na intake and ECF volume. Let’s
say you had an eat-all-you-can in Mcdonald’s, so there is a sudden
increase in Na intake. The job of the kidney to maintain a constant plasma
osmolality and to excrete solutes therefore there is a corresponding
increase in excretion of NaCl. Because of the high intake in Na, where Na
goes water follows. You now have an increase in blood volume or ECF
volume. That’s why we are prohibiting hypertensive patients in taking in
a lot of salts because this aggravates their hypertension. If you sustain a
high salt diet, ECF volume is increased so the blood volume is really high.
Then you have decided to have a healthy living so solute intake
drops. Correspondingly, solute excretion decreases also in order to
maintain plasma osmolality and with that, blood volume or ECF volume
goes back to base line.

Angiotensin II
o
 ECF vol,  RAAS
o
PCT:  NaCl reabsorption

 Na-H antiport
o
o


Starling forces adjustment
LOH, DCT, CD:  Na reabsorption
 sensitivity of the tubuloglomerular feedback
Other effects:
o
Aldosterone release
o
Weak vasoconstrictor – renal artery, afferent arteriole
o
Strong vasoconstrictor – efferent arteriole
o
Mesangial cell contraction:  Kf due to  surface area
Let’s look at the different substances that will regulate renal
handling of Na. first you have your angiotensin II. When your ECF
volume drops or when RAAS is activated, angiotensin II increases.
Angiotensin II will target PCT increasing Na reabsorption via increasing
your Na-H antiport and it will affect your Starling forces. Angiotensin II
will also target the loop of Henle, DCT and in the collecting ducts
increasing Na reabsorption and it will also increase the sensitivity of
tubuloglomerular feedback. Other effects of angiotensin II, we all know
that via RAAS it will stimulate aldosterone release. Angiotensin II is a
vasoconstrictor so it will weakly constrict the renal artery in the afferent
arteriole but it is a strong vasoconstrictor in the efferent arteriole. It will
also potentiate mesangial cell contraction altering Kf, decreasing its
surface area. So basically angiotensin II will also change GFR.

Aldosterone
o
ECV regulation
o
: RAAS, hyperkalemia
o
: natiuretic peptides, hypokalemia
o
 Na reabsorption

 Na-Cl symport

 Na-K pump

 ENaC

 Sgk1

 CAP1, prostatin
o
LOH, DCT, CD:  NaCl reabsorption
o
DCT, CD:  K secretion
o
Paracellular Cl reabsorption
o
H2O reabsorption
Aldosterone is important for ECF volume regulation. So it
regulates fluid volume because when it reabsorbs solutes, there is a
commensurate reabsorption of water so basically you reabsorb isotonic
fluids.
RAAS and hyperkalemia will increase aldosterone release. Your
ANP and hypokalemia will decrease aldosterone release. The function of
aldosterone is to increase reabsorption of NaCl via increasing the
different activities of transport mechanisms. Your aldosterone will target
the loop of Henle, DCT and collecting ducts to increase NaCl reabsorption
and in the collecting ducts and DCT, when it targets your principal cells it
will potentiate K secretion. You also potentiate paracellular Cl
reabsorption because when you reabsorb a positive Na ion, a negative ion
like Cl goes along with it. You also have reabsorption of water.
This is your RAAS. In the kidneys, you will produce renin. In
the liver you will produce angiotensinogen. Renin will activate your
angiotensinogen forming angiotensin I. Angiotensin converting enzyme
(ACE) found in the lungs and kidneys will activate angiotensin I to
angiotensin II which is the most potent form. It was already mentioned
earlier the effects of angiotensin II: it potentiates sympathetic activity.
When your sympathetics are activated, renal vessels constrict and GFR
goes down. If GFR goes down, formation of filtrate is down; the flow of the
filtrate is down. By virtue of your gradient time limitation, Na
reabsorption increases. Angiotensin II will reabsorb your NaCl and your
angiotensin II will potentiate the release of aldosterone permitting now
reabsorption of NaCl and excretion of K. Angiotensin II is a
vasoconstrictor and it will also potentiate the release of ADH.

ANP, BNP
o
 NaCl and H2O reabsorption in the CD
o
 total peripheral resistance
o
 ADH secretion, ADH-mediated H2O reabsorption

Uroguanylin, guanylin
o
Released by neuroendocrine cells of the GIT, kidneys
o
 NaCl, H2O reabsorption
o
 Na excretion

PCT:  Na-K pump, Na-H anitport

DCT, CT:  ROMK
Your atrial natriuretic peptide (ANP) is produced in the atrium.
Your brain natriuretic peptide (BNP) is produced in the ventricles
although initially it was isolated in the brain but as far as in the general
circulation is concerned, it is being produced in the ventricles. Basically,
your natriuretic peptides will decrease NaCl and water reabsorption in
the collecting ducts, they also decrease the total peripheral resistance and
they will decrease ADH secretion and ADH mediated water reabsorption.
Uroguanylin and guanylin are produced in the GIT and in the
kidneys when we have a high salt diet. A high salt diet will permit the
release of uroguanylin and guanylin increasing now excretion of your
solutes so there is a decrease in NaCl and water reabsorption and the
function of uroguanylin and guanylin is to target the PCT decreasing NaK
pump and Na-H antiport. They will also target your DCT and CD
decreasing now your ROMK which is a K channel.

Epinephrine, norepinephrine
o
:  ECF vol
o
 NaCl, H2O reabsorption with  ECF vol
o
 RAAS

Dopamine
o
:  ECF vol
o
 NaCl, H2O reabsorption

Adrenomedullin
o
: CHF,  BP
o
 RBF, GFR
o
 NaCl, H2O reabsorption

Urodilantin
o
Kidneys
o
:  BP, ECV
o
 NaCl and H2O reabsorption in the CD
Your sympathetics on the other hand, when the effective
circulating volume or ECF volume decreases, that increases your
sympathtics increasing now NaCl and water reabsorption. Again RAAS
will potentiate sympathetic effects. For dopamine, if ECF increases there
is an increase in dopamine. The role of dopamine is to decrease NaCl and
water reabsorption.
Adrenomedullin and urodilantin are being produced by the
kidneys. When an individual has a CHF or long standing hypertension,
you increase the release of adrenomedullin whose job is to increase renal
blood flow and GFR which decreases NaCl and water reabsorption. For
8
Shannen Kaye B. Apolinario, RMT
urodilantin, long standing hypertension or an increase in ECF volume
increases urodilantin, decreasing salt and water reabsorption.
o
o

Cortisol
o
↑ Na reabsorption
o
↑ GFR, ↓ Na reabsorption if filtered load > reabsorption
Renal blood flow
o
Redistribution to deeper renal tissues, ↑ Na retention
Physical factors
o
Efferent arteriole
o
 resistance,  Ppc,  back-leak of NaCl and H2O,  solute
and H2O reabsorption
o
↑ PG, ↑ GFR, ↑ ∏C, ↑ H2O reabsorption in the PCT
Cortisol is a glucocorticoid being produced by the adrenal
gland. Glucocorticoids will have some mineralocorticoid effects and your
mineralocorticoid like aldosterone will have some glucocorticoid effects.
So with cortisol, you generally have an increase in Na reabsorption.
However, cortisol will increase GFR. In that regard, there is a decrease in
Na reabsorption if the filtered load is greater than reabsorption rate.
For renal blood flow, redistribution to deeper renal tissues
would permit Na retention. Meaning to say, if your tubules will go deep to
the renal medulla, more solutes will be pumped into the interstitium
promoting Na retention.
Now we go to Starling forces particularly the action of efferent
arteriole. If your efferent arteriole constricts, the hydrostatic pressure in
the peritubular capillaries will decrease. That will decrease the back leak
of NaCl and water into the tubular fluid. With that, you now have an
increase in solute and water retention or reabsorption.
Let’s
say
you
have
your
peritubular
capillary,
interstitium/blood and tubules. The efferent arteriole constricts,
therefore the blood flow going to the peritubular capillaries decreases.
The hydrostatic pressure in the peritubular capillaries decreases and if it
decreased, it will promote reabsorption so the solutes will not go to the
tubules and that’s your back leak. So the solutes will go to the blood,
increase solute and water reabsorption.
An increase in glomerular hydrostatic pressure increases your
GFR. If GFR increases, you concentrate your plasma proteins so oncotic
pressure increases promoting reabsorption of water.
o

Glomerulotubular balance
o Filtered load = GFR x Na in filtrate
o
 GFR, filtered load,  reabsorption of Na and H2O

 GFR,  FF,  plasma CHON concentration,  πpc, 
solute and H2O reabsorption

 filtered CHO, amino acids,  Na reabsorption at
PCT
o
Reabsorption of Na and H2O increases in proportion to
increase in GFR and filtered load of Na
Tubuloglomerular feedback
o
RBF, GFR are kept constant despite changes in BP
For glomerulotubul;ar balance, we all know that if you increase
GFR and filtered load, rate of reabsorption increases. If the filtered load of
Na is increased, the reabsorption of Na must also be increased.
This is the formula for filtered load: GFR times the Na
concentration in the filtrate. How does that happen? If GFR increases, you
increase your filtration fraction. Filtration fraction reflects the
concentration of plasma proteins thus increasing oncotic pressure. If you
increase oncotic pressure, you reabsorb water. Via solvent drag, you also
reabsorb solutes. If you have a high carbohydrate or protein diet, you
increase also sodium reabsorption in the PCT in order to reabsorb
carbohydrates and amino acids. So reabsorption of Na and water
increases in proportion to increase in GFR and filtered load of Na.
9
Shannen Kaye B. Apolinario, RMT
For your tubuloglomerular feedback, renal blood flow and GFR
are kept constant for as long arterial pressure range is within
autoregulatory range.
Segment
Percentage
of Filtrate
Reabsorbed
Mechanism of Na+
Entry across the
Apical Membrane
Major Regulatory
Hormones
Proximal
tubule
67%
Na+-H+ antiporter,
Na+ symporter with
amino acids and
organic solutes,
1Na+-1H+-2Cl--anion
antiporter,
paracellular
Angiotensin II
Norepinephrine
Epinephrine
Dopamine
Loop of
Henle
25%
1Na+-1K+-2Clsymporter
Aldosterone
Angiotensin II
Distal
tubule
≈5%
NaCl
symporter
(early)
Na+ channels (late)
Aldosterone
Angiotensin II
Collecting
duct
≈3%
Na+ channels
Aldosterone, ANP,
BNP, urodilatin,
uroguanylin,
guanylin,
angiotensin II
In this table, you have the different segments of your nephron,
the percentage of Na being reabsorbed and the different transport
mechanisms. You also have your regulatory hormones that will affect
reabsorption of Na.
Potassium





K secretion depends on Na availability in the distal tubules
Filtered
Reabsorbed
o PCT: 67%
o LOH: 20%
o DCT, CT
Secreted
o
DCT, CT
Regulation of K excretion is via regulation of K secretion
o Principal cells
o ↓ K secretion

↓ Na at the distal tubules

↑ H secretion
For K, K secretion depends on Na availability. If you will recall
the mechanism of K secretion, for every K that will be secreted, Na must
be reabsorbed - it will just exchange. For renal handling of K, K is filtered,
it is reabsorbed, it may be secreted. In the PT, 67% of K is reabsorbed; in
the loop of Henle you have NaKCC2 pump and 20% of K is reabsorbed. In
the DCT and collecting tubules, it will depend on the presence of
aldosterone.
Regulation of K excretion is via regulation of K secretion by the
principal cells so aldosterone will target the principal cells. In this case, if
you have a decrease in Na in the renal tubules, K secretion decreases (if
there is low amount of Na available, the amount of K that will be excreted
is also low.) Also, if you have high H ion concentration, you have a
decrease in K secretion and this is now the role of your intercalated cells.
Intercalated cells with the action of aldosterone, aldosterone will
promote secretion of K or H. If H is high in the body just like acidosis,
what your intercalated cells will do is they will rather lose H maintaining
K. One of the primary regulators for K secretion or excretion is plasma K.

Regulation of plasma K
o Epinephrine

α stimulation:  K release from cells, liver

β2 stimulation:  K uptake of cells
o
Insulin

 K uptake of cells
o
Aldosterone

 K uptake of cells

 K excretion

Hyperkalemia:  K secretion
–
 Na-K pump
–
 K permeability in the apical membrane
–
 aldosterone
–
 tubular flow rate
So here, we’ll look at effects of different substances in plasma
K. First you have epinephrine. Depending on the receptor, if you stimulate
α receptors, that will promote K release particularly in the liver so that’s
hyperkalemia. But if you stimulate your β2 receptors, you promote K
uptake – hypokalemia.
Aldosterone

DCT, CT:  K secretion
–
Principal cells
–
 Na-K pump, ENaC, SGK1, K channel
activation,
prostatin,
apical
membrane
permeability to K

:  angiotensin II, plasma K

:  plasma K, natiuretic peptides
For insulin, you increase K intake together with glucose.
Aldosterone will promote hypokalemia. For aldosterone, it will decrease
K uptake and increase K secretion or excretion.
Regulation of K reabsorption and secretion. One of the main
factors that will dictate renal handling of K is plasma K. So if you have
hyperkalemia, you potentiate K secretion via these mechanisms.
o
Metabolic acidosis:  plasma K
o
Metabolic alkalosis, Respiratory alkalosis:  plasma K

↓ H secretion

↑ K secretion
o
Respiratory acidosis: no effect
o
 plasma osmolality:  plasma K

 ICF vol
o
Cell lysis:  plasma K

Tumor lysis syndrome

Rhabdomyolysis

GI ulcers
o
For metabolic alkalosis and respiratory alkalosis, just the
opposite effects of the above mentioned.
For respiratory acidosis, there are no effects but the reason as
to why is still unknown.
Increasing plasma osmolality increases plasma K. If plasma
tonicity increases, water inside the cell will go out. If water inside the cell
will go out, the concentration of K inside the cell increases so K will go
out.
For cell lysis, you increase your plasma K. Tumour lysis
syndrome is commonly observed among cancer patients undergoing
chemotherapy. When the cell dies, K released. Rhabomyolysis: if the
skeletal muscles are damaged during trauma, that increases K in the
plasma. For GI ulcers or bleeding ulcers, blood or red blood cells will be
digested in the GI tract releasing K. K is absorbed in the GIT that increases
K.
Strenuous exercise increases plasma K. Skeletal muscles are
excitable cells. If you keep on stimulating them, you always have an action
potential. If you have an action potential, Na enters and K goes out. It also
increases lactic acid – metabolic acidosis.
Regulation of K reabsorption and secretion
o
Plasma K
10
Aldosterone would target the DCT and collecting tubules
promoting K secretion so in the principal cells you activate these
transport mechanisms. When angiotensin II increases, you increase
aldosterone. If you increase plasma K, you also increase aldosterone. If
plasma K goes down or with the presence of natriuretic peptide, you
decrease aldosterone.
o
ADH

Principal cells
–
 Na uptake,  electochemical driving force for
exit of K across the apical membrane,  K
secretion
–
 tubular flow,  K secretion
–
Net effect: constant K excretion
o
 filtrate flow rate

 K secretion at DCT, CT

 activation of PKD1/PKD2 Ca conducting channel
complex
–
 activation of K channels

 Na in the filtrate,  Na uptake,  electrochemical
driving force for K exit
 exercise:  plasma K

Lactic acid
For metabolic acidosis, this increases plasma K. if you have
high amounts of H+ in the body, you have a concentration gradient
between ECF and ICF compartment with regards to H+. H+ enters the cell.
H+ being a positive ion, another positive ion must go out. The most
abundant intracellular cation is K so it will go out in order to maintain
electrical neutrality. Another effect of acidosis is that your H+ will inhibit
your NaK pump. If your NaK is inhibited, during repolarization, K will not
enter.

o
Shannen Kaye B. Apolinario, RMT
ADH targets the principal cells increasing Na uptake. If you
increase Na uptake, that will increase the electrochemical driving force
for the exit of K across the apical membrane because you reabsorb a
positive ion. To maintain electroneutrality, another positive ion should go
out so that’s K therefore you increase K secretion. However as far as ADH
is concerned, you also reabsorb water. So if you reabsorb water, the flow
rate decreases. Remember as far as renal handling of K is concerned, this
is via gradient time limitation so when tubular flow decreases, the
concentration gradient for K is low therefore K secretion goes down. You
will note that as far as ADH is concerned, it has two opposite effects but at
the end of the day, the net effect is constant K secretion or excretion.
If you increase your filtrate flow rate, you increase K secretion.
You also increase the activation of PKD1 and 2 Ca conducting channels.
What these channels do is to permit the entry of Ca. Ca will activate the
intracellular machinery increasing activation of K channels so K goes out.
Also you increase the Na in the filtrate increasing Na uptake and that
increases the electrochemical driving force for the exit of K.
o Glucocorticoids

 K excretion
–
 GFR
–
 SGK1 activity,  ENaC, K channel activation
o
Acid-base balance

Acidosis
–
 K secretion
–
 Na-K pump, electochemical driving force for
K exit,  filtrate flow
–
 apical permeability for K
–
 Na-K pump,  Na excretion,  aldosterone

Alkalosis
–
 K secretion
For glucocorticoids, it promotes K excretion and it also permit
an increase in GFR rate and increase in several transport mechanism.
For acid base balance, during acidosis, there is a decrease in K
secretion. If you have acidosis, your intercalated cells would rather
remove H to retain K. There is a decrease in NaK pump, your
electrochemical driving force for K exit and you also have an increase in
filtrate low. You also decrease the permeability for K and by decreasing
NaK pump; you increase Na excretion that will promote aldosterone
release. So aldosterone will promote H excretion.
For alkalosis, the opposite effects.
This is K secretion by the DCT and collecting ducts. If the
individual has hyperkalemia, the increase in plasma K has a direct effect
on the DCT and collecting tubule increasing its secretion. Hyperkalemia
will also increase flow rate. So net effect is K excretion – it goes out.
Looking at the effect of aldosterone. In acute, aldosterone will
target DCT and collecting ducts promoting K secretion that’s why K
secretion goes up. However with the reabsorption of water, flow rate
decreases. As far as flow rate is concerned, since renal handling of K is
gradient time dependent, in this regard, K excretion decreases. Here you
have an increase in K secretion and decrease in K secretion and the net
effect is no change.
Calcium





CHON-bound is not filtered
Excretion is low
↑ PTH, ↑ Ca reabsorption
↑ Vit D, ↑ Ca reabsorption
↑ calcitonin, ↓ Ca reabsorption
For Ca and phosphate, they are primarily being regulated by
three important hormones: PTH, vitamin D and calcitonin. For Ca, they
may exist as ionized or protein bound. If Ca is protein bound, it will not be
filtered by the kidneys so only the ionized Ca is filtered by the kidneys.
Your PTH and vitamin D increase Ca reabsorption but calcitonin will
decrease Ca reabsorption.
Phosphate




Buffers the renal tubules
↑ PTH, ↓ PO4 reabsorption
↑ Vit D, ↑ PO4 reabsorption
↑ calcitonin, ↓ PO4 reabsorption
For phosphate, they will act as buffers. Again, three hormones
will also regulate renal handling of phosphate: PTH, vitamin D and
calcitonin. Take note that PTH and calcitonin decreases phosphate
reabsorption but vitamin D will increase phosphate reabsorption.
Chloride

Reabsorption is associated with handling of Na and H2O
Magnesium
Here you have metabolic acidosis. When you have acute
metabolic acidosis, you inhibit your NaK pump. Inhibiting NaK pump
decreases K excretion. During acute metabolic acidosis, K excretion goes
down. You therefore accumulate K in the body, plasma K increases. When
plasma K increases, that will permit the release of aldosterone. If
aldosterone is released, K excretion increases. So during acute metabolic
acidosis, K excretion goes down. For chronic metabolic acidosis, K
excretion goes up.

K secretion by the DCT and CD


CHON-bound is not filtered
Filtered Mg are reabsorbed
Sulfates

Tm: 0.06mM/min
For Cl reabsorption, it is associated with handling of Na and
water via passive transport or simple diffusion. For Mg, protein bound Mg
is not filtered and your filtered Mg are reabsorbed through Clodin 16 in
the ascending limb. For your sulfate, they are actively transported,
transport maxima is 0.6.
Ammonia, Hydrogen, Bicarbonate

NH3 and H participates in acid-base regulation



HCO3 participates in acid-base balance
All filtered HCO3 is reabsorbeed
Alkalosis
o
↓ HCO3 reabsorption
Acidosis
o
↑ HCO3 reabsorption

11
Shannen Kaye B. Apolinario, RMT
For ammonia and hydrogen together with bicarbonate, they
will participate in acid base balance. Take note that all of filtered
bicarbonate is reabsorbed. When a patient has alkalosis, there is a
decrease in bicarbonate reabsorption but if a patient has acidosis, there is
an increase in bicarbonate reabsorption.
Glucose, Amino Acids
•
Glucose
o
Tm: 320 mg/min
o
Renal threshold: 220 mg/min
•
Amino acids
o
Different amino acids will have various carriers
o
Tm: 1.5 mM/min
For glucose and amino acids, both are actively reabsorbed. For
glucose the transport maxima is 320 but the renal threshold is 220. Renal
threshold is the amount of glucose present in plasma wherein it will
appear in the urine. You will note that the renal threshold is less than
transport maxima. Transport maximais the concentration wherein you
saturate your carriers. For example, if glucose concentration exceeds
renal threshold but lower than the transport maxima, it will still appear
in the urine. Why is that even if the concentration of glucose is lower than
the transport maxima, it still appeared in the urine? The reason for this is
that not all nephrons will have the same amount of carriers.
For amino acids, different amino acids will have different
carriers and transport maxima is 1.5.
Vitamin C. Urea, Uric Acid

Vit C
o
Filtered, reabsorbed, and secreted
o
Tm: 2 mg/min
o
↑ adrenal steroids, ↑ vit C secretion
o
↑ filtered load of Na, ↑ vit C secretion

Urea
o
Filtered and reabsorbed at varying degrees
o
Reabsorption depends on ADH

Uric acid
o
Tm: 15 mg/min
Vitamin C is filtered, reabsorbed and secreted. Transport
maxima is 2. If you have an increase in adrenal steroids or an increase in
the filtered load of Na, that increases vitamin C secretion.
For urea, it is filtered and reabsorbed at varying degrees
depending on ADH.
For uric acid, this is actively secreted and transport maxima is
15.
Creatine, Creatinine

Creatine
o
Filtered and reabsorbed
o
No Tm has been demonstrated

Creatinine
o
Tm: 16 mg/min
Creatine is an essential energy source for the muscle so it is
filtered and reabsorbed, no transport maxima exhibited. But for
creatinine, a by-product of creatine, it is secreted actively, transport
maxima is 16.
“The fear of the Lord is the beginning of wisdom, the
knowledge of the Holy One is understanding.”
-Proverbs 9:10
GOD BLESS YOU 
12
Shannen Kaye B. Apolinario, RMT
Far Eastern University
Nicanor Reyes Medical Foundation
Institute of Medicine
1D – Batch 2020
Renal Physiology III
Regulation of Plasma and Water Volume, and Osmotic
Equilibrium and Optimal Ionic Balance in the Plasma
Dr. Ronald Allan Cruz – January 17, 2017
NORMAL PHYSILOGIC CONDTION:
MORE IMPORTANT is AN INCREASE IN PLASMA
TONICITY than the drop in blood volume.
 Should are plasma tonicity increases by 1-2%,
it will already stimulate the release of ADH.
REGULATION OF PLASMA AND WATER VOLUME
Normal Blood Volume: 5L
Formed Elements in the blood: 2L
NORMAL PLASMA VOLUME: 3L
NORMAL PLASMA OSMOLALITY: 280-285 mOsm/L
(282 mOsm/L) to be exact
Average Specific Gravity of Plasma: 1.008 – 1.010
These are what the kidneys do in order to maintain to a
CONSTANT PLASMA VOLUME and PLASMA TONICITY:
1.
2.
3.
4.
5.
Conserve fluids
Excrete solutes
50-1200 mOsm/L of urine
Sp gr: 1.002-1.400
UO: 0.5-18 l/day
 UO: 0.5-1 ml/kg/hr
Kidneys can excrete and reabsorb water such that urine
can be DILUTED or CONCENTRATED.
Diluted urine
 As low as 50 mOsm/L of urine
 Specific gravity of 1.002
Concentrated urine
 1200 -1400 mOsm/L of urine
 Specific gravity of 1.400
SPECIFIC GRAVITY
 Comparison of fluid to distilled water
 Water : distilled ratio
 Sp gr of 1 = it is distilled water
 Higher sp gra, the more solute it contains and
the more concentrated the fluid is
UNDER CERTAIN PATHOLOGIC CONDITON:
DROP IN BLOOD VOLUME supersedes plasma tonicity.
 A drop in blood volume of 5-10% even if the
plasma tonicity is 282 mOsm/L, ADH will be
released.
 Example: Gunshot wound (profusely bleeding)
 BP drops  decreased blood volume with
constant plasma tonicity  ADH release.
ADH increases the activity of these transporters:
1. UT – A1 & UT – A3 = urea transporters
2. NKCC2 =
3. ENaC = epithelial sodium channel
4. Na-Cl symporter
OTHER FACTORS AFFECTING ADH RELEASE:
1. Osmoreceptors
 Located at the antero-ventral portion of the 3rd
ventricle (AV3V)
 Detects tonicity of the surrounding fluid
o Example: when plasma tonicity
increases, fluid in the CNS (CSF) will
move into the plasma via osmosis.
o This will increase the tonicity of the
CSF.
o If osmoreceptors surrounded by
hypertonic medium, they will shrink
because water from the cell will go
out via osmosis.
o This will trigger generation of AP by
osmoreceptors to be sent to the
supraoptic
and
paraventricular
nuclei for the production of ADH and
for the release of ADH by the
neurohypophysis.
How is this done by the kidneys?
ANTIDIURETIC HORMONE (ADH) / VASOPRESSIN
 A neurohormone
 Produced in the hypothalamus specifically:
o Supraoptic nuclei
o Paraventricular nuclei
 Transported via AXONAL TRANSPORT down
to the posterior pituitary gland to be stored.
 Stimulus for ADH release
o 1-2% increase in Plasma tonicity
o 5-10% decrease in blood volume
 Increased water reabsorption especially in the
late DCT and collecting tubules (go back to
renal II for further explanation)
Signals from osmoreceptors will also go to the
SUBFORNICAL REGION and ORGANO VASCULOSUM
OF LAMINA TERMINALIS (both are centers)
 These centers when stimulated, will trigger
the THIRST MECHANISM
2. BARORECEPTORS and CARDIOPULMONARY
REFLEXES will send signals to the median preoptic
nuclei which in turn, it will send signals to the
supraoptic and paraventricular nuclei to increase the
synthesis and release of ADH.
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3. ALCOHOL
 Inhibits the release of ADH
 This why we pee a lot when we consume
alchol
TAKE NOTE:
ADH reabsorbs water only BUT it regulates Plasma
Osmolality.
Aldosterone reabsorbs water together with Na BUT it is
the one that regulates Plasma volume.
Diagram:
1.
2.
3.
4.
Shown is hypothalamus which is magnified.
a. Seen is the supraoptic and
paraventricular nuclei of the
hypothalamus
You can also see the osmoreceptors,
baroreceptors and cardiopulmonary
receptors.
a. Impulses from these regions will now
send impulses to supraoptic and
paraventricular nuclei
ADH is produced then transported to the
posterior pituitary gland
It will be released in the bloodstream,
targeting the DCT and collecting ducts to
increase water reabsorption
Table: Factors increasing and decreasing ADH production and release
Diagram:
1. If water intake is decreased, plasma osmolality
increases and osmoreceptors will be
stimulated.
2. ADH will be release
3. This will target the DCT and Collecting tubule
for increase water reabsorption
a. Water will go back to the body
4. The net effects are:
a. Urine volume decreases
b. Urine concentration /osmolality
increases (hypertonic urine)
c. Decreased
plasma
osmolality,
bringing it back to 282 mOsm/L.
Diagram:
1. If water intake is increased, plasma osmolality
decreases and osmoreceptors are NOT
stimulated
2. There will be no release of ADH
3. AQP2 activity in the DCT and CT decreases
4. Decrease H2O reabsorption
5. The net effects:
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a.
b.
c.
Increase Urine volume
Decrease urine concentration /
tonicity ( hypoosmotic urine)
Increase plasma osmolality back to
the normal average
TAKE NOTE:
ADH’s MAIN EFFECT
REABSORPTION.
IS
TO
INCREASE
H2O
Graph: Plasma osmolality Vs. ADH release.
Combination of the 2 previous graphs
1.
2.
3.
The green line is same as the red line in the
previous two graphs (A and B).
As we can see, increased plasma osmolality,
the amount of ADH release also increases but
take into account the BP.
We can see that:
a. LOWER BP: The threshold for ADH
release decreases
b. HIGHER BP: The threshold for ADH
release increases
This graph will show the effect of chronic changes in BP
because at different changes in BP, the set off point for
ADH release adjusts.
CHRONIC
HYPOTENSION:
From
280
mOsm/kg H2O set off point, ADH is now
released at 270 mOsm/kg H20
CHRONIC HYPERTENSION: Below 290
mOsm/kg H20, there is no release of ADH. The
set off point is increased to 290 mOsm/kg
H2O.
A.
B.
Plasma osmolality Vs. ADH
 As the plasma tonicity increases,
beyond 282MOsm/L, ADH levels go
up.
Blood Pressure Vs. ADH
 The lower the blood volume or BP,
ADH released is increased
Figure: this will be the tubular cells in the DCT and CT.
1. ADH will activate V2 receptors
2. These V2 receptors will activate a G protein
increasing the activity of adenylyl cyclase.
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3.
4.
5.
6.
7.
8.
Cyclic AMP now increases
cAMP being a secondary messenger will
increase Protein Kinase A
Protein Kinase A will have two effects:
a. Activate
genetic
machinery,
increasing the synthesis of AQP2
b. More importantly, it can also
phosphorylate AQP2
Once phosphorylated, AQP2 will now be
inserted into the apical surface of the cell.
a. Not shown but there are also AQP in
the basolateral membrane
Water can now be reabsorbed.
If phosphate group is removed, AQP2 will now
be endocytosed:
a. It can now be degraded
b. Or it can be recycled
CLINICAL APPLICATION
Syndrome of Inappropriate ADH (SIADH)
 Increase ADH production
o Due to some CNS lesions or trauma
that the hypothalamus keeps on
producing ADH
 Outcomes:
o Increased H2O retention because
water is reabsorbed continuously.
o Hypoosmotic body fluid
o Hyperosmotic urine (concentrated)
Nephrogenic Syndrome of Inappropriate
Antiduiresis
 Normal or less ADH levels
 A problem in V2 receptor
o V2 receptors are CONSTANTLY
activated even without the presence
of ADH
o So the effects are similar: continuous
reabsorption of H2O
Diabetes Insipidus
 Has two types
o Central DI

Decrease in ADH

And usually, a decrease in
Nuerophysin (substance
that transports ADH down
to the neurohypophysis) so
ADH is not transported so
ADH will be less

Hypoosmotic urine

Increase urine volume

Increase in plasma tonicity
o Nephrogenic DI

Similar to NSIA

V2 receptors defect

Less receptors

Hypoosmotic urine

Increase urine volume

Hypertonic plasma
ADH also acts as a vasoconstrictor, so patients with Nephrogenic
DI have a higher BP compared to patients with Central DI because
V1 receptors in BVs are present and functional. ADH when attached
to V1 receptors cause systemic vasoconstriction.
THIRST MECHANISM
 Thirst is triggered by:
o 2-3% increase in plasma tonicity
o 10-15% decrease in blood volume
 Thirst HAS A GREATER THRESHOLD than
ADH secretion
ADH threshold
o 295 mOsm/kg H2O thirst
= 285 mOsm/L
threshold
o This simply means that when plasma
tonicity hits 285 mOsm/kg H2O, ADH
will be released however the
sensation of thirst is still absent
o So when plasma tonicity hits 295,
ADH is also released but it is only
then we will experience thirst

When a person feels the
feeling of thirst, he/she is
already dehydrated
A person must be able to consume around 1.5 – 3L of
water every day to be hydrated.
FACTORS AFFECTING THIRST
A.
B.
Angiotensin ii
 Increases thirst sensation
Receptors present in the Oropharyngeal
area and Upper GIT
 Decreases Thirst but that doesn’t
mean that a person is adequately
hydrated
Example: When we experience thirst, any fluid that we
take will stimulate the oropharyngeal and Upper GIT
receptors decreasing the sensation of thirst but that
doesn’t mean we become well hydrated. If we are taking
in Coke, we feel thirsty a little bit later. So the best thirst
quencher is water.
REABSORPTION OF WATER IN THE DIFFERENT
PART OF THE NEPHRONS





PCT – 65% of H2O is reabsorbed (MAJORITY)
LOH: descending limb – 20% of H2O is
reabsorbed
LOH: ascending limb – solutes are reabsorbed
DCT – H2O permeability is ADH-dependent
CT – H2O permeability is ADH-dependent
DCT and CT are responsive to ADH. In these segments, this is where
FINAL MODIFICATION OF URINE will occur depending on the needs
Escoto,
KC //should
Gloriani,
KP
of the body such that plasma
tonicity
be maintain
to 282
4 of
mOsm/L so with that urine osmolality, urine
can16
be diluted or
concentrated.
OBLIGATORY URINE VOLUME
 Minimum amount of fluid that must be
excreted with solutes
o Excretion: 600 mOsm/day
o Concentrating ability : 1200 mOsm/L
o 600 mOsm/day / 1200 mOsm/L
o 0.5 L/day
Let’s say that we want to secrete 600 mOsm in a day.
This amount of solute must be suspended in a fluid
because we urinate in liquid form not solid. The amount
of fluid must be excreted together with these amount of
solute is the obligatory urine volume.
How is this done?
 If we want to remove 600 mOsm in a day
 The maximum concentrating ability of the
kidney is 1200 mOsm
o This is from the tonicity of the renal
medulla
 To get the obligatory urine volume:
o Divide: 600 mOsm / 1200 mOsm
o
The answer will be 0.5 L of water is
needed to dissolve 600 mOsm of
solutes to be excreted.
THREE FACTORS MAKING THE RENAL MEDULLA
HYPERTONIC
1.
2.
3.
A.
Countercurrent mechanism
 Contributes solute to the renal
interstitium
 Increasing the activity of NKCC2
 Contributes 600 mOsm of NaCl to the
interstitium
Recycling of Urea
 Contributes solute to the renal
interstitium
Function of the Vasa Recta
 it will not add solutes to the
interstitium BUT it will maintain the
tonicity of the renal medulla
COUNTERCURRENT MECHANISM
PCT
DCT
NKCC2
Practical Application




Sea water: 2400 mOsm/L
Concentrating ability : 1200 mOsm/L
2400 mOsm/day / 1200 mOsm/L
2L/day
Seawater has a tonicity of 2400 mOsm/L. When we
drink seawater, we want to remove that 2400 mOsm of
solutes. To get the obligatory urine volume:
2400 / 1200 = 2 L
This means that 2L of water is needed to dissolve 2400
mOsm of solutes to be excreted. We can see that you
only drank 1 L but excreted 2L of water. This means
that drinking hypertonic solution will make a person
more dehydrated.
HOW DO WE CONENTRATE THE URINE?
1. ADH
2. Hypertonic Renal Medula
 1200 mOsm/L
 Once the filtrate flows through the
Loop of Henle, water will be reabsorb
due to the tonicity of the renal
medulla; increasing the tonicity of
the urine
AQP1
LOH
Figure: Numbers represent tonicity
Batch 1: Filtrate in isotonic environment
1. Let’s say everything first is isotonic at 300
mOsm. Following the flow of the solute:
2. If the filtrate is passing through the
descending limb and the filtrate is isotonic,
water will not be reabsorb.
3. The filtrate will now go the ascending limb
4. Solutes will now be reabsorb in the thick
ascending limb due to the presence of NKKC2
 NKCC2 will actively pump solutes
into the interstitium
 This will now increase the tonicity of
the interstitium
Batch 2 of filtrate:
1. As filtrate is now going through the
descending limb, water will now be reabsorb
 This is due to the increased tonicity
in the interstitium
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2.
3.
The tonicity of the filtrate goes up because
water is removed.
When it ascends the ascending limb, more
solutes is pumped to the interstitum since the
tonicity of the filtrate is higher.
 This will increase the tonicity of the
interstitium more.
VASA RECTA
Venous
Arterial
DCT
PCT
DCT
PCT
CD
NKCC2
LOH
AQP1
LOH

Batch 3 of filtrate
1. With the third batch, more water will be
reabsorbed in the descending limb
2. And as it goes to the ascending limb, more
solutes will be pumped into the interstitium
a. Increasing its tonicity once again

Countercurrent multiplier – the tonicity of the
interstitium that keeps on increasing.
 This will now in turn give the
corticopapillary osmotic gradient

‘
Figure: Process of Countercurrent Mechanism. This
summarizes on what is discussed above.


As you can see, the flow of the blood and the
flow of the filtrate is anti-parallel
Majority of water is reabsorbed in the PCT
(67%)
15% of the water is reabsorbed in the
descending limb.
Water that is reabsorbed from the tubules will
not stay in the interstitium so it will not affect
the tonicity of the medulla.
Water will now go to the vasa recta due to the
presence of the Plasma proteins inside.
o Plasma proteins exerts osmotic
potential, attracting water to blood
vessels
TAKE NOTE:
Reabsorbed water from the PCT and descending Limb of
LOH directly goes to the venous side to be brought back
immediately to the general circulation.
Diagram: Shows the effect of
ADH (yellow circles)
 When ADH is
present, water will
be reabsorb,
increasing the
concentration of
urine.
 Water will not stay
in the interstitium,
it will go to the vasa
recta due to the
osmotic potential
generated by the
plasma proteins.
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B.
UREA RECYCLING
TAKE NOTE:
The net effect of urea is just to stay in the kidneys but
some urea will be excreted and that depends on ADH.
DCT
For Urea recycling to be most efficient, ADH must be
present; otherwise, the tonicity of urea remains low.
PCT
CD
LOW ADH  LOW UREA CONCENTRATION GRADIENT
 UREA CAN’T GO OUT OF CD so it is basically excreted.

If ADH is chronically absent, the tonicity of
renal medulla is still hypertonic because
600mOsm will come from NKCC2.
C.
Figure: The numbers represent the concentration of
Urea
1.
In the PCT and descending limb of LOH, water
is reabsorbed
2. Once water is reabsorbed, concentration of
urea increases
3. In the DCT and early portion of CD, the cell
membrane is impermeable to urea. (as
represented by the black borders)
4. When the filtrate reaches the DCT and CD,
ADH is present
5. Once ADH is present, water is reabsorbed
a. The concentration of urea increases
6. In the later portion of CD, cell membrane
becomes permeable to urea
7. There will be a concentration gradient for urea
8. Urea in the late CD will go out
9. Then it will go back again in to the ascending
limb then out again at the late CD
10. So basically, it is just going in and out.
1200mOsm of solutes
 Maximum concentrating ability of the kidneys
 This from:
o UREA = 600 mOsm of solutes
additional to the interstitium
o NaCl = 600 mOsm of solutes
additional to the interstitium
 This is the tonicity of the renal medulla
VASA RECTA
 Another factor that makes the renal
medulla hypertonic
 Will not add solutes but it will
maintain the tonicity of the renal
medulla
 Has a unique configuration: U SHAPE
 Low blood flow

Constitutes 7% of Renal
blood flow
 Acts as solute exchangers /
countercurrent exchangers

It minimizes solute loss
 If RBF is increased and more blood
enters the vasa recta (increasing
medullary renal blood flow), this
will increase solute washout.

Instead of solutes coming
back, more are washed
away

The tonicity of renal
medulla decreases;
decreasing the
concentrating ability of
the kidney
 Delivers O2 and nutrients
 Delivers substances for secretion
 Pathway to return reabsorbed
substances to the circulatory system.

When we reabsorb glucose
and amino acids, they are
brought into the vasa recta
 Concentrates or dilutes the urine

Concentration of the venous
side is higher because you
already reabsorb from the
filtrate (AA, solutes, etc)
TAKE NOTE:
If the vasa recta is a straight blood vessel, the water that
goes out can’t go back.
EFFECTS OF CHRONIC TAKING OF PAIN RELIEVERS:
If blood flow going to the vasa recta is further
decreased, this will constrict the blood vessels. O2 and
nutrients delivery to the tubular cells decreases. They
become ischemic and you now have renal injury.
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7 of 16
Arterial
Venous
B.
Figure: the numbers represent tonicity
1.
2.
3.
4.
5.
6.
7.
In the arterial side of the vasa recta, just like
any other capillary bed, this is where
FILTRATION OCCURS.
 This is due to the presence of
hydrostatic pressure
Water will now go out into the interstitium
from the arterial side.
As water goes out, the concentration of plasma
increases
Since the vasa recta has a unique configuration
which is U shape, the effects are:
 As blood goes to the venous side, the
concentration of plasma is high
exerting osmotic potential
 Water that went out, will also come
back in
Notice in the venous side, there is a higher
concentration of solute.
This will drive the solute out from the venous
side
Then the solutes will go back to the arterial
side.
CONCENTRATING ABILITY OF THE KIDNEYS
A.
Dilute urine / H2O diuresis
 Absent ADH, diluted urine is formed
•
Water is secreted
 Tonicity of renal medulla = 600
mOsm/L
•
Due to NaCl given by
NKCC2
Concentrated urine / Antidiuresis
 ADH is present, concentrated urine is
formed
•
Water is reabsorbed from
the DCT and CD
•
ADH
enhances
urea
recycling
 Tonicity of renal medulla = 1200
mOsm / L
•
This is from NaCl and Urea
TWO FACTORS IN THE FORMATION OF
CONCENTRATED URINE
1.
2.
ADH
CORTICOPAPILLARY OSMOTIC GRADIENT or
THE HYPERTONIC RENAL MEDULLA
3 FACTORS IN THE HYPERTONICITY OF RENAL
MEDULLA
1.
2.
3.
Countercurrent exchanger – add solutes
Urea recycling – add solutes
Role of Vasa Recta – maintains tonicity
HYPERTONICITY OF RENAL MEDULLA
PRODUCTION:
1.
2.
3.
4.
Active transport of solutes in the thick
ascending limb of LOH (NKCC2)
Active transport of ions from the CT
Urea
↓ osmosis from the medullary tubules into the
interstitium
FACTORS AFFECTING THE COUNTERCURRENT
MECHANISM
ANATOMICAL FACTORS
 ↑ length of LOH: ? osmotic gradient

The longer the LOH, the longer the
thick ascending limb, more NKCC2,
more solutes can be added to the
interstitium

Increasing the osmotic gradient
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
↑ juxtamedullary nephrons: ? osmotic
gradient

More NKCC2, more solutes are
pumped into the interstitium

Increasing the osmotic gradient
PHSYIOLOGICAL FACTORS
 ↑ flow rate in the LOH: ? osmotic gradient

The faster the flow, more solute
washout, increasing solute loss

Decreasing the osmotic gradient
 ↑ flow rate in the vasa recta: ? osmotic
gradient

The higher the blood flow, more
solute washout, increasing solute
loss

Decreasing the osmotic gradient


↑ ADH: ? osmotic gradient

One effect of ADH other than it
enhances urea recycling, it acts as
vasoconstrictor

Constrict blood vessels, blood flow
drops, decreasing solute wash out

Increasing the osmotic gradient
↑ urea: ? osmotic gradient

Increasing the osmotic gradient
FREE WATER CLEARANCE
 Ability to concentrate or dilute the urine
 Rate at which solute-free water is excreted
 We can equate this to excretion:
o When something is cleared from the
body, this simply means it goes out of
the body
 CLEARANCE OF H20 (+) / +CH2O = water is
excreted
o Absent ADH
 CLEARANCE OF H20 (-) / -CH2O = water is
NOT excreted, it stays in the body
o ADH is present
Quantification of Free Water Clearance
CH2O = V – Cosm
CH2O = free H2O clearance
V = urine flow rate
Cosm = osmolar clearance
 Uosm x V / Posm
CH2O = V – Cosm
CH2O = 1 – [(600 x 1)/300]
-1 ml/min
•
This means that ADH is present so
H2O is conserve
•
The higher the numerical value, the
greater the degree of reabsorption or
secretion of water
If 0CH2O / clearance of free water is zero:
 The patient is taking loop diuretics
o Loop diuretics inhibits NKCC2
o No solutes are added into the
interstitium
 The tonicity of the renal medulla gradually
decreases up to isotonicity
o If the filtrate flows through the LOH,
water is not reabsorbed due to
isotonicity
o Water is not added to the filtrate
 The urine is NOT diluted
 The urine is NOT concentrated
PCT




Obligatory H2O reabsorption occurs
It is not influenced by hydration status
It is not influenced by ADH
Whether you are not dehydrated or not, it will
always absorb 65 – 67% of the filtered water.
DCT and CT
 Facultative H2O reabsorption occurs
 This will depend on ADH
o Increased ADH  increased H2O
reabsorption as high as 17%
 Affected by the hydration status
o Dehydration  increased H2O
reabsorption
Uosm = get the urine osmolality
Posm = get the plasma osmolality
Application:
•
V: 1 ml/min
•
Uosm: 600 mOsm/L
•
Posm: 300 mOsm/L
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WATER REABSORPTION IN
SEGMENTS OF THE NEPHRON
THE
DIFFERENTS
QUESTION:
If the tonicity of renal medulla is high, what will be the
urine tonicity?
C. If the renal medulla’s tonicity is high, it will
reabsorb water
D. If water is reabsorbed, you basically remove
water from the filtrate
E. By removing water from the filtrate, what
stays in the filtrate is solutes
 This makes the urine concentrated
There are also other factors like ADH, hydration status,
aldosterone.
For hydration status:
 You can have a dilute urine if well hydrated
 A concentrated urine if dehydrated
WATER and Na REABSORPTION
ADH




REGULATION OF OSMOTIC EQUILIBRIUM AND IONIC
BALANCE IN THE PLASMA – RENAL HANDLING OF
SOLUTES
 Movements of other components of the filtrate
(solutes)
 Secretion, reabsorption of substances like
glucose, K, Na and etc.
Reabsorbs H2O
Regulate tonicity
In response to  osmolarity
In response to  ECF vol
ALDOSTERONE
 Reabsorbs Na
o Together with Na, water follows
 Regulate volume
 In response to  ECV
In the diagram, you’ll see the extracellular compartment
and the intracellular compartment together with the
ions present there. The two are separated by the cell
membrane.
Take note that Na and Cl are located more
extracellularly whereas you K, PO4 and proteins are
located intracellularly. Remember that the kidneys can
only alter the extracellular compartment. The
intracellular compartment will follow afterwards.
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SODIUM
 Most abundant extracellular cation
 Determines the ECF volume
 In the PCT:
o majority of Na is reabsorbed
 DCT and CD;
o Na reabsorption is connected with
acid-base balance

This is the reason why hypertensive
patients are advised to decreased
salty foods.
Should the patient decrease Na intake, there is
also a drop in Na excretion.
Na loss will decrease ECF volume
1.
Humoral Factors
o



↓ Na reabsorption, ↓ H secretion
o Recall that you have the NaH exchanger present in the
tubules
o Decreasing Na
reabsorption, H ion
secretion is also decreased
because once Na is
reabsorbed, H goes out.
↑ Na reabsorption, ↑ K secretion
o This through the principal
cells
o Increased activity of Na-K
pump, more Na is
reabsorbed in exchange for
K.
Diagram: Amount of Na reabsorbed in the different segments of the
nephron
FACTORS AFFECTING SODIUM HANDLING
(REABSOPRTION AND SECRETION) – water also
follows
Table: Substances that affect Na reabsorption.
Diagram:
 If Na intake increases, to maintain
homeostasis, the kidneys must excrete the
same amount of Na  increased Na excretion
o The shaded part represents Na
retention
 With Na retention, we all know that where Na
goes, water follows  ECF volume increases
2.
Sympathetics
 Potentiate RAAS
o RAAS will increase
angiotensin II and
aldosterone
3.
Cortisol – dual effects
 Mineralocorticoid effects
o Increase Na reabsorption
 Increases GFR so decreased Na
reabsorption
o If GFR increases, Na
reabsorption decreases
o Filtered load > reabsorption
rate
o By increasing GFR, the flow
of filtrate is fast so Na
reabsorption is less
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4.
5.
Renal Blood Flow
 Blood going to the deeper renal
tissues in the deeper medulla that
will promote Na retention
o Countercurrent mechanism
Physical Factor
 Starling forces
DIAGRAM: RAAS
1.
2.
3.
4.
Renin is produced in the kidney
Renin converts angiotensinogen to angiotensin
I in the liver
Angiotensin I goes to the lungs
ACE converts angiotensin I to angiotensin II
EFFECTS OF ANGIOTENSIN II - ↑ H2O & Na reabsorb..
Ex.
Decrease resistance of afferent arteriole
(dilate)
↓
Hydrostatic pressure in the peritubular
capillaries increases
↓
Increase Na back leak
↓
Fluid in the peritubular capillaries can go
out to the renal tubule
↓
Decrease reabsorption of Na
Ex.
a)
b)
c)
d)
e)
Increase glomerular hydrostatic pressure
↓
Increases filtration rate
↓
Increase filtration fraction
↓
Increase oncotic pressure in the
peritubular capillaries
↓
Water is attracted – decreasing Na
backflow
↓
Increase water reabsorption
↓
Na is also reabsorbed in the PCT – solvent
drag
Diagram: RAAS; effects of angiotensin II
Potentiates sympathetic activity
 Increase Na reabsorption
Increase Na reabsorption in the tubules
Potentiates the release of aldosterone
 Aldosterone will increase Na
reabsorption
Acts as a vasoconstrictor
 Decreasing the blood flow
 Weak vasoconstrictor: afferent
arteriole and renal artery
 Strong vasoconstrictor: efferent
arteriole
Potentiates ADH release
ANGIOTENSIN II
 released when effective circulation volume
drops
 part of RAAS
 at the PCT, this will increase Na reabsorption
o Na-H antiport
 LOH, DCT & C: increases Na reabsorption
 Increases the sensitivity of tubulogolmerular
feed back
 Helps in the contraction of mesangial cells
o Decreasing Kf  decreasing surface
area
ALDOSTERONE
 Regulate effective circulating volume
 When RAAS activated or when we have
hyperkalemia
o Increases the release of aldosterone
 Natriuretic peptide and hypokalemia
o Decrease aldosterone
 Hyperkalemia is the more potent for the
stimulation of aldosterone release
o Hyperkalemia supersedes RAAS
 Increase Na reabsorption
o ↑ Na-Cl symport
o ↑ Na-K pump
o ↑ ENaC
o ↑Sgk1
o ↑CAP1, prostatin
 Targets DCT, CD and a little bit of LOH for
increased NaCl reabsorption
 Increase K secretion in the DCT and CD
N NATRIURETIC PEPTIDE
 Opposite effects to aldosterone
 Increase Na clearance
o Na goes out together with H2O
Escoto, KC // Gloriani, KP
12 of 16
UROGUANYLIN, GUANYLIN
 Released by GIT and kidneys
 Decrease Na reabsorption
SYMPATETHICS (NOREPINEPHRINE AND
EPINEPHRINE)
 Decrease effective circulating volume drops –
activating sympatethics
o Increase NaCl and H2O reabsorption
 Potentiated by RAAS
DOPAMINE
 Increase ECV  dopamine goes up
 Decrease NaCl and H2O reabsorption
ADRENOMEDULIN
 Produced by the kidneys
 When a patient has a congestive heart failure
(CHF) or long standing hypertension 
adrenomedulin inreases
 Increase RBF and GFR
 Decrease NaCl and H2O reabsorption
URODILATIN
 Produced by the kidney
 Long standing hypertension & increase ECF
volume  increases urodilatin production
 Decreases NaCl and H2O reabsorption
GLOMERULOTUBLAR BALANCE
 Increase filtered load  increase reabsorption
rate of Na
Increased GFR
↓
↑ Filtration fraction
↓
↑ oncotic pressure in the peritubular capillaries due to
plasma CHON
↓
Water goes back to peritubular capillaries
↓
Solute is also reabsorbed via solvent drag
Increased CHO and Amino acid intake (all of them must
be reabsorbed), this will increase Na reabsorption.
In Tubuloglormerular / glomerulotubular feedback
 RBF and GFR should be constant. This is also
regulated by glomerulotubular balance because it
determines the amount of Na going to the macula densa
and the macula densa is the one responsible in
activating tubuloglomerular feedback.
Table: Different segments of your nephron, the
percentage of Na being reabsorbed and the different
transport mechanisms. You also have your regulatory
hormones that will affect reabsorption of Na.
RED TEXT – increase reabsorption
BLUE TEXT – decrease reabsorption
POTASSIUM
 K secretion depends on Na availability
o If Na is available then K will secreted
 Majority of K reabsorption occurs in PCT
 K is secreted in the late DCT and CD
o Via the principal cells
o This is how you regulate K excretion
Na not available
↓
Decreased K secretion
NOTE: When Na is reabsorbed, K will be secreted in the
principal cell
For intercalated cells:
Metabolic Acidosis – the body will have the preference
of secreting H+ instead of K
↓
K secretion decreases (increased plasma K)
hyperkalemia
EFFECTS OF SYMPATETHICS on K – dual effect
 Alpha receptor stimulation
o Promote K release
 Beta2 receptor stimulation
o Promote K uptake
EFFECT OF INSULIN on K
 Increase K uptake together with glucose
EFFECTS OF ALDOSTERONE
 Increase K secretion
 Decrease K uptake
EFFECT OF METABOLIC & RESPIRATORY ALKALOSIS
 Opposite to metab acidosis, ↓ plasma K
Escoto, KC // Gloriani, KP
13 of 16
RESPIRATORY ACIDOSIS
 no effect in K homeostasis simply because the
lungs will try to correct acid-base disorders
CONDITIONS THAT  PLASMA K
 Acidosis
 ↑ plasma osmolality
o Decrease in intracellular fluid volume
 Cell lysis
o Potassium goes out of the cell
increasing plasma K
 Exercise
o Transient increase in plasma K due
to Action potentials
o When we produce AP, when we
depolarize, Na enters and everytime
we repolarize, K goes out increasing
plasma K.
FACTORS THAT  K SECRETION
 Hyperkalemia
o Will increase aldestorone production
o Aldosterone increases K secretion
 Aldosterone
o Increases K secretion in the DCT and
CT
o Increase in angiotensin II and plasma
K  increases aldosterone
o Decrease in plasma K and natriuretic
peptides  decreases aldosterone
 ADH
o Other than reabsorbing water, it also
acts as vasoconstrictors

When BVs are constricted
 ↓GFR  decreased
tubular flow  decreases K
secretion.
o In the principal cells, you increase
the electrochemical driving force
for the exit of K increases K
secretion
o Net effect of K is zero = constant K
secretion and excretion
 ↑ flow of tubular fluid / flow of the filtrate
o Increases K secretion
o Activates primary cilia

Activates K channels, K goes
out
o Increase Na in the filtrate  increase
Na
uptake

increased
electrochemical driving force for K to
exit
 Glucocorticoids
o Mineralocorticoid effects of cortisol
(increase Na reabsorption)
o Promotes K excretion
 Acid-base balance
o See earlier discussion of alkalosis
and acidosis
Figure: Potassium handling in the phase of metabolic
acidosis where in you have acute and chronic.
Acute Metabolic acidosis
 Decreased in K excretion
o The principal cells and intercalated
cells will rather retain K and excrete
H+
 The body will reabsorb K and removes H+
Evolution to Chronic Metabolic Acidosis
 With a decrease in K excretion, you now
slowly goes to chronic metabolic acidosis
o This will increase plasma K
(hyperkalemia)
 This will trigger the release of aldosterone
o Aldosterone will now promote the
release of K from the principal cells
 So in chronic MA, K goes out
Table: Few conditions and how K handling happens.
*not discussed by Dr. RAC but he said go over it so I
grabbed texts from Apolinario’s trans*
Escoto, KC // Gloriani, KP
14 of 16
This is K secretion by the DCT and collecting ducts. If
the individual has hyperkalemia, the increase in plasma
K has a direct effect on the DCT and collecting tubule
increasing its secretion. Hyperkalemia will also increase
flow rate. So net effect is K excretion – it goes out.
Looking at the effect of aldosterone. In acute,
aldosterone will target DCT and collecting ducts
promoting K secretion that’s why K secretion goes up.
However with the reabsorption of water, flow rate
decreases. As far as flow rate is concerned, since renal
handling of K is gradient time dependent, in this regard,
K excretion decreases. Here you have an increase in K
secretion and decrease in K secretion and the net effect
is no change.
CALCIUM and PHOSPHATE
 Three hormones will come into play
o PTH
o Vit. D
o Calcitonin

Sulphate
 majority is reabsorbed in PCT
 Transport Maxima (Tm) = 0.06 mM/min
Ammonia (NH3) and Hydrogen
 Participates in the acid-base regulation
 NH3 participates in Glutamine metabolism
o When Glutamine is metabolized, 2
moles of HCO3 is added into the
blood that will participate in acidbase balance
Bicarbonate
 HCO3 participates in acid-base balance.
 All filtered HCO3 are reabsorbed
o
Since all HCO3 is reabsorbed, there is
excess H compared to HCO3 making
the urine acidic
 Alkalosis: decreased HCO3 reabsorption
 Acidosis: Increased HCO3 reabsorption
Glucose




Calcium
 Protein bound are not filtered
 Only ionized Ca is filtered and reabsorbed
Phosphate
 Acts as buffers
CHLORIDE, MAGNESIUM & SULFATE
 All are reabsorbed
Chloride
 majority is reabsorbed in PCT
 passively reabsorbed
 reabsorption is associated with handling of Na
and H2O
Magnesium
 Free Mg is filtered and reabsorbed
 Reabsorbed through Claudin-16 due to back
leak
Protein-bound Mg is not filtered
Actively reabsorbed (transport maxima)
o Maximum rate of absorption
TM: 375 mg/min
Renal Threshold for reabsorption rate: 220
mg/min
Renal Threshold for plasma glucose = 200 mg
/ dL
o If blood glucose levels will exceed
200 mg / dL, it will now start to
appear in the urine (glucosuria)
Application: (1:31:00)

If plasma glucose level = 200mg/dL, the
amount of glucose being filtered is 200
mg/min

The reabsorption rate is 220 mg/min

At this rate, glucose will already start to
appear in the urine
o Notice that it is much less in the
transport maxima
How come glucose will start to appear in the urine
even though transporter are not saturated?

Let’s have two side containing nephrons
o First side = nephrons containing 300
transporters (300 mg /min of
glucose)
o 2nd side = 200 transporters (200 mg
/ min)
o TM will be at 300 because that is the
maximum transport rate

A plasma will contain 150 mg of glucose and
all of the nephrons will be given 150 mg of
glucose
o 150 mg of glucose will be reabsorbed
by both sides leaving no glucose in
the urine
Escoto, KC // Gloriani, KP
15 of 16



Another plasma comes and contains 200 mg of
glucose
o 200 mg of glucose will be reabsorbed
by both sides leaving no glucose in
the urine
Another plasma again comes and contains 250
mg of glucose
o The 2nd side will reabsorb 200 mg of
glucose
o The first side will reabsorb 250 mg of
glucose
o 50 mg of urine will be left in the
urine even though TM is not reached
So the answer is NOT ALL NEPHRON
CONTAINS THE SAME NUMBER OF
TRANSPORTERS
o That is why we want to maintain
blood glucose level at less than 200
mg/dL
Amino acids
 Different amino acids will have various
carriers
 Tm: 1.5 mM/min
Vitamin C
 Filtered, reabsorbed, and secreted
o Depending on the concentration
 Tm: 2 mg/min
 ↑ adrenal steroids, ↑ vit c secretion
 ↑ filtered load of Na, ↑ vit c secretion
Urea


Filtered and reabsorbed at varying degrees
Reabsorption depends on ADH
Uric acid
 Reabsorbed
 Tm: 15 mg/min
Creatine
 Filtered and REABSORBED
 No Tm has been demonstrated
Creatinine
 Filtered and SECRETED
 Tm: 16 mg/min
Escoto, KC // Gloriani, KP
16 of 16
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
Autonomic Nervous System (defn)
Structures of the nervous system
12 Pairs of Cranial Nerves
Portion of the nervous system which controls the visceral functions of the body
1. Cardiac function
2. Blood pressure
3. Respiration
4. Glandular activity
1. Brain
2. Spinal Cord
3. Cranial Nerves
4.
Spinal Nerves
5. Ganglia
6. Enteric Plexus
7. Sensory Receptors
Mnemonic: Oh Oh Oh To Touch And Feel Very Green Vegetables AH
I.
Olfactory
II. Optic
III. Oculomotor
IV.
V.
VI.
Trochlear
Trigeminal (Opthalmic/Maxillary/Mandibular)
Abducens
VII. Facial
VIII. Vestibulocochlear
IX. Glossopharyngeal
X. Vagus Nerve
31 Pairs of Spinal Nerves
XI. Accessory Nerve
XII. Hypoglossal Nerve
Note: Cranial Nerves that are part of ANS – III, VII, IX, X
8 Cervical Nerves (C1-C8)
12 Thoracic Nerves (T1-T12)
(Note: highlighted - part of ANS)
5 Lumbar Nerves (L1-L5)
5 Sacral Nerves (S1-S5)
5 Components of a Reflex Arc
Reflex Arc Activity
Sensory Receptors
4 Types of Nerve Fibers
Afferent (Sensory)
Efferent (Motor)
Divisions of the Peripheral Nervous System
CPalafox (1A)
Cervical Plexus
Brachial Plexus
Intercostal/Thoracic Nerves
Subcostal nerve
Lumbar Plexus
Sacral Plexus
1 Pair of Coccygeal Nerves/Roots
1. Sensory receptors
2. Afferent nerve – is a sensory nerve, transmits sensory impulses from the sensory receptors to the
center
3. Center – CNS (brain and spinal cord)
4. Efferent nerve - is a motor nerve, transmits motor impulses from the center to the different
effector cells
5. Effector Cells – four types (Skeletal, cardiac, smooth muscle, glands)
1. Receptor potential – local potential generated by sensory receptors when stimulated.
2. If threshold voltage, Local Potential Action Potential / Sensory Impulse - Transmitted by an
afferent nerve to the center.
3. The center will analyze the sensory impulse, and then generate a motor impulse.
4. Motor impulse will be transmitted by efferent nerve to the different effector cells/organs.
5. Effector cells perform the function, as dictated by the motor impulse.
Sensory receptors are specialized structures located in almost all parts of the body, stimulated by changes
inside/outside the body.
1. Mechanoreceptors (ex. intestinal walls, stretching of walls because of retained food)
2. Thermoreceptors (ex. skin, changes in temperature)
3. Photoreceptors (ex. eyes, changes in the wavelength of light)
4. Chemoreceptors (ex. mouth, chemical composition of food)
5. Baroreceptors (ex. blood vessels, arterial wall is stretched during BP increase)
6. Nociceptors (ex. Free nerve endings – for pain)
Somatic
Visceral
1. Somatic Afferent (Sensory)
2. Visceral Afferent (Sensory)
From:
To:
From:
To:
Head
CNS
Viscera (Internal organs)
CNS
Body wall
Extremeties
3. Somatic Efferent (Motor)
4. Visceral Efferent (Motor)
From:
To:
From:
To:
CNS
Striated Voluntary
CNS
Internal Organs
Muscles (Skeletal
Glands
Muscles)
Smooth and Cardiac
(Involuntary) Muscles
SOMATIC NERVOUS SYSTEM
AUTONOMIC NERVOUS SYSTEM
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
Peripheral Nervous System
1.
2.
Central Nervous System
1.
2.
Difference between Somatic and
Autonomic Nervous System
PERIPHERAL NERVOUS SYSTEM
12 pairs Cranial Nerves and its branches (originating from the brain stem)
31 pairs Spinal Nerves and its branches (originating from the segments of the spinal cord)
CENTRAL NERVOUS SYSTEM
Brain
Spinal Cord
Somatic
Autonomic
Reflexes
VOLUNTARY MOVEMENT / CONSCIOUS /
DELIBERATE RESPONSE
Function
Orients individual to the external environment;
bring about movement for locomotion
Located in the head, body wall, extremeties
•
Somatic senses (tactile, thermal, pain and
proprioceptive sensations) and
•
Special senses (vision, hearing, taste, smell
and equilibrium)
•
One-neuron fiber, directly forms a link
with the effector cell at the
neuromuscular junction (NMJ)
Sensory Input/ Receptors
Structure of the Efferent Nerve / Fibers
single Somatic Efferent Fiber
ONE NEURON PATHWAY:
•
Main Center
Effector Cell / Innervation
NTA
Inhibit or Block transmission of motor
impulses
Effect if innervation is cut
•
Excitation / Inhibition
•
Subdivisions of ANS
Enteric NS
1.
2.
3.
4.
5.
Anatomical Differences between SNS and
PSNS
Origin of Pre-ganglionic fiber
CPalafox (1A)
•
Visceral Efferent Fibers divided by the
peripheral ganglion (PG)
TWO NEURON PATHWAY
•
Preganglionic (CNS- Preganglion-PG)
•
Postganglionic (PG-PostganglionEffector)
Exception: Adrenal Medulla (CNS-AM) fiber
is identical to autonomic preganglionic
fibers; cells of AM are identical to
autonomic postganglionic fibers
CNS - Somatic Efferent Fiber Effector Cell )
Mainly by Cerebral cortex; lesser by basal
ganglia, cerebellum, spinal cord
Skeletal striated muscle
Acetylcholine
At 2 locations: Center and NMJ junction
•
INVOLUNTARY MOVEMENT / UNCONSCIOUS /
AUTOMATIC INSTANTANEOUS RESPONSES
Note: some are mostly involuntary/partly voluntary
(respiration, micturation, defecation)
Regulates functions of different internal organs; involved
in constancy of internal env. of the body (HOMEOSTASIS)
Located in internal organs
Associated with interoceptors (sensory receptors in
blood vessels, visceral organs, muscles and nervous
system) that monitor conditions in the internal
environment
•
Two-neuron fiber, synapse first with
peripheral/autonomic ganglion
•
Autonomic ganglion – neuron outside the CNS;
located at the center.
No contraction if nerve is cut; complete
paralysis, atrophy
NON AUTOMATIC cell – ex. Skeletal
muscle cell
Always leads to excitation of the muscles
(Contraction of the skeletal muscle)
Hypothalamus, brain stem, spinal cord
Visceral/ Smooth, cardiac muscle, or gland cells
Acetylcholine and Norepinephrine
At 3 locations: Center, Peripheral Ganglia, Neuroeffector
Junctions
•
Can maintain activity
•
Cardiac – has automatic cell; ex. synoatrial node
•
Visceral cells also have automatic cells.
•
AUTOMATIC cell – capable of generating its own
action potential spontaneously, independent of
stimulation.
•
Can lead to excitation or inhibition of the effector
cells
Smooth Muscle: contraction or relaxation;
Cardiac: increased or decreased rate and force
of contraction;
Glands: Increased or decreased secretion of
glands)
1. Enteric NS
2. Sympathetic NS (SNS)
3. Parasympathetic NS (PSNS)
GIT Has its own nervous system
Neurons lie in the GIT wall (esophagus to anus):
a.
Myenteric or Auerbach Plexus – GIT motor
b. Meissner’s plexus regulate secretory activity of GIT
Can regulate activities GIT activities but ENTERIC activities are regulated by SNS and PNS.
SYMPA postganglionic fibers will synapse with GIT neurons. Indirectly innervates the organs of the GIT.
SYMPA stimulation will decrease GIT motor and secretory activities
PARASYMPA preganglionic fibers that will synapse with the Enteric NS (like a peripheral ganglion).
PARASYMPA stimulation will increase GIT motor and secretory activities
SNS
PSNS
Thoracolumbar division
•
Craniosacral division
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
1.
Innervates
Location of the Peripheral Ganglion
(See Fig. 15.2 15.3 of Tortora)
Originate from the spinal cord (T1-L3)
T1-T2: Head and Neck; smooth muscle of eye
and salivary glands
2. T3-T5: Thoracic region; heart, lungs and
bronchi
3. T6-T12: Enteric NS; stomach, small intestine,
proximal half of large intestine, liver, pancreas
and gall bladder
4. L1-L3: distal half of large intestine, rectum,
anus, genitourinary system
5. T1-L3: sweat glands and the vascular smooth
muscle
SYMPATHETIC AND PREVERTEBRAL GANGLIA
Near the center and far from effector cells
1. sympathetic chain - 22 pairs of ganglion
(beside vertebral column: paravertebral
location)
•
Superior cervical ganglion
•
Middle cervical ganglion
•
Stellate ganglion
2. collateral ganglia -3 pairs of ganglion
(Abdominal/pelvic region, in front of vertebral
column: prevertebral)
•
Celiac ganglion
•
Superior mesenteric
•
Inferior mesenteric
1.
2.
1.
TERMINAL GANGLIA
A. Ganglia far from the center but near the
effector cells
1. III Oculomotor: celiary ganglion: smooth muscle
of the eye
2. VII Facial:
a.
pterigopalatine ganglion: nasal and
lacrimal glands
b. Submandibular ganglion: submandibular
glands
3. IX Glossopharyngeal: otic ganglion: parotid
glands
B.
4.
Length
Branching of Preganglionic fibers
Neurotransmitter Agent
Locations where NTAs are released
Steps in Biochemical Transmission
CPalafox (1A)
Ganglia far from the center and inside the
effector cell
X Vagus, Sacral parasympathetic nerves (pelvic
nerves) a.
Vagus nerve:
•
Thoracic cavity (heart, lungs, bronchi)
•
Abdomen (Esophagus, stomach, small
intestine, proximal half of the large
intestine, Liver, pancreas, gall bladder)
b. Pelvic nerves: Distal half of large intestine,
rectum, anus, genitourinary system
•
•
•
•
•
Preganglionic fiber < Postganglionic fiber
Short Pre Long Post
Extensive branching
1 Pre : 20post
Sympathetic effects are more widespread and
diffuse
1.
2.
1.
2.
1.
Cholinergic Transmission – mediated by Acetylcholine (Ach)
Noradrenergic or Adrenergic transmission – by Norepinephrine (Nor)
Somatic Efferent : NMJ
Autonomic Efferent: region of peripheral ganglion and neuroeffector junction
Synthesis and Storage of neurotransmitter agent – synthesis in the ribosomes; stored in secretory
vesicles
Release of NTA at the synaptic cleft – motor impulse reaches nerve ending; highly permeable to Calcium
ions (influx); interaction of membrane proteins - Syntaxin and synaptobrevin – cause vesicles to fuse
with nerve terminal membrane; exocytose the NTA into the synaptic cleft
Interaction - NTA binds with receptors and elicits a physiologic response from effector cell
Deactivation of NTA – unbinding from the receptor
Ligand-activated / Ion channels
2. G-Protein coupled receptor
NTA + Receptor Opens specific ion channels
NTA + Receptor activate G-proteins bound to
a.
If Na+ channels, Na+ influx, depolarization
the inner surface of the cell membrane
will lead to excitation
Activate specific intracellular (I/C) enzymes
b. If K+ channels, K+ efflux, hyperpolarization
that will lead to formation of intracellular
will lead to inhibition
ligands (aka Second Messengers), which
c.
If channels are on effector cell, elicit an
will mediate the action of the NTA on the
immediate but short-lived response from
effector cell.
the effector cell.
Produces a delayed response but longer
Ex. Ach binding to nicotinic receptors on
duration that persists even if NTA is no
membrane of skeletal muscle cell longer present
Ach+Nicotinic: Ligand-gated channel
a.
NTA + Receptor activate G-Proteins activate enzyme system, (+) Adenylyl
cyclase formation of ↑cAMP (cyclic
2.
INTERACTION STEP / Membrane Receptors
Some originate from brain stem (CN III, VII, IX, X)
Some originate from spinal cord (S2-S4)
3.
4.
1.
•
•
•
•
•
Preganglionic fiber > Postganglionic fiber
Long Pre Short Post
Limited branching
1Pre : 1Post
PS Effects are more localized except those of the
vagus nerve
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
b.
Deactivation of NTA
Cholinergic transmission is present in:
Adrenergic transmission is present in:
adenosyl monophosphate is the I/C ligand
or second messenger) activate (+)
protein kinase A phosphorylation of
other enzymes that will elicit specific
responses from the cell
Ex. Catecholamines (Nor, EP) + beta
receptors;
Acetylcholine + muscarinic receptors
beta receptors and muscarinic receptors
are G-protein coupled receptors
NTA + Receptor activate G-Proteins activate enzyme system, (+)
phospholipase C breakdown of
phosphoinositol biphosphate PIP2,
forming 2 products:
i. Inositol triphosphate IP3 increase I/C Ca2+; Calcium can
function as second messenger
ii. Diacyl glycerol DAG (+) Protein
kinase C causes phosphorylation
of I/C proteins stimulate specific
biochemical responses from the cell
Ex. Catecholamines + alpha receptors;
Acetylcholine + muscarinic receptors
(depending on the location in the body)
Enzymatic deactivation - deactivation by enzymes in
the synaptic cleft
Ex. Ach deactivation by acetylcholinesterase
1. Cholinergic effects short in duration
Re-uptake
Ex. Deactivation of norepinephrine
1. After unbinding from the receptor
2. Actively transported back in the terminal but
will not be stored in vesicles. These will be
destroyed by monoamineoxidase
3. Other NEP: circulated in the blood and
transported to the liver, where NEP is
deactivated by enzyme catechol-O-methyl
transferase (COMT)
1. All somatic neuromuscular junction (Somatic to skeletal muscle)
2. All autonomic ganglia (all preganglionic to all postganglionic in both SNS and PSNS)
3. All parasympathetic neuroeffector junctions (all PS effects to internal organs; biochemically, PSNS is
referred as Cholinergic division; PSNS division is craniosacral (anatomically) and cholinergic
(biochemically))
4. Sympathetic cholinergic neuroeffector junctions, only if effectors are sweat glands and vascular smooth
muscles present in skeletal muscles.
5. All sympathetic adrenergic neuroeffector junction. (all sympathetic effects to internal organs)
Sympathetic division is thoracolumbar (anatomically) and noradrenergic (biochemically).
Somatic NS
Parasympathetic NS
Sympathetic Cholinergic
Sympathetic Adrenergic
(Syncholinergic) NS
(Synadrenergic) NS
C
C
C
Ach
EC
Ach
PG
PG
Ach
Ach
EC
C
Ach
EC
** Only in sweat glands and
vascular smooth muscles
present in skeletal muscles
Cholinergic Transmission
CPalafox (1A)
Ach
PG
NEP
EC
** most sympathetic effects
to internal organs are
mediated by NEP
Transmission mediated by Acetylcholine
1. Synthesis of Acetylcholine: Choline + Acetyl CoA Ach, catalyzed by choline acetyl transferase. It will be
stored temporarily in vesicles located at the nerve ending.
2. (Release) When an AP reaches the nerve ending, there will be Ca2+ influx, which will cause Ach to be
released into the synaptic cleft.
3. (Interaction) Ach binds to membrane receptors (cholinergic receptor) on the effector cell.
4. (Deactivation) Main mechanism is enzymatic destruction/deactivation by acetylcholinesterase, which is
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
also present in the synaptic cleft, where it can immediately deactivate acetylcholine. This makes
cholinergic or Parasympathetic effects short in duration.
1. Nicotinic – can also be stimulated by small dose 2. Muscarinic – can be stimulated by small doses
of nicotine
of muscarine
a.
Present in all somatic neuromuscular
a.
all parasympathetic neuroeffector junction
junction (membrane of skeletal muscle
b. all sympathetic cholinergic neuroeffector
cells contain Nicotinic receptors)
junction (sweat glands, vascular smooth
b. Present in all autonomic peripheral
muscle present in the skeletal muscle
Subdivided into M1-M5:
ganglia
c.
c.
Mainly made of proteins, classified as
•
M1 – brain, stomach (if M1 receptors
Ligand-gated receptor: (+) open Na+
in stomach is stimulated, increase in
channel
gastric secretion)
d. Always elicits an excitatory reaction
•
M2 – most abundant heart and
visceral smooth muscles
•
M3 – visceral smooth muscles and
glands
•
M4 – visceral smooth muscles and
glands
•
M5 – least abundant; present only in
sphincter muscles of the iris,
esophagus, parotid glands, cerebral
blood vessels
d. G-protein coupled receptor response
may be either excitatory or inhibitors
Transmission mediated by NEP
1. Synthesis of NEP:
a.
Steps:
phenylalanine β tyrosine, catalyzed by phenylalanine hydroxylase.
β tyrosine DOPA, catalyzed by tyrosine hydroxylase.
DOPA Dopamine, catalyzed by DOPA decarboxylase.
Dopamine Norepinephrine, catalyzed by dopamine β-hydroxylase.
b. Location: at the nerve ending of sympathetic adrenergic efferent / postganglionic nerve endings.
c.
Regulation: by a negative feedback mechanism; if there is an excess of dopamine and
norepinephrine, it will cause inhibition of the enzyme tyrosine hydroxylase.
d. A sagittal section of adrenal glands reveals 2 parts:
outer part: adrenal cortex (secretes steroid hormones) and
inner part: adrenal medulla (converts norepinephrine epinephrine, catalyzed by
phenylethanolamine-N-methyl transferase).
e. Sympathetic adrenergic postganglionic nerve endings can synthesize/release NEP only.
Adrenal medulla can synthesize/release both NEP and EP (collectively known as catecholamines).
2. (Release) When an AP reaches the nerve ending, there will be Ca2+ influx, which will cause NEP to be
released into the synaptic cleft.
3. (Interaction) NEP or EP binds to membrane receptors (noradrenergic or adrenergic receptors) on the
effector cell.
4. (Deactivation) Main mechanism is reuptake. Actively transported back in the terminal but will not be
stored in vesicles. These will be destroyed by monoamineoxidase. Other NEP: circulated in the blood and
transported to the liver, where NEP is deactivated by enzyme catechol-O-methyl transferase (COMT).
This makes adrenergic or Parasympathetic effects short in duration.
Types of Cholinergic receptors
Adrenergic Transmission
4 Types of Adrenergic receptors
1.
α1
a.
2.
•
•
Organ
Heart
CPalafox (1A)
4.
α2
a.
b.
•
3.
Present in visceral smooth muscles and
glands
Present only at nerve terminal
NEP+ α2 NEP inhibition
Negative feedback mechanism, inhibit
further release of norepinephrine
Alpha receptors when stimulated, mostly elicit
excitatory reaction (exemptions below)
Examples:
NEP+ α1 Radial muscle of iris, muscle
contracts (excitatory) = increase in
pupillary size;
EP+ α1 vascular smooth muscle, muscle
contracts (excitatory) = vasoconstriction
Exemptions: Digestive system, pancreatic
islets, bronchial gland, effects are inhibitory
Cholinergic
M2
•
•
•
β1
a.
Only in heart
β2
a.
Present in visceral smooth muscles and
glands
Beta receptors when stimulated, elicit mostly
inhibitory reaction (exemptions below)
Examples:
NEP + smooth muscle receptors in
Bronchial wall, smooth muscles relax =
broncodilation;
EP+ β2 Vascular smooth muscle, muscle
relaxes = vasodilation
Exemptions: heart, bronchial glands, pancreatic
islets, effects are excitatory
Adrenergic:
β1
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
Salivary glands
Intestinal wall
Bronchial
Adrenal Medulla:
Differentiate from other visceral organs in
the body:
Difference from the rest of the
sympathetic adrenergic system:
M3-M4
M2-M3-M4
M3-M4
Sympathetic: innervated by postganglionic fibers
Sympathetic adrenergic: release NEP to immediate
vicinity of neuroeffectors
α1, β2
α1, β2
α1, β2
Adrenal Medulla
AM is innervated by pre-ganglionic fibers.Cells of AM
are histologically similar to a sympathethic ganglion
•
When the sympathetic division is stimulated,
the AM is also stimulated, which causes it to
release NEP and EP. These NTA are released and
circulated in the blood stream, and are
distributed to sympathetic neuroeffector
junctions in all parts of the body.
•
Reinforces/potentiates the sympathetic
adrenergic effects.
•
AM considered a part of sympathetic adrenergic
nervous system
Sympathetic preganglionic fibers
Ach
(N) Adrenal Medulla
NEP + EP ***
Circulation
(+)α1, β1, β2 receptors ***
↑sympathetic adrenergic effects
*** Comparison between the effects of NEP and EP
•
NEP is a strong stimulator of α and β1 receptors
but is a weak stimulator of β2.
•
EP is a strong stimulator of α1, β1, β2 receptors.
Dual Innervation and Antagonistic Effects
Physiologic/Functional Differences
between Sympathetic and
Parasympathetic Nerves
Energy
Duration
Effects
CPalafox (1A)
•
Sympathetic NS and PSNS are PHYSIOLOGIC ANTAGONISTS, produces opposite effects.
1.
Dual innervation of the SAME structure of the SAME organ produces OPPOSITE effects.
Ex. Heart
Sympathetic N (↑HR) SA Node  Vagus/CNX, Parasympathetic (↓HR)
2.
Dual innervation of 2 DIFFERENT structures in the SAME organ produces OPPOSITE effects.
Ex. Eyeball – Pupil regulates the amount of light entering the eye
Iris: radial muscle (Sympathetic): absence of light pupil dilates
Sphincter muscle (Oculomotor CN3 parasympathetic): presence of light pupil constricts
3.
Dual innervation of 2 DIFFERENT structures in the SAME organ produces SYNERGISTIC effects.
Ex. Salivary gland
Para: profuse increase in salivary secretion: loose, watery secretion
Sympa: mild moderate increase in salivary secretion: viscous secretion
4.
Single innervations
No parasympathetic innervation. Sympathetic innervation only.
Ex. Kidneys, sweat gland, pilo arrector muscle in skin, vascular smooth muscle
SyNS
PSNS
Catabolic
Longer, Prolonged duration
Reason: Norepinephrine at NEJ that is not
immediately deactivated; additionally
mediated by norepinephrine and epinephrine
in the blood stream
Fight-or-Flight
Stimulation of sympathetic nerves enables
individuals to cope or withstand stressful
conditions
Anabolic
Short duration
Reason: Mediated by Ach, immediately
deactivated
Rest/Digest
Conservation/restoration of the body’s
processes
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
Fight-or-Flight (Catabolic)
↑HR
↑BP
Nor
Epi
Response
Timing
Center
Rest/Digest (Anabolic)
↓HR
↓BP
β1
Peripheral Vasoconstriction
α1
M2,
M3
Peripheral Vasodilation
Ach
↑Lipid Breakdown
β2
↓Lipid Breakdown
Coronary Dilation
Bronchial Dilation
β2
Bronchoconstriction
Glycogen Glucose
β2
Generalized, diffuse response
Reason: extensive branching of the preganglionic fibers
Coordinated; response occurs at the same time
Muscarinic receptor
Nicotinic receptors
M3
M3
Glucose Glycogen
Localized response, except for Vagus nerve
Reason: limited branching, except for Vagus
nerve
Coordinated; but some processes do not have to
occur at the same time (ex. micturation, defecation,
erection)
Head ganglion of the ANS – Hypothalamus
•
Anterior hypothalamus – coordinates
Cholinergic activities
•
Posterior/ Lateral hypothalamus –
coordinates Adrenergic activities
Example: Baroreceptor Reflex
Increased Arterial Blood Pressure (ABP) stretch arterial walls
(+) Baroreceptor (-)/inhibit Vasomotor center (medulla)
Decrease sympathetic outflow
Increase parasympathetic outflow
Vasodilation
Decrease cardiac activity
Decrease cardiac activity
Decrease ABP
Decrease ABP
Pharmacological Differences
A.
B.
CPalafox (1A)
Parasympathetic
Cholinergic
↑ / Potentiate cholinergic or parasympathetic
effect
↑ synthesis of Ach
↑ release of Ach
↑ interaction between Ach and cholinergic
receptor
(-) deactivation of Ach
PARASYMPATHOMIMETIC –mimics the effects
of parasympathetic stimulation
Anticholinergic
↓ / Block cholinergic or parasympathetic effect
synthesis of Ach
↓ release of Ach
Block interaction between Ach and cholinergic
receptor
↑ inactivation of Ach
PARASYMPATHOLYTIC
A.
B.
Sympathetic Adrenergic
Adrenergic
↑ / Potentiate adrenergic or sympathetic effect
↑ synthesis of NEP
↑ release of NEP
↑ interaction between NEP and adrenergic
receptor
(-) inactivation of NEP
SYMPATHOMIMETIC –mimics the effects of
sympathetic stimulation
Antiadrenergic
↓ / Block adrenergic or sympathetic effect
synthesis of NEP
↓ release of NEP
Block interaction between NEP and adrenergic
receptor
↑ deactivation of NEP
SYMPATHOLYTIC
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
Autonomic Nervous System (defn)
Structures of the nervous system
12 Pairs of Cranial Nerves
Portion of the nervous system which controls the visceral functions of the body
1. Cardiac function
2. Blood pressure
3. Respiration
4. Glandular activity
1. Brain
2. Spinal Cord
3. Cranial Nerves
4.
Spinal Nerves
5. Ganglia
6. Enteric Plexus
7. Sensory Receptors
Mnemonic: Oh Oh Oh To Touch And Feel Very Green Vegetables AH
I.
Olfactory
II. Optic
III. Oculomotor
IV.
V.
VI.
Trochlear
Trigeminal (Opthalmic/Maxillary/Mandibular)
Abducens
VII. Facial
VIII. Vestibulocochlear
IX. Glossopharyngeal
X. Vagus Nerve
31 Pairs of Spinal Nerves
XI. Accessory Nerve
XII. Hypoglossal Nerve
Note: Cranial Nerves that are part of ANS – III, VII, IX, X
8 Cervical Nerves (C1-C8)
12 Thoracic Nerves (T1-T12)
(Note: highlighted - part of ANS)
5 Lumbar Nerves (L1-L5)
5 Sacral Nerves (S1-S5)
5 Components of a Reflex Arc
Reflex Arc Activity
Sensory Receptors
4 Types of Nerve Fibers
Afferent (Sensory)
Efferent (Motor)
Divisions of the Peripheral Nervous System
CPalafox (1A)
Cervical Plexus
Brachial Plexus
Intercostal/Thoracic Nerves
Subcostal nerve
Lumbar Plexus
Sacral Plexus
1 Pair of Coccygeal Nerves/Roots
1. Sensory receptors
2. Afferent nerve – is a sensory nerve, transmits sensory impulses from the sensory receptors to the
center
3. Center – CNS (brain and spinal cord)
4. Efferent nerve - is a motor nerve, transmits motor impulses from the center to the different
effector cells
5. Effector Cells – four types (Skeletal, cardiac, smooth muscle, glands)
1. Receptor potential – local potential generated by sensory receptors when stimulated.
2. If threshold voltage, Local Potential Action Potential / Sensory Impulse - Transmitted by an
afferent nerve to the center.
3. The center will analyze the sensory impulse, and then generate a motor impulse.
4. Motor impulse will be transmitted by efferent nerve to the different effector cells/organs.
5. Effector cells perform the function, as dictated by the motor impulse.
Sensory receptors are specialized structures located in almost all parts of the body, stimulated by changes
inside/outside the body.
1. Mechanoreceptors (ex. intestinal walls, stretching of walls because of retained food)
2. Thermoreceptors (ex. skin, changes in temperature)
3. Photoreceptors (ex. eyes, changes in the wavelength of light)
4. Chemoreceptors (ex. mouth, chemical composition of food)
5. Baroreceptors (ex. blood vessels, arterial wall is stretched during BP increase)
6. Nociceptors (ex. Free nerve endings – for pain)
Somatic
Visceral
1. Somatic Afferent (Sensory)
2. Visceral Afferent (Sensory)
From:
To:
From:
To:
Head
CNS
Viscera (Internal organs)
CNS
Body wall
Extremeties
3. Somatic Efferent (Motor)
4. Visceral Efferent (Motor)
From:
To:
From:
To:
CNS
Striated Voluntary
CNS
Internal Organs
Muscles (Skeletal
Glands
Muscles)
Smooth and Cardiac
(Involuntary) Muscles
SOMATIC NERVOUS SYSTEM
AUTONOMIC NERVOUS SYSTEM
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
Peripheral Nervous System
1.
2.
Central Nervous System
1.
2.
Difference between Somatic and
Autonomic Nervous System
PERIPHERAL NERVOUS SYSTEM
12 pairs Cranial Nerves and its branches (originating from the brain stem)
31 pairs Spinal Nerves and its branches (originating from the segments of the spinal cord)
CENTRAL NERVOUS SYSTEM
Brain
Spinal Cord
Somatic
Autonomic
Reflexes
VOLUNTARY MOVEMENT / CONSCIOUS /
DELIBERATE RESPONSE
Function
Orients individual to the external environment;
bring about movement for locomotion
Located in the head, body wall, extremeties
•
Somatic senses (tactile, thermal, pain and
proprioceptive sensations) and
•
Special senses (vision, hearing, taste, smell
and equilibrium)
•
One-neuron fiber, directly forms a link
with the effector cell at the
neuromuscular junction (NMJ)
Sensory Input/ Receptors
Structure of the Efferent Nerve / Fibers
single Somatic Efferent Fiber
ONE NEURON PATHWAY:
•
Main Center
Effector Cell / Innervation
NTA
Inhibit or Block transmission of motor
impulses
Effect if innervation is cut
•
Excitation / Inhibition
•
Subdivisions of ANS
Enteric NS
1.
2.
3.
4.
5.
Anatomical Differences between SNS and
PSNS
Origin of Pre-ganglionic fiber
CPalafox (1A)
•
Visceral Efferent Fibers divided by the
peripheral ganglion (PG)
TWO NEURON PATHWAY
•
Preganglionic (CNS- Preganglion-PG)
•
Postganglionic (PG-PostganglionEffector)
Exception: Adrenal Medulla (CNS-AM) fiber
is identical to autonomic preganglionic
fibers; cells of AM are identical to
autonomic postganglionic fibers
CNS - Somatic Efferent Fiber Effector Cell )
Mainly by Cerebral cortex; lesser by basal
ganglia, cerebellum, spinal cord
Skeletal striated muscle
Acetylcholine
At 2 locations: Center and NMJ junction
•
INVOLUNTARY MOVEMENT / UNCONSCIOUS /
AUTOMATIC INSTANTANEOUS RESPONSES
Note: some are mostly involuntary/partly voluntary
(respiration, micturation, defecation)
Regulates functions of different internal organs; involved
in constancy of internal env. of the body (HOMEOSTASIS)
Located in internal organs
Associated with interoceptors (sensory receptors in
blood vessels, visceral organs, muscles and nervous
system) that monitor conditions in the internal
environment
•
Two-neuron fiber, synapse first with
peripheral/autonomic ganglion
•
Autonomic ganglion – neuron outside the CNS;
located at the center.
No contraction if nerve is cut; complete
paralysis, atrophy
NON AUTOMATIC cell – ex. Skeletal
muscle cell
Always leads to excitation of the muscles
(Contraction of the skeletal muscle)
Hypothalamus, brain stem, spinal cord
Visceral/ Smooth, cardiac muscle, or gland cells
Acetylcholine and Norepinephrine
At 3 locations: Center, Peripheral Ganglia, Neuroeffector
Junctions
•
Can maintain activity
•
Cardiac – has automatic cell; ex. synoatrial node
•
Visceral cells also have automatic cells.
•
AUTOMATIC cell – capable of generating its own
action potential spontaneously, independent of
stimulation.
•
Can lead to excitation or inhibition of the effector
cells
Smooth Muscle: contraction or relaxation;
Cardiac: increased or decreased rate and force
of contraction;
Glands: Increased or decreased secretion of
glands)
1. Enteric NS
2. Sympathetic NS (SNS)
3. Parasympathetic NS (PSNS)
GIT Has its own nervous system
Neurons lie in the GIT wall (esophagus to anus):
a.
Myenteric or Auerbach Plexus – GIT motor
b. Meissner’s plexus regulate secretory activity of GIT
Can regulate activities GIT activities but ENTERIC activities are regulated by SNS and PNS.
SYMPA postganglionic fibers will synapse with GIT neurons. Indirectly innervates the organs of the GIT.
SYMPA stimulation will decrease GIT motor and secretory activities
PARASYMPA preganglionic fibers that will synapse with the Enteric NS (like a peripheral ganglion).
PARASYMPA stimulation will increase GIT motor and secretory activities
SNS
PSNS
Thoracolumbar division
•
Craniosacral division
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
1.
Innervates
Location of the Peripheral Ganglion
(See Fig. 15.2 15.3 of Tortora)
Originate from the spinal cord (T1-L3)
T1-T2: Head and Neck; smooth muscle of eye
and salivary glands
2. T3-T5: Thoracic region; heart, lungs and
bronchi
3. T6-T12: Enteric NS; stomach, small intestine,
proximal half of large intestine, liver, pancreas
and gall bladder
4. L1-L3: distal half of large intestine, rectum,
anus, genitourinary system
5. T1-L3: sweat glands and the vascular smooth
muscle
SYMPATHETIC AND PREVERTEBRAL GANGLIA
Near the center and far from effector cells
1. sympathetic chain - 22 pairs of ganglion
(beside vertebral column: paravertebral
location)
•
Superior cervical ganglion
•
Middle cervical ganglion
•
Stellate ganglion
2. collateral ganglia -3 pairs of ganglion
(Abdominal/pelvic region, in front of vertebral
column: prevertebral)
•
Celiac ganglion
•
Superior mesenteric
•
Inferior mesenteric
1.
2.
1.
TERMINAL GANGLIA
A. Ganglia far from the center but near the
effector cells
1. III Oculomotor: celiary ganglion: smooth muscle
of the eye
2. VII Facial:
a.
pterigopalatine ganglion: nasal and
lacrimal glands
b. Submandibular ganglion: submandibular
glands
3. IX Glossopharyngeal: otic ganglion: parotid
glands
B.
4.
Length
Branching of Preganglionic fibers
Neurotransmitter Agent
Locations where NTAs are released
Steps in Biochemical Transmission
CPalafox (1A)
Ganglia far from the center and inside the
effector cell
X Vagus, Sacral parasympathetic nerves (pelvic
nerves) a.
Vagus nerve:
•
Thoracic cavity (heart, lungs, bronchi)
•
Abdomen (Esophagus, stomach, small
intestine, proximal half of the large
intestine, Liver, pancreas, gall bladder)
b. Pelvic nerves: Distal half of large intestine,
rectum, anus, genitourinary system
•
•
•
•
•
Preganglionic fiber < Postganglionic fiber
Short Pre Long Post
Extensive branching
1 Pre : 20post
Sympathetic effects are more widespread and
diffuse
1.
2.
1.
2.
1.
Cholinergic Transmission – mediated by Acetylcholine (Ach)
Noradrenergic or Adrenergic transmission – by Norepinephrine (Nor)
Somatic Efferent : NMJ
Autonomic Efferent: region of peripheral ganglion and neuroeffector junction
Synthesis and Storage of neurotransmitter agent – synthesis in the ribosomes; stored in secretory
vesicles
Release of NTA at the synaptic cleft – motor impulse reaches nerve ending; highly permeable to Calcium
ions (influx); interaction of membrane proteins - Syntaxin and synaptobrevin – cause vesicles to fuse
with nerve terminal membrane; exocytose the NTA into the synaptic cleft
Interaction - NTA binds with receptors and elicits a physiologic response from effector cell
Deactivation of NTA – unbinding from the receptor
Ligand-activated / Ion channels
2. G-Protein coupled receptor
NTA + Receptor Opens specific ion channels
NTA + Receptor activate G-proteins bound to
a.
If Na+ channels, Na+ influx, depolarization
the inner surface of the cell membrane
will lead to excitation
Activate specific intracellular (I/C) enzymes
b. If K+ channels, K+ efflux, hyperpolarization
that will lead to formation of intracellular
will lead to inhibition
ligands (aka Second Messengers), which
c.
If channels are on effector cell, elicit an
will mediate the action of the NTA on the
immediate but short-lived response from
effector cell.
the effector cell.
Produces a delayed response but longer
Ex. Ach binding to nicotinic receptors on
duration that persists even if NTA is no
membrane of skeletal muscle cell longer present
Ach+Nicotinic: Ligand-gated channel
a.
NTA + Receptor activate G-Proteins activate enzyme system, (+) Adenylyl
cyclase formation of ↑cAMP (cyclic
2.
INTERACTION STEP / Membrane Receptors
Some originate from brain stem (CN III, VII, IX, X)
Some originate from spinal cord (S2-S4)
3.
4.
1.
•
•
•
•
•
Preganglionic fiber > Postganglionic fiber
Long Pre Short Post
Limited branching
1Pre : 1Post
PS Effects are more localized except those of the
vagus nerve
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
b.
Deactivation of NTA
Cholinergic transmission is present in:
Adrenergic transmission is present in:
adenosyl monophosphate is the I/C ligand
or second messenger) activate (+)
protein kinase A phosphorylation of
other enzymes that will elicit specific
responses from the cell
Ex. Catecholamines (Nor, EP) + beta
receptors;
Acetylcholine + muscarinic receptors
beta receptors and muscarinic receptors
are G-protein coupled receptors
NTA + Receptor activate G-Proteins activate enzyme system, (+)
phospholipase C breakdown of
phosphoinositol biphosphate PIP2,
forming 2 products:
i. Inositol triphosphate IP3 increase I/C Ca2+; Calcium can
function as second messenger
ii. Diacyl glycerol DAG (+) Protein
kinase C causes phosphorylation
of I/C proteins stimulate specific
biochemical responses from the cell
Ex. Catecholamines + alpha receptors;
Acetylcholine + muscarinic receptors
(depending on the location in the body)
Enzymatic deactivation - deactivation by enzymes in
the synaptic cleft
Ex. Ach deactivation by acetylcholinesterase
1. Cholinergic effects short in duration
Re-uptake
Ex. Deactivation of norepinephrine
1. After unbinding from the receptor
2. Actively transported back in the terminal but
will not be stored in vesicles. These will be
destroyed by monoamineoxidase
3. Other NEP: circulated in the blood and
transported to the liver, where NEP is
deactivated by enzyme catechol-O-methyl
transferase (COMT)
1. All somatic neuromuscular junction (Somatic to skeletal muscle)
2. All autonomic ganglia (all preganglionic to all postganglionic in both SNS and PSNS)
3. All parasympathetic neuroeffector junctions (all PS effects to internal organs; biochemically, PSNS is
referred as Cholinergic division; PSNS division is craniosacral (anatomically) and cholinergic
(biochemically))
4. Sympathetic cholinergic neuroeffector junctions, only if effectors are sweat glands and vascular smooth
muscles present in skeletal muscles.
5. All sympathetic adrenergic neuroeffector junction. (all sympathetic effects to internal organs)
Sympathetic division is thoracolumbar (anatomically) and noradrenergic (biochemically).
Somatic NS
Parasympathetic NS
Sympathetic Cholinergic
Sympathetic Adrenergic
(Syncholinergic) NS
(Synadrenergic) NS
C
C
C
Ach
EC
Ach
PG
PG
Ach
Ach
EC
C
Ach
EC
** Only in sweat glands and
vascular smooth muscles
present in skeletal muscles
Cholinergic Transmission
CPalafox (1A)
Ach
PG
NEP
EC
** most sympathetic effects
to internal organs are
mediated by NEP
Transmission mediated by Acetylcholine
1. Synthesis of Acetylcholine: Choline + Acetyl CoA Ach, catalyzed by choline acetyl transferase. It will be
stored temporarily in vesicles located at the nerve ending.
2. (Release) When an AP reaches the nerve ending, there will be Ca2+ influx, which will cause Ach to be
released into the synaptic cleft.
3. (Interaction) Ach binds to membrane receptors (cholinergic receptor) on the effector cell.
4. (Deactivation) Main mechanism is enzymatic destruction/deactivation by acetylcholinesterase, which is
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
also present in the synaptic cleft, where it can immediately deactivate acetylcholine. This makes
cholinergic or Parasympathetic effects short in duration.
1. Nicotinic – can also be stimulated by small dose 2. Muscarinic – can be stimulated by small doses
of nicotine
of muscarine
a.
Present in all somatic neuromuscular
a.
all parasympathetic neuroeffector junction
junction (membrane of skeletal muscle
b. all sympathetic cholinergic neuroeffector
cells contain Nicotinic receptors)
junction (sweat glands, vascular smooth
b. Present in all autonomic peripheral
muscle present in the skeletal muscle
Subdivided into M1-M5:
ganglia
c.
c.
Mainly made of proteins, classified as
•
M1 – brain, stomach (if M1 receptors
Ligand-gated receptor: (+) open Na+
in stomach is stimulated, increase in
channel
gastric secretion)
d. Always elicits an excitatory reaction
•
M2 – most abundant heart and
visceral smooth muscles
•
M3 – visceral smooth muscles and
glands
•
M4 – visceral smooth muscles and
glands
•
M5 – least abundant; present only in
sphincter muscles of the iris,
esophagus, parotid glands, cerebral
blood vessels
d. G-protein coupled receptor response
may be either excitatory or inhibitors
Transmission mediated by NEP
1. Synthesis of NEP:
a.
Steps:
phenylalanine β tyrosine, catalyzed by phenylalanine hydroxylase.
β tyrosine DOPA, catalyzed by tyrosine hydroxylase.
DOPA Dopamine, catalyzed by DOPA decarboxylase.
Dopamine Norepinephrine, catalyzed by dopamine β-hydroxylase.
b. Location: at the nerve ending of sympathetic adrenergic efferent / postganglionic nerve endings.
c.
Regulation: by a negative feedback mechanism; if there is an excess of dopamine and
norepinephrine, it will cause inhibition of the enzyme tyrosine hydroxylase.
d. A sagittal section of adrenal glands reveals 2 parts:
outer part: adrenal cortex (secretes steroid hormones) and
inner part: adrenal medulla (converts norepinephrine epinephrine, catalyzed by
phenylethanolamine-N-methyl transferase).
e. Sympathetic adrenergic postganglionic nerve endings can synthesize/release NEP only.
Adrenal medulla can synthesize/release both NEP and EP (collectively known as catecholamines).
2. (Release) When an AP reaches the nerve ending, there will be Ca2+ influx, which will cause NEP to be
released into the synaptic cleft.
3. (Interaction) NEP or EP binds to membrane receptors (noradrenergic or adrenergic receptors) on the
effector cell.
4. (Deactivation) Main mechanism is reuptake. Actively transported back in the terminal but will not be
stored in vesicles. These will be destroyed by monoamineoxidase. Other NEP: circulated in the blood and
transported to the liver, where NEP is deactivated by enzyme catechol-O-methyl transferase (COMT).
This makes adrenergic or Parasympathetic effects short in duration.
Types of Cholinergic receptors
Adrenergic Transmission
4 Types of Adrenergic receptors
1.
α1
a.
2.
•
•
Organ
Heart
CPalafox (1A)
4.
α2
a.
b.
•
3.
Present in visceral smooth muscles and
glands
Present only at nerve terminal
NEP+ α2 NEP inhibition
Negative feedback mechanism, inhibit
further release of norepinephrine
Alpha receptors when stimulated, mostly elicit
excitatory reaction (exemptions below)
Examples:
NEP+ α1 Radial muscle of iris, muscle
contracts (excitatory) = increase in
pupillary size;
EP+ α1 vascular smooth muscle, muscle
contracts (excitatory) = vasoconstriction
Exemptions: Digestive system, pancreatic
islets, bronchial gland, effects are inhibitory
Cholinergic
M2
•
•
•
β1
a.
Only in heart
β2
a.
Present in visceral smooth muscles and
glands
Beta receptors when stimulated, elicit mostly
inhibitory reaction (exemptions below)
Examples:
NEP + smooth muscle receptors in
Bronchial wall, smooth muscles relax =
broncodilation;
EP+ β2 Vascular smooth muscle, muscle
relaxes = vasodilation
Exemptions: heart, bronchial glands, pancreatic
islets, effects are excitatory
Adrenergic:
β1
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
Salivary glands
Intestinal wall
Bronchial
Adrenal Medulla:
Differentiate from other visceral organs in
the body:
Difference from the rest of the
sympathetic adrenergic system:
M3-M4
M2-M3-M4
M3-M4
Sympathetic: innervated by postganglionic fibers
Sympathetic adrenergic: release NEP to immediate
vicinity of neuroeffectors
α1, β2
α1, β2
α1, β2
Adrenal Medulla
AM is innervated by pre-ganglionic fibers.Cells of AM
are histologically similar to a sympathethic ganglion
•
When the sympathetic division is stimulated,
the AM is also stimulated, which causes it to
release NEP and EP. These NTA are released and
circulated in the blood stream, and are
distributed to sympathetic neuroeffector
junctions in all parts of the body.
•
Reinforces/potentiates the sympathetic
adrenergic effects.
•
AM considered a part of sympathetic adrenergic
nervous system
Sympathetic preganglionic fibers
Ach
(N) Adrenal Medulla
NEP + EP ***
Circulation
(+)α1, β1, β2 receptors ***
↑sympathetic adrenergic effects
*** Comparison between the effects of NEP and EP
•
NEP is a strong stimulator of α and β1 receptors
but is a weak stimulator of β2.
•
EP is a strong stimulator of α1, β1, β2 receptors.
Dual Innervation and Antagonistic Effects
Physiologic/Functional Differences
between Sympathetic and
Parasympathetic Nerves
Energy
Duration
Effects
CPalafox (1A)
•
Sympathetic NS and PSNS are PHYSIOLOGIC ANTAGONISTS, produces opposite effects.
1.
Dual innervation of the SAME structure of the SAME organ produces OPPOSITE effects.
Ex. Heart
Sympathetic N (↑HR) SA Node  Vagus/CNX, Parasympathetic (↓HR)
2.
Dual innervation of 2 DIFFERENT structures in the SAME organ produces OPPOSITE effects.
Ex. Eyeball – Pupil regulates the amount of light entering the eye
Iris: radial muscle (Sympathetic): absence of light pupil dilates
Sphincter muscle (Oculomotor CN3 parasympathetic): presence of light pupil constricts
3.
Dual innervation of 2 DIFFERENT structures in the SAME organ produces SYNERGISTIC effects.
Ex. Salivary gland
Para: profuse increase in salivary secretion: loose, watery secretion
Sympa: mild moderate increase in salivary secretion: viscous secretion
4.
Single innervations
No parasympathetic innervation. Sympathetic innervation only.
Ex. Kidneys, sweat gland, pilo arrector muscle in skin, vascular smooth muscle
SyNS
PSNS
Catabolic
Longer, Prolonged duration
Reason: Norepinephrine at NEJ that is not
immediately deactivated; additionally
mediated by norepinephrine and epinephrine
in the blood stream
Fight-or-Flight
Stimulation of sympathetic nerves enables
individuals to cope or withstand stressful
conditions
Anabolic
Short duration
Reason: Mediated by Ach, immediately
deactivated
Rest/Digest
Conservation/restoration of the body’s
processes
Physiology A: AUTONOMIC NERVOUS SYSTEM
Lectured by: Dr. Valerio
Fight-or-Flight (Catabolic)
↑HR
↑BP
Nor
Epi
Response
Timing
Center
Rest/Digest (Anabolic)
↓HR
↓BP
β1
Peripheral Vasoconstriction
α1
M2,
M3
Peripheral Vasodilation
Ach
↑Lipid Breakdown
β2
↓Lipid Breakdown
Coronary Dilation
Bronchial Dilation
β2
Bronchoconstriction
Glycogen Glucose
β2
Generalized, diffuse response
Reason: extensive branching of the preganglionic fibers
Coordinated; response occurs at the same time
Muscarinic receptor
Nicotinic receptors
M3
M3
Glucose Glycogen
Localized response, except for Vagus nerve
Reason: limited branching, except for Vagus
nerve
Coordinated; but some processes do not have to
occur at the same time (ex. micturation, defecation,
erection)
Head ganglion of the ANS – Hypothalamus
•
Anterior hypothalamus – coordinates
Cholinergic activities
•
Posterior/ Lateral hypothalamus –
coordinates Adrenergic activities
Example: Baroreceptor Reflex
Increased Arterial Blood Pressure (ABP) stretch arterial walls
(+) Baroreceptor (-)/inhibit Vasomotor center (medulla)
Decrease sympathetic outflow
Increase parasympathetic outflow
Vasodilation
Decrease cardiac activity
Decrease cardiac activity
Decrease ABP
Decrease ABP
Pharmacological Differences
A.
B.
CPalafox (1A)
Parasympathetic
Cholinergic
↑ / Potentiate cholinergic or parasympathetic
effect
↑ synthesis of Ach
↑ release of Ach
↑ interaction between Ach and cholinergic
receptor
(-) deactivation of Ach
PARASYMPATHOMIMETIC –mimics the effects
of parasympathetic stimulation
Anticholinergic
↓ / Block cholinergic or parasympathetic effect
synthesis of Ach
↓ release of Ach
Block interaction between Ach and cholinergic
receptor
↑ inactivation of Ach
PARASYMPATHOLYTIC
A.
B.
Sympathetic Adrenergic
Adrenergic
↑ / Potentiate adrenergic or sympathetic effect
↑ synthesis of NEP
↑ release of NEP
↑ interaction between NEP and adrenergic
receptor
(-) inactivation of NEP
SYMPATHOMIMETIC –mimics the effects of
sympathetic stimulation
Antiadrenergic
↓ / Block adrenergic or sympathetic effect
synthesis of NEP
↓ release of NEP
Block interaction between NEP and adrenergic
receptor
↑ deactivation of NEP
SYMPATHOLYTIC
Renal Physiology IV: Body Fluids and Acid-Base Balance
(Ronald Allan Cruz, MD)
Body Fluids
plasma is 60% and formed elements are 40%. Take note that your 40%
will actually be your haematocrit.


H2O intake: 2.3L/day
o
2100 ml intake
o
200 ml CHO oxidation

H2O loss: 2.3L/day
o
7o0 ml insensible loss

350 ml evaporation from skin

350 ml respiration
o
100 ml sweat
o
100 ml feces
o
1400 ml urine
Basically the average man would have a 2.3 L of water intake
per day and of course the same amount of urine will have to go out. On
the average, it is around 2.1 L, this is our oral intake so this is the
supposed average intake of water and around 200 mL will be coming
from the oxidation of carbohydrates – when glucose is broken down you
have water and CO2. You have an average of 2.3 L per day but it varies
depending on the means of that person but whatever amount that was
taken in should have the same amount that will go out.
Capillary membrane
o
Donnan effect
In this diagram, the dark line will represent the capillary
membrane. This actually separates your plasma from the interstitial
compartment. Your capillary membrane will not permit the passage of
plasma proteins so your plasma proteins will be located within the
plasma. Since plasma proteins are highly negative, they will attract
cations and repel anions. Because of this set up, you can also observe the
Donnan effect within the capillary membrane.
Water losses would be 2.3 L per day also. This is lost by several
means. Around 7oo mL would be from insensible water losses. This is
from evaporation of water from the skin and around 350 mL from
respiration. As far as evaporation from the skin is concerned, the
cornified layer of the skin actually prevents rapid evaporation of fluids so
in this layer, particularly cholesterol and lipid membranes on the skin, if
this layer is lost you actually increase the evaporative process – lose more
water. Typical example would be burnt victims because their epidermal
layer was lost, water losses would also be faster. Part of the management
of burns is fluid administration.
Around 100 mL is lost from the sweat although this varies
depending on the physical activity and environmental temperature. 100
mL would be going out via the stool and this will also vary. In cases of
diarrhoea, more water will be lost. Around 1.4 L will be coming out
through the urine.
70 kg man

60% of body weight is H2O

42 L



Extracellular fluid: 20%
o
Interstitial fluid: 15%
o
Plasma: 5%
Transcellular fluid
Intracellular fluid: 40%



14 L

11 L

3L
1-2 L
28 L
In this diagram, the horizontal line here will represent the cell
membrane separating the extracellular from the intracellular
compartment. And in this graph, you’ll take note of your anions and
cations. As far as extracellular compartment is concerned, this is
primarily composed of Na, Cl and bicarbonate whereas in the intracellular
compartment, you have your K, phosphates and proteins.
The most abundant substance in the body is water. So 60% of
our body weight is basically water and this is divided into two
compartments: extracellular and intracellular compartment. 40% of our
body weight would be intracellular water so much of the water that we
have is actually located within the cell. Your extracellular fluid which is
around 20% of our body weight is divided into two basic compartments:
interstitial fluid and plasma. A specialized compartment is termed as
transcellular fluid – a specialized extracellular compartments like
synovial fluid, CSF, pericardial fluid, peritoneal fluid etc. and is around 2L.

Blood
o
Blood volume: 7%

Plasma: 60%

Formed elements: 40%
70 kg man

5L

3L

2L
Given a 70 kg man, here you can see the distribution of water
in the different compartments. Looking at blood, 7% of our body weight
would be blood so given a 70 kg man, that is around 5 L. Blood is a
specialized compartment such that it will contain extracellular and
intracellular fluid. Extracellular fluid would be plasma and the water
within your formed elements is the intracellular fluid. You will note that
1
Shannen Kaye B. Apolinario, RMT
In this table, this shows the different solutes found in the
different compartments in the body particularly in plasma, the interstitial
space and the intracellular space. The substances highlighted in red are
particularly located extracellularly and the substances highlighted in blue
are located intracellularly. In here you also have your total osmolarity.
Indicator-Dilution Principle




Measurement of fluid volumes in different compartments
CA x V A = C B x VB
VB = 10mg/ml x 1ml
0.01 mg/ml
= 1000 ml
First let us talk about the indicator dilution principle. The
indicator dilution principle basically allows us to measure these
compartments. How is this done? First is you utilize the formula:
concentration of A times volume of A is equal to the concentration of B
times the volume of B.
minus the ECF volume. To get your total blood volume, that’s plasma
divided by one minus haematocrit or you can utilize a radiolabeled RBC.
Osmotic Equilibria Between Extracellular and Intracellular Fluid



Plasma and interstitial fluid volume
o
Hydrostatic pressure
o
Colloid osmotic pressure
Extracellular and intracellular fluid volume
o
Osmotic effect of solutes
Intracellular fluid is isotonic with the extracellular fluid
Let’s look at equilibration of compartments. For your plasma
and interstitial fluid volume, this is being separated by capillary
membrane. As far as equilibration is concerned, Starling forces will play a
major role to the hydrostatic pressure and osmotic pressure present in
the two compartments – vascular (plasma) and interstitial compartments.
When it comes to intracellular compartments, the cell membrane will
limit this such that the osmotic effects of solutes now will determine
equilibration for the two compartments. Take note that the ECF is
isotonic.
Osmosis and Osmotic Pressure
For example, if you have this set up, you have a fluid here with
an unknown volume and you want to know. What you do is to inject or
administer a dye or indicator with a known concentration and known
volume and allow it to disperse. Get a sample and check for the
concentration then you will be able to get the volume of compartment.
For example you want to determine the volume of B. You administer the
indicator having a concentration of 10 mg/mL and having a volume of 1
mL. Allow it to disperse and get a sample. The concentration of the
sample is 0.01. Mathematically, you can get the volume of container
which is 1 L.
This indicator dilution principle is being used to measure the
different compartments in the body so what we need now to know is
what are the appropriate indicators that are going to be used. In selecting
an indicator, you need three criteria: first, this indicator has to disperse
evenly within the volume you want to measure (even distribution);
second, this indicator should stay in the compartment you want to
measure; thirdly, it should not be metabolized by the cell. These are the
three criteria in selecting an appropriate indicator.




Total body H2O: 3H2O, 2H2O
Extracellular vol: inulin, 22Na
o
Plasma vol: 125I-albumin
o
Interstitial vol = extracellular vol – plasma vol
Intracellular vol = total H2O – extracellular vol
Total blood vol = plasma/ (1-hct)
51Cr-labeled RBC
Here you have the different indicators that are utilized to
measure certain compartments. For your total body water we utilize
heavy water – tritium or deuterium. Since it is water, it will go to all the
compartments.

Osmoles
o
Total number of osmotically active particles in a solution
o
1 osm = 1 mol = 6.02x1023 particles
o
1 mOsm = 0.001 osm

Osmolality
o
Osm/kg of H2O

Osmolarity
o
Osm/L of H2O
Osmoles is the total number of osmotically active particles in a
solution such that one mole of a substance is actually one osm or 6.02x10
23 particles (Avogadro’s number). Translating this to mOsm, simply move
the decimal point so that’s .001 osm.
Osmolality is osm per mass of water. Osmolarity is osm per
volume of water. Chemically speaking, osmolality is more accurate than
osmolarity. Osmoles per kilogram is more accurate than osmoles per liter
even though 1 L is 1 kg of water. Why? Because osmolarity being volume
is affected by temperature. The higher the temperature, the greater the
volume; the lower the temperature, the volume contracts. Your mass
stays the same regardless of temperature. However in the human body or
physiologically speaking, both may be interchanged since the human
body has a relatively constant body temperature of 37oC. Even if you have
a fever, the volume of water will not expand.



1 mole/L of glucose = 1 osm/L
1 mole/L of NaCl = 2 osm/L
1 mole/L of Na2So4 = 3 osm/L
So here you have the number of osmotically active particles by
different substances. If you have 1 mole/L of glucose, that’s actually 1
osm per L. However when you have salts, salts in solution will ionize
easily. For example if you have NaCl placed in water, it will dissociate into
Na and Cl therefore 1 mole/L of salt is actually 2 osm per L since it
dissociated into two. When there are three ionisable particles like
Na2SO4, placed in a solution, you will have 2 ions of Na and 1 sulfate –
there are 3 ionizable particles.
For extracellular fluid volume, we utilize inulin and an isotope
of Na. If you want to measure the plasma volume, you can have
radiolabeled albumin because albumin stays in the plasma.

Osmotic pressure
o
The pressure required to oppose osmosis
o
Indirectly measures H2O and solute concentrations
To get interstitial volume, simply get your ECF volume minus
the plasma volume. For your intracellular volume, you have total water

 osmotically active particles,  osmotic pressure
o
Independent of the size of the particle
2
Shannen Kaye B. Apolinario, RMT
o
Na2SO4 > NaCl > albumin = glucose
be multiplied with van’t Hoff’s law getting now 5,519.8 mmHg. And this is
now the actual osmotic pressure of NSS.
When you say osmotic pressure, this is the pressure required
to oppose osmosis and indirectly measures water and solute
concentration such that if a solution has a high osmotic pressure it means
that the solution or solute concentration is high. It indirectly reflects
solute concentration.
The higher the osmotically active particles, the greater the
osmotic pressure. If you have a lot of ionisable particles or the greater the
number of particles, the greater the osmotic pressure is. In this case,
Na2SO4 having 3 ions will have a greater osmotic potential than NaCl
having only 2 ions and both of which will have greater osmotic potential
comparing it to glucose and albumin because both glucose and albumin is
not ionisable. As far as size is concerned, osmosis is NOT directed on size.
Osmotic potential is the same even if its size is big or small. For example
albumin and glucose, albumin is a much bigger molecule compared to
glucose however both of their osmotic potential is the same.

van‘t Hoff’s law
o
π=CRT

π – mmHg

C – concentration of solutes in osm/L

R – ideal gas constant

T – temperature, 310 kelvin


1 osm/L = 19300 mmHg
1 mosm/L = 19.3 mmHg
In measuring osmotic pressure, we utilize van’t Hoff’s law.
This is pressure equal to the concentration of solutes times gas constant
times temperature. Using your van’t Hoff’s law, 1 osm per liter is actually
19,3oo mmHg. Because it is quite big, what we use in physiology and
medicine is mOsm. In 1 mOsm per liter of solute, you have 19.3 mmHg
pressure.


1 osm/L = 19300 mmHg
1 mosm/L = 19.3 mmHg

0.9%NaCl = 5944 mmHg
o
0.9 g/100 ml
o
9 g/L
o
9 g/L / 58.5 g/mol = 0.154 mol/L
o
o
o
0.154 mol/L x 2 = 0.308 osm/L
308 mosm/L
308 mosm/L x 19.3 mmHg/mosm/L = 5944 mmHg
How is van’t Hoff’s used? For example you have 0.9% NSS. How
high is its osmotic pressure? 0.9% is actually 9 g per 100 mL. To get
similar units, we utilize 9 g/L and your 9 g/L is divided to the molecular
weight of NaCl (58.5 g/mol). You will get 0.154 mol/L. 0.154 mol/L will
be multiplied by two since you have two ionisable particles then you will
get 0.308 osm per liter then change it to mOsm by simply moving the
decimal point and then multiply it with van’t Hoff’s law. You will be able
to get 5,944 mmHg and so this is the osmotic pressure of NSS.

Osmotic coeffecient
o
Correction factor

NaCl: 0.93
o
Looking at the interstitial and intracellular compartments,
your interstitial and intracellular compartment will have the same
osmotic pressure. You would notice that their corrected osmolar activity
is both 281, pressure is both 5,420. However if you will compare it with
plasma, osmotic pressure of plasma is higher – 5,440 because of plasma
proteins.
308 mosm/L x 0.93 = 286 mosm/L
But that’s not the end since we need to take into account a
correction factor or osmotic coefficient because when NaCl is placed in a
solution, majority of solutes or salt will dissociate or ionize. However, Na
is a positive ion and Cl is a negative ion so some of these particles may
NOT dissociate because of ionic attraction. Not all will dissociate
completely. With that, if your Na and Cl will stick together, they count as
one particle only. With that, you need to take into account the correction
factor for NaCl so that’s 0.93. This simply means only 93% of NaCl will
dissociate in the solution. From your 308 mOsm/L, you multiply that with
your correction factor to get 286 mOsm. 286 now here is the one that will
3
Again, you have the different substances. Take note a lot of
them are ions and because of that, cations will still be attracted to anions
that’s why you have to have correction factors. If you will look at the
bottom portion of the table, this is computed total mOsm and this is now
your corrected osmolar activity. You will notice that it is lower because
some cations will be associated with an anion – they will not dissociate
100%. Your 282 here is the one that you will multiply with van’t Hoff’s
law giving you 5443 mmHg for your plasma.
Shannen Kaye B. Apolinario, RMT

1 mosm/L = 19.3 mmHg



Hypotonic solutions
Isotonic solutions: 0.9%NaCl, PLR
Hypertonic solutions
When we say isotonic, what does that mean? Isotonic means
that the solute will have the same osmotic pressure with plasma. It is not
about concentration. If you look at an isotonic solution like NSS, it is not
about concentration because NSS would contain NaCl. Plasma would
contain Na, Cl, K, Mg, Ca, plasma proteins etc., it is about osmotic
pressure. When we say isotonic solution, these are solutions that will
have the same osmotic potential as plasma. Meaning to say, it has the
same ability to attract water regardless of the particles.
Here we have isotonic solutions, NSS and PLR. Both will not
have the same concentration as plasma. A lot of students will say that D5
water is an isotonic solution. D5 water is NOT isotonic, it is isoosmotic.
Why? Your glucose does not act like lactate or sodium. Lactate and
sodium stays outside the cell but glucose enters the cell. When glucose
enters the cell, D5 water will behave as hypotonic solution because some
glucose are removed in the extracellular compartment (it entered the
cell) and more water is outside the cell. Glucose or D5 water technically
speaking is not isotonic, it is isoosmotic.
When osmotic potential is higher, that’s your hypertonic
solution. If your osmotic potential is lower, that’s hypotonic solution.
Glucose and Other Solutions


Glucose
Amino acids
o
o
o
Adjusted to isotonicity
Administered slowly
Metabolized by the body, excess H2O is excreted
With regards to fluids with glucose and amino acids, as what
we’ve mentioned, glucose and amino acids will enter the cell thus they
are ineffective osmoles. That’s why when we have a patient that is in
shock, we do not give D5 water, we give NSS to increase the blood
volume. Things to take note of with regards to these substances: they
must be adjusted to isotonicity – “toxic” or hard to make because you
have to take into account your glucose or amino acids entering the cell
and they must be administered slowly.
Volumes and Osmolalities of Extracellular and Intracellular Fluid in
Abnormal States
Clinical Abnormalities of Fluid Volume Regulation
Fluid Compartments
Hyponatremia
In calculating changes in intracellular and extracellular fluid
volumes
o
H2O moves rapidly across the cell membrane
o
Cell membranes are almost completely impermeable to
solutes

 NaCl: hypoosmotic dehyreation
o
Electrolyte, H2O loss
o
Diarrhea, vomiting
o
Diuretics
o
Addison’s disease
In calculating changes in the ICF and ECF volumes, take note
that water moves rapidly across the cell membrane. Recall that the cell
membrane is a semi permeable membrane permitting the passage of
water but not solutes.

 H2O: hypoosmotic overhydration
o
SIADH

Adding Saline Solution to the Extracellular Fluid
Hypernatremia


 NaCl
 H2O

Hyperosmotic dehydration
o
DI
o
Excessive sweating

Hyperosmotic overhydration
o
Conn’s syndrome
o
2o hyperaldosteronism
For clinical abnormalities of fluid volume and regulation this is
your hypo and hypernatremia. ***read on this*** When we say
hyponatremia, it means decreased Na and hypernatremia means
increased Na and this doesn’t necessarily mean you have derangements
in Na. For example, if you have hyponatremia, a lot of times Na is not
really low but actually water is increased.
Edema
Intracellular Edema

In this diagram, you have your volume, osmolarity and
intracellular and extracellular compartment. When you add an isotonic
solution tonicity is the same. However your extracellular compartment
volume increases whereas your intracellular compartment stays the
same.
If you add a hypotonic solution, the tonicity decreases. Water
will enter the cell therefore the volume of the intracellular compartment
increases and the volume of extracellular compartment increases as well.
When you add a hypertonic solution, tonicity increases. Water
inside the cell will go out via osmosis so your intracellular volume
decreases and your extracellular volume increases.
4
Shannen Kaye B. Apolinario, RMT
Intracellular swelling
o
 metabolism
o
 nutrition
o
 ion pump activity
o
 osmosis
o
Inflammation
There are two types of edema – intracellular and extracellular
edema. Intracellular edema means that water accumulates within the cell
due to a decrease in metabolism, decreased nutrition because you
decrease your ion pump activity. Because of that, Na cannot go out so it
stays inside the cell and water follows or goes with it so it increases
osmosis then your cell becomes inflamed. Typical example would be
cerebrovascular accident infarct. With that, you decrease blood supply
going to CNS. Neurons are excitable and highly dependent on Na K pump.
If your NaK pump will not work, Na stays inside the cell, water enters the
cell, your brain swells. That’s why stroke patients if infarct, most likely,
intracranial pressure increases.
Safety Factors That Prevent Edema

Extracellular Edema

 fluid in the interstitial space
o Plasma leakage
o Failure of the lymphatic drainage
When we say extracellular edema you have accumulation of
fluid in the interstitial compartment. It may be due to plasma leakage or
failure of lymphatic drainage and the forces that will affect extracellular
edema is you have your filtration rate.

F = Kf x [(Pc+πi)-(Pi+πc)]
o
F – filtration rate
o
Kf – filtration coefficient
o
Pc – capillary hydrostatic pressure
o
πi – interstitial oncotic pressure
o
Pi – interstitial hydrostatic pressure
o
πc – capillary oncotic pressure


Normally we do not instantly would have edema because we
have safety factors that will prevent edema. We have three: low
compliance of the interstitium, increased lymph flow and wash down of
interstitial proteins.
Low of the Interstitium




So here you have your filtration coefficient and Starling forces.
If you will recall, these are the factors that will affect the amount of water
going into the interstitium.

F = Kf x [(Pc+πi)-(Pi+πc)]
o
F – filtration rate
o
Kf – filtration coefficient
o
Pc – capillary hydrostatic pressure
o
πi – interstitial oncotic pressure
o
Pi – interstitial hydrostatic pressure
o
πc – capillary oncotic pressure
o
Low compliance of the interstitium
o
Negative pressure
o
Interstitial gel
o
Proteoglycan and collagen filaments
Increased lymph flow 10-50x
Washdown on interstitial fluid CHON
-3 mmHg
12L
As long as pressure is negative, small changes in fluid vol are
associated with large changes in Pi
Low compliance
o
C=V/P
The low compliance of the interstitium is due to three factors:
the negative pressure in the interstitial compartment, the interstitial gel,
proteoglycans and collagen filaments. So first you have the negative
pressure in the interstitium. The interstitial compartment is said to have
a pressure of -3 so it has a vacuum effect. And in the interstitial
compartment, we have around 12 L of fluid.
Lymphatic drainage
For edema to occur you have four important factors to take
note of and they are highlighted in red. The font highlighted in red, when
they are deranged then extracellular edema will occur. For example
changes in your filtration coefficient, capillary hydrostatic, capillary
oncotic pressure and lymphatic drainage. For each factor you have
several examples.
In this table you have the different factors: increased capillary
pressure, decreased plasma proteins, increased capillary permeability
and blockage of lymphatics. All of these will result to extracellular edema.
5
Shannen Kaye B. Apolinario, RMT
Looking at this graph, you have your pressure and fluid
volume. Looking at the normal pressure in the interstitium of -3, we have
around 12 L of water in the interstitial compartment. As long as the
pressure is in the negative range, small changes of fluid are associated
with large changes in your interstitial hydrostatic pressure. If hydrostatic
pressure increases, this will oppose filtration so less water will go into the
interstitial compartment. We have mentioned that because of the -3
pressure, there is a vacuum effect creating a rigid structure within your
interstitial compartment – it is like having a glass bottle filled with water
to the brim then it has a rubber stopper. This is a closed system with a
fixed volume of fluid. If you injected a small amount of water, the
pressure inside increases and that pressure is your interstitial
hydrostatic pressure so if you try to push more water into the bottle, it is
harder because the hydrostatic pressure increases further.
Because also of the negative pressure, there is low compliance
in the interstitial compartment. Compliance is equal to the change in
volume per change in pressure or expansibility, its opposite is elasticity.
Interstitial compartment has a low compliance just like a rigid glass
bottle. But take note this is only true your pressure is in the negative
range.

Interstitial gel
o
Prevents flow of fluid
o
Offers elastic resistance to compression
o
Compact “brush pile”
o
Interstitial fluid vol does not change greatly
Another factor for the low compliance of the interstitial
compartment is the gel. The interstitial gel prevents flow of fluid and it
will offer elastic resistance to compression. You have a compact brush
pile and the interstitial fluid does not change greatly. Because of your
negative pressure (suction or vacuum effect) your interstitial gel will
compact such that it will prevent the flow of water. Water from the upper
portions of the body because of your compact gel does not easily go to the
lower extremities.

Proteoglycan filaments
o
Acts as spacer
o
Modulates flow of fluid
o
Flow of nutrients and metabolites are not compromised
Thirdly, you have your proteoglycan filaments. If your gel
prevents the flow of water, your proteoglycan filaments will act as
spacers in between such that they modulate the flow of water but more
importantly its job is to permit the flow of nutrients and metabolites.
Interstitium






Looking at this graph, based on mathematical extrapolation,
they looked on what will be the volume of the interstitium if it becomes
positive. Based on their computation, there will be a modest increase in
fluid but actually their observation was: a small increase in pressure will
have a great increase in volume because your interstitial compartment
increases its compliance already. So it is very important that the pressure
is -3. The safety factor is 3 mmHg before reaching zero. This is the graph
extrapolated mathematically and this is the graph actually observed.
Increased Lymph Flow



The second factor is the lymph flow. This returns the fluid and
proteins into the circulation. An increase in lymph flow up to 10-15x; that
better drains your interstitial compartment such that if you increase your
filtered fluid, you increase your interstitial hydrostatic pressure
consequently increasing lymph flow – drainage is higher. Here you have a
safety factor of 7 mmHg.
Washdown of the Interstitial Fluid Protein



> 0 mmHg
 compliance
Fluid accumulates,  free fluid
“Brush pile” is pulled apart
 gel form
 spaces between cells
If the pressure becomes positive or beyond zero, compliance
now increases so fluid now will accumulate. Since the pressure has
become positive, you lose the vacuum effect – everything will disperse
and there will be larger spaces in between allowing water to flow freely
resulting to edema.
Lymphatics are permeable to CHON
Interstitial fluid CHON is carried by lymph flow
o  lymph flow,  interstitial CHON,  πi
7 mmHg
The third factor is the wash down of proteins. Lymphatics are
permeable to proteins and interstitial fluid proteins will be carried by
lymph. With that, you decrease now the interstitial oncotic pressure. That
adds another 7 mmHg.
Safety Factors That Prevent Edema


Here you have the brush pile being pulled apart. You have a
decrease in your gel form and increased spaces in between. It is
important that your interstitial compartment be within the negative
range.
Returns fluid and CHON to the circulation
 lymph flow: 10-50x
o
 filtered fluid,  Pi,  lymph flow
7 mmHg

Low compliance of the interstitium
o
Negative pressure
o
Interstitial gel
o
Proteoglycan and collagen fillaments
o
3 mmHg
Increased lymph flow 10-50x
o
7 mmHg
Washdown on interstitial fluid CHON
o
7 mmHg
Taking into account all of these factors: compliance is 3 mmHg,
lymph flow is 7 mmHg and protein wash down is 7 mmHg for a total of 17
mmHg pressure as a safety factor. What does that mean? For edema to
occur, your capillary pressure or hydrostatic pressure should exceed 17
mmHg so you have a net filtration and that’s the time where the fluid will
accumulate within the interstitial compartment.
Fluids in the Potential Spaces of the Body
Potential Spaces
6
Shannen Kaye B. Apolinario, RMT




Pleural cavity
Peritoneal cavity
Pericardial cavity
Synovial cavity

Fluid is present to reduce friction

Fluid is exchanges between capillaries and the potential space

Lymphatics drain fluid from potential space

Negative fluid pressure
Basically, the transcellular compartments are specialized
compartments: synovial, pericardial, peritoneal, pleural fluid etc. and the
purpose of the fluid are to reduce friction during movement. Just like any
extracellular compartment, fluid is exchanged between capillaries and
potential space and of course lymphatics will also drain these spaces.
Concentration



Take note also that these compartments will also have a
negative pressure. For example in the pleural cavity it is -7 to -8,
pericardial: -3 to -5, joint spaces: -5 to -6. If pressure becomes positive
just like the interstitial compartment, fluid will accumulate. If in the
pleural cavity that is pleural effusion, in the abdomen it is ascites, in the
pericardial fluid it is tamponade.
Acid-Base Balance
Hydrogen Ion

Extracellular concentration: 0.00004 mEq/L



pH = -log [H]
pH = - log [0.00000004 Eq/L]
pH = 7.4

pH: 7.35-7.45
The extracellular concentration of H in the body will determine
pH or body pH. Here you have 0.00004 mEq/L of H+ present in the body.
To get the pH, pH is –log times the H ion concentration. Plugging the
values in, you will have 7.4 and this is the normal pH of the body. In the
clinics, it is in a range: 7.35-7.45.
Chemical buffer systems
o
Intracellular
o
Extracellular
Respiratory system
Renal system
As far as controlling H ion concentration in the body, you have
the buffers: kidneys and the lungs. These are the systems that will control
body pH. Your chemical buffer systems are primarily located
intracellularly and extracellularly. In acidosis, there is hyperventilation to
release carbonic acid so blood pH will go back to normal. Your
respiratory system will comprise of around 30-40% of the entire acidbase balance. The most important is the renal system.
When we have derangements in pH, the chemical buffer
system instantaneously or it is the first one to react to bring pH back to
normal. Within minutes, respiratory system (around 3-15 minutes) will
kick in via hyperventilation or hypoventilation in an attempt to correct
pH. However the disadvantage of the respiratory system is that it will
only handle volatile acids most importantly carbonic acid because
carbonic acid is the only acid that will be converted into a gas – CO2. Your
respiratory system will only handle volatile acids. The kidneys are the most
important not only will they handle non-volatile acids but they will also
handle bases but the disadvantage of the renal system that it takes a very
long time. If the chemical buffer system is instantaneous, respiratory
system within minutes, the renal system will take days such that full
compensation can be achieved within 3 to 5 days.
Intracellular Buffers

Intracellular CHON
o
H + Hgb  HHgb

pK: 7.4
Chemical buffer systems particularly intracellular buffers will
be done by intracellular proteins. Haemoglobin will act as a buffer such
that it is able to bind a H ion or it can release H depending on the
situation. Recall the oxygen dissociation curve: if H+ is increased, it will
give off oxygen because it is now the H+ that will “ride” with
haemoglobin. Haemoglobin will act as a buffer having a pK of 7.4. What
does a pK of 7.4 mean? This means that around this pH value you have
maximum buffering capacity.
Chemical Buffer System
In this table here you have the different compartments in the
body with their corresponding H ion concentration and pH. Take note
arterial blood is 7.4, venous blood is a little bit acidic which is 7.35
because of carbonic acid. Gastric HCl will have a pH of 0.8. Take note as
far as urine is concerned; it can either be acidic or alkaline. In the clinics,
it is not abnormal to find alkaline urine. More commonly in the
laboratory, the normal urine samples usually are acidic but just like what
was mentioned earlier, if the urine sample is alkaline it is not always an
abnormal result. Ask the patient as to why their urine sample is alkaline.
Is the patient taking in drugs, eating a lot of grape fruit or cranberries?
These fruits will alkalanize urine so alkaline urine may be a normal
finding.


Acid: releases H ions
Base: accepts H ions
o
H2CO3  H + HCO3
Acid releases H ion while a base accepts the H ion. For
example, in this chemical reaction of carbonic acid dissociating into H and
bicarbonate, your carbonic acid is the conjugate acid while the
bicarbonate is the conjugate base. Take note the reaction is reversible – it
can either go forward or backward.
7
Shannen Kaye B. Apolinario, RMT

Buffer + H  BufferH


Intracellular buffers
Extracellular buffers
o
HCO3 buffer system
o
PO4 buffer system
Other chemical buffer systems are bicarbonate buffer system
and phosphate buffer system and both are simple reactions. So you have
your buffer biding to H+ and you have now buffer-H+ complex and this is
reversible.
Bicarbonate Buffer System

H2CO3
o
CO2 + H2O  H2CO3
NaHCO3
o
H2CO3  H + HCO3
o
Na + HCO3  NaHCO3


CO2 + H2O  H2CO3  H + HCO3
Na + HCO3  NaHCO3

The bicarbonate buffer system is an important extracellular
buffer. Given the equation, how is NaHCO3 is formed? CO2 plus water is
carbonic acid. Carbonic acid dissociates. Your Na now will combine with
bicarbonate forming NaHCO3. Taking all of these and creating one
equation, again CO2 + H2o is carbonic acid. With your carbonic
anhydrase, ions will dissociate, Na will combine to bicarbonate to form
sodium bicarbonate.


CO2 + H2O  H2CO3  H + HCO3
Na + HCO3  NaHCO3
o
Add lactic acid
If you add an acid like lactic acid, you increase your H+
facilitating the backward reaction. When H+ increases by adding lactic
acid, your reaction will favour the formation of carbonic acid and this will
dissociate or reconstitute CO2 and H2O so you now have neutral
substances.


CO2 + H2O  H2CO3  H + HCO3
Na + HCO3  NaHCO3
o
Add NaOH
If you put an alkaline like sodium hydroxide, it will favour the
forward reaction. H+ will combine to one of the H+ from carbonic acid
forming water so that creates your bicarbonate and this will combine
with Na forming sodium bicarbonate.
wherein the system will have maximum buffering capacity. Meaning to
say from 6.1, even if you add an acid or base, the changes in pH is
minimal. Bicarbonate buffer system is an extracellular buffer.
Phosphate Buffer System





H2PO4, HPO4
Intracellular buffer
Renal tubular buffer
HCl + Na2HPO4  NaH2PO4 + NaCl
NaOH + NaH2PO4  Na2HPO4 + H2O

pK: 6.8
The phosphate buffer system is an important intracellular
buffer together with intracellular proteins and it is an important buffer in
the renal tubules. This is a simple chemical reaction for your phosphate
buffer. For example, if you add an acid, your HCl will react with Na2HPO4
giving us NaH2PO4 and salt. You will note that they just exchanged ions
giving now a neutral compound. If you add a base like sodium hydroxide,
it will react to NaH2PO4 giving you Na2HPO4 and water and again, it is a
neutral compound. Its pK is around 6.8
Isohydric principle.

H = K1 x (HA1/A1) = K2 x (HA2/A2) = K3 x (HA3/A3)

Any condition that changes the balance of one system also
changes the balance of the others
Quantitative Dynamics

H2CO3  H + HCO3

Dissociation constant K
o
K = (K x [HCO3])/[H2CO3]
o
H = K x [H2CO3]/[HCO3]
o
H = K x [CO2]/[HCO3]
o
H = K x (0.03mmol/mmHg x PCO2)/[HCO3]
o


pH = -log K
H = K x (0.03mmol/mmHg x PCO2)/[HCO3]
pK = -log K
o
-log H = -log K -log (0.03 x PCO2)/[HCO3]
o
pH = pK -log (0.03 x PCO2)/[HCO3]
o
pH = pK +log [HCO3]/(0.03 x PCO2)
o
pH = 6.1 +log [HCO3]/(0.03 x PCO2)
For quantitative dynamics, this simply explains the
Henderson-Hasselbach equation so it will compute for pH given a
known concentration of bicarbonate and CO2. In the laboratory,
bicarbonate and CO2 amounts in the blood are taken from the ABG
(arterial blood gas). With this, you can actually compute for the blood pH.
Bicarbonate Buffer System
Here you have your H+ concentration equal to the HendersonHasselbach equation of one system, equal to the equation of system two,
equal to the equation of system three. When we say isohydric principle,
any change in the H+ concentration or blood pH, all three systems will
adjust simultaneously. For example, the first system will represent
intracellular buffers, the second system will be bicarbonate, the third
system will be the phosphate buffer. If the pH of the body changes, all of
these will adjust simultaneously. In the same manner, if one system
becomes deranged, for example bicarbonate system – it increased or
decreased in the body, your first and the third system will adjust
accordingly in order to maintain pH.
Respiratory System




Controls extracellular CO2
o
H2CO3: volatile acid
Alveolar ventilation modulates PCO2
50-75% effectiveness
1-2x buffering power than the chemical buffer systems
Basically, the respiratory system will control CO2 and carbonic
acid so this is now your volatile acid. Alveolar ventilation will modulate
your pCO2 – it depends if you will hypo or hyperventilate. It is said to be
50-75% effective having a buffering power around 1 to 2 times greater
than the chemical buffer system. The respiratory system will act within
minutes.
Renal System
This is now the pK of your buffer system which is around 6.1.
You have your pH, acid, bicarbonate. When we say pK, this is the pH
8
Shannen Kaye B. Apolinario, RMT



Excretes acidic or basic urine
4320 mEq/day HCO3 is filtered
4400 mEq/day of H is secreted
o
4320 mEq of H secreted to reabsorb HCO3
o
80 mEq of H excreted as non-volatile acids

Acid-base balance
o
Secretion of H ions
o
Reabsorption of HCO3
o
Generation of new HCO3
The renal system is the most important component in
controlling blood pH because they will primarily handle acids and bases.
Around 4,320 mEq of bicarbonate is filtered and 4,400 mEq of H+ is
secreted by the renal tubules. From your 4,400, 4,320 of H+ secreted will
go to your bicarbonate for reabsorption. So, if 4,320 goes to bicarbonate
for reabsorption, you will have an excess of 80 (4,400-4,320 = 80). This
80 mEq of H+ are the non-volatile acids or acids that are not handled by
the lungs like uric acid, lactic acid etc. That’s why when you get a urine
sample, more commonly it is acidic.
Take note that for acid-base balance to occur you need several
processes: secretion of H+, reabsorption of bicarbonate, and production
of a new bicarbonate.
Hydrogen Ion Secretion




Na-H counter transport
To reabsorb HCO3, H must be secreted
o
4320 mEq/day: filtered HCO3
o
4400 mEq/day: secreted H

4320 mEq/day H: HCO3

80 mEq/day H: non-volatile acids
H2PO4, HPO4, NH3, urate, citrate buffers
HCO3 reabsorption
This are the different segments of the nephron. The numbers
represent bicarbonate filtration and the percent reabsorbed. Take note
that here you have 4,320 mEq filtered and from there, 85% will be
reabsorbed from the PCT. So majority of the bicarbonate is reabsorbed
within the PCT and 10% in the thick ascending limb and around 4.9% in
the DCT and collecting ducts. 4,320 filtered and 4,400 is H+ secretion and
take note that around 4,300 of H+ will bind with bicarbonate and 80 mEq
of H+ will bind with non-volatile acids like phosphate, ammonia, uric and
citrate buffers.
dissociates. Bicarbonate is reabsorbed. Here you have your H+. Because
of primary pump, it will power the secondary pump. In the urine, sodium
bicarbonate is filtered (4,300+) this dissociates and Na will enter via
secondary pump, H+ will exit via secondary pump. H+ will combine with
bicarbonate reconstituting carbonic acid. Carbonic acid reverts back to
H20 and CO2. CO2 can easily diffuse into the cell membrane and again the
same process occurs.
Take note that to reabsorb bicarbonate, you need a H+ so that
you form carbonic acid and CO2. Without H+, sodium bicarbonate goes
out into the urine. Take note that you have one to one correspondence –
for every 1 bicarbonate, you need 1 H+. Take note also that bicarbonate
reabsorbed here is NOT the same bicarbonate that is filtered however
you have one to one correspondence for as long as there is one H+
present. For as long as this reaction continuous to take place, bicarbonate
inside the cell accumulates creating now a gradient in the blood,
bicarbonate goes out.
DCT, CT Intercalated cell: Hydrogen Ion Secretion
Let us now look at the DCT and collecting ducts particularly the
intercalated cell. Here you have secretion of H+. Again, CO2 produce
carbonic acid, bicarbonate and H+. Your H+ will be pumped out via H+
pump. Bicarbonate will go out into the blood using a bicarbonate-Cl
counter transport. This is your intercalated cell, take note that you
generate a new bicarbonate molecule.
DCT, CT Intercalated cell: Phosphate Buffer
Bicarbonate Reabsorption
For your phosphate buffer, it is an important buffer for the
renal tubules. Bicarbonate buffer system is reabsorbed while the
phosphate buffer is not reabsorbed so it bears the burden of controlling
pH within the tubules.
This is now your tubular cell more importantly in the PCT. This
is your interstitial compartment or blood, tubular cell and filtrate. How
can we reabsorb bicarbonate? Your tubular cells will produce CO2. From
there it combines with water forming carbonic acid. Carbonic acid
9
Shannen Kaye B. Apolinario, RMT
This is your Na-PO4 buffer and you have here your renal
tubules. The same reaction: CO2 + H2O -> carbonic acid, bicarbonate and
H+. Primary pump will power the secondary pump. The Na from
phosphate buffer will enter the cell and H+ exits. H+ will combine with
phosphate buffer now then this exits via the urine. Take note that you
produce a new bicarbonate. Basically we are now talking on how we are
producing a new bicarbonate.
Other buffer systems can also act within the tubular cells like
ammonia, urate and citrate. So all of these can actually bind with secreted
H+ ion. When that happens, a new bicarbonate is produced.
For glutamine, when it is metabolized, ammonium is produced
and 2 molecules of bicarbonate are also produced. So the NH3Cl is
excreted as well in the urine.

Titration of H in the tubular lumen
o
H + HCO3: reabsorption of HCO3
o
H + buffers: generation of a new HCO3

Acidosis: excess H
o
Reabsorption of all filtered HCO3
o
Generation of new HCO3
DCT, CT Intercalated cell: Aldosterone Effect
To reabsorb bicarbonate, H+ is needed. To generate a new
bicarbonate, H+ will combine to non-bicarbonate buffers.
During acidosis, there is excess H+ so here you have
reabsorption of all of the filtered bicarbonate because if you want to
reabsorb one bicarbonate, you need to have H+. So if the H+ is in excess,
all bicarbonate will be reabsorbed. The excess H+ will combine to a nonbicarbonate buffer generating new bicarbonate.
Hydrogen Ion Secretion

For aldosterone effect, basically it increases the action of NaK
pump increasing the secondary pump, more H+ will go out therefore
more bicarbonate goes out into the blood. That is why if we have
hyperaldosteronism, the manifestation is alkalosis.
Stimuli for secretion of H ions
o
 PCO2
o
 extracellular pH
o
Excess aldosterone

 loss of H, NH4, titratable acids

 HCO3
DCT, CT Intercalated cell: Ammonia Buffer
Ammonia buffer is almost the same with the principle behind.
You produce your carbonic acid, bicarbonate and H+. H+ is pumped out
via H+ pump. Ammonia is due to amino acid metabolism and it can easily
diffuse out of the cell. NH3 becomes ammonium. It will combine to a
filtered anion like Cl- so here you have ammonium chloride then it goes
out into the urine. Again, new bicarbonate is produced.
For the stimuli of secretion of H+ ions, here are the conditions:
if CO2 within the body increases (respiratory acidosis), blood pH drops or
when you have an increased aldosterone. We have already mentioned
that as far as aldosterone is concerned, it powers the primary pump for
facilitation H+ secretion.
Quantifying Acid-Base Excretion

HCO3 excretion
o
V x UHCO3

Removal of HCO3 from the blood, or the addition of
H into the blood

NH4 excretion
o
V x UNH3

Amount of new HCO3 added into the blood

Titratable acids
o
Non-HCO3, non-NH4 buffer excreted
o
Measured via titration with NaOH

PO4, organic buffers
Generation of New Bicarbonate
In quantification of acid-base secretion, we want to know how
much H+ is excreted out of the body. To get the value, three components
are needed: bicarbonate excretion, ammonium excretion and titratable
acids.
10
Shannen Kaye B. Apolinario, RMT
Your bicarbonate excretion is your urine flow rate times the
concentration of bicarbonate in the urine. This simply measures the
removal of bicarbonate from the blood or the additional of H+ in the
blood.

Ammonium excretion is urine flow rate times the
concentration of ammonia in the urine and this measures the amount of
new bicarbonate added into the blood.
Titratable acids are non-bicarbonate and non-ammonium
buffer excreted like the phosphate, citrate, urate buffers and this is
measured via titration via NaOH. Using a urine sample, you use a pipette
and it is titrated in the laboratory. If the solution turns pink, it is the
amount of NaOH consumed therefore that is the amount of H+ present.
When we say acidosis, you have an excess H+ and your H+ is
greater than bicarbonate therefore H+ is excreted resulting to an acidic
urine and 100% of bicarbonate is reabsorbed. You also produce a new
bicarbonate via non-bicarbonate buffers like ammonium excretion and of
course the patient is hyperventilating.


Net acid excretion
o
(NH4 excretion + urinary titratable acid) – HCO3
excretion

Acid-base balance
o
Net acid excretion = non-volatile acid production
o
Acidosis:  H excretion,  NH4 excretion,  HCO4 addition
into the blood
o
Alkalosis: no NH4 and titratable acid excretion,  HCO4
excretion, no new HCO3 generated
Once the three variables are there, net acid excretion can now
be computed – how much H+ are excreted in the body. Here you have
NH4 excretion plus urinary titratable acids minus bicarbonate. To
maintain acid-base balance, net excretion should equal to non-volatile
acid production. Non-volatile acid production is used like uric acid, lactic
acid because your non-volatile acid is being handled by the kidneys while
volatile acids are being handled by the lungs.
Acidosis: excess H
o
H > HCO3
o
H is excreted, acidic urine
o
Reabsorption of all filtered HCO3
o
Generation of new HCO3
o
 NH4 excretion
o
Lungs:  ventilation
Alkalosis: excess HCO3
o
HCO3 > H
o
HCO3 is excreted, alkaline urine
o
 H secretion
o
NH4 and titratable acids are not excreted
o
No new HCO3
o
Lungs:  ventilation
In alkalosis, excess bicarbonate greater than H+. Because of the
excess bicarbonate, not all will be reabsorbed. Bicarbonate is excreted
producing an alkaline urine. You have less H+ secretion and ammonium
and titratable acids will NOT be excreted. Take note we do not generate a
new bicarbonate and as far as the lungs are concerned, there is
hypoventilation.
If the individual has acidosis, you have an increase in H+
excretion, increased ammonium excretion and increased bicarbonate
addition into the blood. In alkalosis, there is no NH4 and titratable acids
excretion, you have increased bicarbonate secretion and no new
bicarbonate is generated.
Acid-Base Disorders

pH = 6.1 +log [HCO3]/(0.03 x PCO2)
Here you have the different substances or parameters that are
measured in an ABG sample. Your H+, O2, CO2 and bicarbonate. The
values will represent normal values (memorize!!!).
In simple interpretation of ABG, we take note of the pH, CO2
and bicarbonate levels. Why is H+ and O2 are taken? H+ and O2 are
important for the management because H+ will determine how much
bicarbonate should be given to correct the problem. O2 will determine if
the patient is hypoxic specially if he is having respiratory acidosis - to
know if the patient has to have cannula, mask or intubated. But as far as
diagnosis is concerned, CO2 and bicarbonate is important.
These are your primary acid-base disturbances: respiratory
acidosis or alkalosis, metabolic acidosis or alkalosis, and their
corresponding derangements.
11
Shannen Kaye B. Apolinario, RMT

Mixed acid-base disorders

Respiratory and renal adjustments have occurred
In the assessment of primary acid-base disorder, the first thing
to look at is the pH to know if it acidosis or alkalosis and then bicarbonate
and CO2 to know if it is metabolic or respiratory disorder. The problem
more often than not, there are complex acid-base disorders so with that,
acid-base nomogram is used. It is used when there is a respiratory and
renal adjustment. Because of that, utilizing your acid-base nomogram is
not really ideal at the onset of the disorder because the chemical buffer
system acts instantaneously, the lungs in minutes but the lungs acts for
days. For example, if a patient had an asthma attack and an ABG was
taken, this may not reflect the same ABG three days from now because
there will still be renal adjustments. Your acid-base nomogram is most
ideal to use when the kidneys and the lungs have adjusted.



pH: 7.3
HCO3: 12 mEq/L
PCO2: 25 mmHg

Metabolic acidosis
What is this anion gap? In the body, to maintain electrical
neutrality, the number of cations should equal the number of anions and
this are the more common ions present in the body – Na, Cl and
bicarbonate. To get the anion gap, this is simply cations (Na) minus
anions (Cl and bicarbonate). If you have normal values for this, the
normal anion gap would be around 8-10 or 10-12 depending on the
laboratory. Take note that you also have other anions and cations present
in the plasma like K, Mg, Ca, albumin, PO4 and sulfates. Your anion gap is
most useful when we have metabolic acidosis.
If you have metabolic acidosis, what will happen to your
bicarbonate? It will decrease. When Na and Cl will not change their
values, you have a drop in your bicarbonate, anion gap increases. The
normal anion gap would be 8-10 so in order to maintain electric
neutrality, if bicarbonate becomes low, for the anion gap to be normal
either Cl will increase or the unmeasured anions will increase. That is
why if we have metabolic acidosis and the anion gap is computed and the
anion gap is deranged then Cl is decreased, we have to request other
anions.
In the graph above, you have your blood pH, bicarbonate
concentration and the red lines or values will represent CO2
concentration. For example, you have a pH of 7.3, bicarbonate of 12, pCO2
of 25. First look at the pH – acidosis. If you look at bicarbonate, it is
decreased – metabolic acidosis but looking at CO2, it is decreased –
respiratory alkalosis. It is mixed acid-base disorder so we use now the
nomogram. Simply plug in the values.



pH: 7.15
HCO3: 7 mEq/L
PCO2: 50 mmHg

Metabolic acidosis with respiratory component
If you plug the values, you will have 2 points. Your primary
disorder is metabolic acidosis. You have a respiratory component by
looking at the value of CO2 which is acidosis because higher than 45 CO2
is acidosis. Your primary disorder is metabolic in origin so you need to
investigate what is the main problem. It is possible that patient has
ketoacidosis and the lungs are already decompensated that’s why he is
having a respiratory acidosis.
Here you have an increased anion gap, the Cl levels are normal.
This simply means that unmeasured anions increased. Here are the
different conditions (table above).
If the anion gap is normal but Cl- increased in response to a
drop in bicarbonate, here are your conditions (table above). So this helps
us in the differential diagnosis of the patient.



pH: 7.40
HCO3: 30 mEq/L
PCO2: 60 mmHg

Correct the underlying cause


Chronic respiratory acidosis with renal compensation

Alkalosis
o
NH4Cl, lysine monohydrochloride
Acidosis
o
NaHCO3, Na-lactate, Na-gluconate
Anion Gap





Plasma: cations = anions
Na, Cl, HCO3 are measured
Plasma anion gap = Na – HCO3 – Cl
Plasma anion gap = 144 – 24 – 108
Plasma anion gap = 10 mEq/L
When we have patients with an acid-base disorder, it is also
important to get their electrolytes like Na, Cl and bicarbonate. It is
important to get these values for us to get the anion gap.



Plasma anion gap = Na – HCO3 – Cl
Plasma anion gap: 8-10 mEq/L
o
Used to diagnose metabolic acidosis
o
Electric neutrality:  Cl or unmeasured anion
 anion gap
o
 anions: PO4, SO4, albumin, organic anions
o
 cations : Ca, Mg, K
12
Shannen Kaye B. Apolinario, RMT
In the correction of acid-base disorders, it is important to
correct the primary problem first. If the patient is having respiratory
acidosis due to asthma or COPD, correct the asthma or COPD first, do not
give bicarbonate right away. Same is true if the patient is having
ketoacidosis, correct glucose derangements first.
For alkalosis, these are the drugs used: ammonium chloride,
lysine monohydrochloride which is more commonly used because it is
safer. For acidosis, sodium bicarbonate, sodium lactate and sodium
gluconate are used. Among the three, the safest to use are the sodium
lactate and sodium gluconate.
Micturition
Micturition is both a conscious and unconscious action. There
are some cortical control with regards to micturition.
Micturition Reflex



R: stretch receptors
Aff: pelvic nerves
C: S2-3


Eff: pelvic nerves
E: detrusor muscle, internal urethral sphincter
micturition reflex, inhibitory impulses then relaxation. So that is how we
control the bladder – “toilet training”.

Cerebral cortex, pons
You will know that as the volume increases within the urinary
bladder, the pressure being generated by your micturition reflex
increases because the micturition reflex is said to be self-regenerating.
Why? When the volume increases, the pressure inside increases and this
is detected by stretch receptors. When the detrusor muscle contracts,
pressure will further increase, stimulating the receptors more, so it will
further increase. There will come a point wherein the pressure in the
urinary bladder is not able to be controlled by the cerebral cortex
because your cerebral cortex primarily controls skeletal muscles that’s
your external urethral sphincter. If your micturition reflex allows
relaxation of internal urethral sphincter and the pressure is too great,
higher than your external urethral sphincter, no matter how you try to
control or stop from urinating, it will still go out.
___“Nahuli? May tanong?”___
When we say micturition, it can either be conscious or
unconscious but when we say micturition reflex, it is unconscious.
Because this is a reflex, the components of the reflex arc should be
present. Present in the urinary bladder are the stretch receptors. When
stimulated by stretch, they will send impulses into the pelvic nerves
(afferent), the center is S2 to S3 (some books would say S2 to S4). The
center will be sending impulses going to the pelvic nerves affecting now
the effectors and the detrusor muscles contracts whereas the internal
urethral sphincter relaxes.
But the activity of the arc is modulated by higher centers –
cortex and the pons. If you look at you reflex arc, stimulation of stretch
receptors will illicit contraction of the urinary bladder and relaxation of
internal urethral sphincter.
This is your urine or fluid volume and pressure. If the bladder
is empty – 0 volume and 0 pressure. fluid slowly accumulates, the bladder
distends stimulating now the stretch receptors. The stretch receptors will
send impulses via pelvic nerves going to C3 and C4. C3 and C4 will be
sending impulses via the same pelvic nerves for the contraction of the
detrusor muscles and relaxation of internal urethral sphincter. When
your detrusor muscles contracts the pressure inside will increase but that
is not the end.
Impulses will also ascend to the pons and the cerebral cortex.
The cerebral cortex will assess if voiding is convenient. Your cerebral
cortex will send inhibitory impulses down to C3 and C4 inhibiting the
center. When the center is inhibited, no excitatory impulses will go to
detrusor muscles and the internal urethral sphincter remains contracted
and the pressure decreases. Urine will accumulate so the process will
repeat – fluid accumulates, stimulation of stretch receptors eliciting a
13
Shannen Kaye B. Apolinario, RMT
“And we know that in all things God works for the good of those who
love Him – for those who have been called according to His purpose.”
-Romans 8:28
GOD BLESS YOU 
Far Eastern University
Nicanor Reyes Medical Foundation
Institute of Medicine
1D – Batch 2020
Renal Physiology IV
Body Fluids and Acid-Base Balance
Dr. Ronald Allan Cruz – January 16, 2017
BODY FLUIDS

60% of our body weight is water
o So if you have a 70kg man, 42L is
water
The 60% of our body fluids are subdivided into two:
1. Extracellular fluid – 20% (14L)
Divided into two:
a. Interstitial fluid : 15% (11L)
b. Plasma : 5% (3L)
2. Intracellular fluid – 40% (28L)
Transcellular fluid – 1-2L

The 3rd space

A specialized compartment

Collection of fluids within specialized
compartments like:
o CSF
o Pericardial fluid
o Pleural fluid
o Peritoneal fluid
o Synovial fluid , etc.
Blood


Water Loss

It should equal water intake so it should be
2.3L also

Further subdivided into:
o 700 mL – insensible losses

Water that we lose and we
are not aware of it

350 mL for evaporation
from skin

350mL from respiration
o 100mL from sweat

Varies depending on
temperature and physical
activity
o 100 mL from feces

Varies if there is a diarrhea
o 1400 mL from urine
Certain conditions can alter the volume:
Patient with burns:

The protective layer of the skin is removed
(epidermis and dermis)

Increase loss of water via evaporation

So one of the cornerstone for the management
of burns would be fluid replacement
EXCHANGE OF FLUIDS BETWEEN COMPARTMENTS
7% of our body weight is basically blood
It is said to be a special compartment because
it contains both extracellular and intracellular
water
o Plasma

The extracellular water

60% of blood volume is
plasma (3L)
o Formed elements

the intracellular water

RBC, platelets, WBC, etc.
that contain water

40% of blood volume (2L)

This is reflected in the clinic
as hematrocrit
Water intake

This is to maintain fluid homeostasis intake
should be equal to output

On the average we take in around 2.3L per
day
o 2100 mL comes from the fluids that
we drink
o 200 mL comes from the breakdown
of glucose / CHO oxidation

We all know that when
glucose is metabolized, CO2
and H2O are one of the
products
Diagram: represents the different ions from the
intracellular and extracellular compartment. Take note
of the various ions present in the both compartments.
The line represents the cell membrane.

Its job is to regulate the flux of water between
two compartments
The Great Escoto
1 of 17
Diagram: Represents the extracellular compartment that
is divided into two: Plasma & interstitial compartment.
The black line represents the endothelial capillary
wall/membrane which separates the two.
ENDOTHELIAL CAPILLARY WALL/MEMBRANE

will not allow plasma proteins to enter the
interstitial compartment

and since PP are negatively charge, GIBBS
DONNAD EFFECT is observed
o some cations are attracted to Plasma
proteins
o some anions are more present at the
interstitial compartment due to ionic
repulsion
For example, you have this container with an unknown
volume and you want to determine its volume. What
you would do is to administer an indicator with a
known volume and concentration.




For example: you have an indicator whose
concentration is 10mg/mL and you administer
1mL of that indicator
You place that indicator inside the system
Allow it to go steady state and determine the
concentration of the system
Let’s say it is 0.01 mg/mL
Application using the formula:
CA= 10mg/mL
VA = 1mL
CB = 0.01 mg/mL
VB = ?
Table: the different substances present in the different
compartments: Plasma, interstitial and intracellular
compartment.
Highlighted in red – located extracellularly
Highlighted in blue – located intracellularly
At the bottom portion, the one highlighted in green, it is
the total osmolality, the total osmolar activity and the
total osmotic pressure
INDICATOR-DILUTION PRINCIPLE

used in measuring specific volumes

Measurement of fluid volumes in different
compartments
CA x VA = CB x VB
CA = Concentration of indicator
VA = volume of indicator
CB = concentration of the system
VB = volume of system
VB = 10mg/ml x 1ml
1.01 mg/ml
VB = 1000 ml
Nasundan paano nakuha yon? You got that? – Dr. Cruz
In determining specific volumes in the body, we need to
utilize an appropriate indicator.
So for in measuring:
1. Total Body H2O – we utilize radio labeled
water or hard water or heavy water
a. 3H2O, 2H2O
2. Extracellular fluid volume – we utilize inulin
or radio labeled Na (22Na)
a. Plasma volume – we utilize radio
labeled albumin (125I-albumin)
b. Interstitial volume – subtract the
plasma volume from extracellular
The Great Escoto
2 of 17
3.
4.
volume (extracellular volume –
plasma volume)
Intracellular volume = Total H2O minus
extracellular volume
Total blood volume = you can use:
a. Plasma / (1-hct)
b. Or you can use radio labeled RBC
(51Cr-labeled RBC)
In employing an appropriate indicator, you need to
fulfill three important criteria:
1.
2.
3.
Your indicator must stay in the compartment
you want to measure
a. If your indicator goes out, you can’t
use it
The indicator must be dispersed evenly in the
compartment you want to measure
Your indicator must not be metabolized within
the compartment you want to measure
Once these criteria are fulfilled, only then you can use
the indicator to measure the particular volume for a
particular compartment.
Osmotic Equilibria Between Extracellular and
Intracellular Fluid


Plasma and interstitial fluid volume
 Recall that between the intravascular
and the interstitial space, it is
separated by the endothelial wall or
capillary wall.
 Starling forces regulates the flow of
H2O between these two structures:
 Hydrostatic pressure
 Colloid osmotic pressure
Extracellular and intracellular fluid volume
 The two compartments are
separated by the cell membrane
 What determine the movement of
water is the: Osmotic effects of
solutes
 Specifically Na because it
determines the volume of
the extracellular fluid
ALWAYS TAKE NOTE:
The intracellular compartment is said to be isotonic
with the extracellular compartment.
Recall of some concepts:
Osmosis – movement of water from low solute
concentration to a high solute concentration
Osmotic pressure – this is the pressure that is required
to stop osmosis.
Osmoles

The total number of osmotically active
particles in a solution
o These are the substances that will
attract water

1osm = 1 mol of a substance = 6.02x1023
particles (Avogadro’s number)

1mOsm = 0.001 osm
Osmolality

This is the osm/kg of H2O
Osmolarity

This is the osm/L of H2O
Chemically speaking

They are different.

Osmolality is more accurate because volume is
affected by temperature
o By increasing the temperature, you
increase the volume but mass stay
the same
Medically speaking

They are interchangeable
o Simply because our body does not
reach 100oC – we have a stable body
temperature.

We reached up to 40o when
we are in fever but that
does not change the volume
drastically.
The number of osmotically active particles by different
substances:
 1 mole/L of glucose = 1 osm/L
 1 mole/L of NaCl = 2 osm/L
 1 mole/L of Na2So4 = 3 osm/L
If you have the same concentration of glucose, NaCl,
Na2SO4, we all know that Na2SO4 when placed in water
will dissociate into three particles: 2 Na and 1 SO4 ions.
Thus it will exert a greater osmotic pressure compare to
one mole of glucose.
Osmotic pressure

The pressure required to oppose osmosis

It is an indirect measure of the number of
solute within the fluid.
o The greater the concentration of the
fluid, the greater the osmotic
potential

What is more important is the number of
ionizable particles:
o Increase osmotically active particles
= increase osmotic pressure
o It is independent to the size of the
particles
Example:
Na2SO4 > NaCl > albumin = glucose
A Na2SO4 exerting a greater osmotic potential than
albumin. Though albumin is a large molecule, given a
same concentration with Na2SO4, it will have a less
osmotic potential.
The Great Escoto
3 of 17
VAN’t HOFF’s Law
o Computes for osmotic pressure
o The unit is the mmHg
9.
It is this 286 mOsm that you will multiply to
19.3 to get your corrected osmotic pressure.
10. So the corrected osmotic pressure is:
π=CRT
π – mmHg
C – concentration of solutes in osm/L
R – ideal gas constant
T – temperature, 310 kelvin
286 mosm/L x 19.3 mmHg/mosm/L = 5519.8 mmHg
of NSS
1osm/L = 19300mmHg
1mOsm/L = 19.3mmHg
1 mOsm of a substance per liter is able to exert a
pressure of 19.3mmHg
APPLICATION
Let’s say we have 0.9% NSS (NaCl). So basically, what is
the pressure exerted by NSS?
1.
2.
Here you have 0.9% NaCl which is equivalent
to 0.9g/100mL H2O
a. It is also equal to 9g/L of H2O
To get the number of moles, you simply
divided that to the molecular weight of NaCL
which is 58.5 g/mol
9 g/L ÷ 58.5 g/mol = 0.154 mol/L
3.
Then we multiply it by 2 because if we place
NaCl in water, it dissociates into Na and Cl.
Nasundan?
a. So if it was Na2SO4, multiply it to 3.
Malinaw?
Table: In the body, here are the different substances present in the
different compartments (plasma, interstitium and intracellular
compartment.
All of these substances will exert osmotic potential.
They will attract water.
0.154 mol/L x 2 = 0.308 osm/L
4.
5.
Convert that to mOsm by moving the decimal
point so = 308 mosm/L. nasusundan so far?
To get the pressure, you simply multiply the
mOsm to 19.3mmHg/mOsm/L
308 mosm/L x 19.3 mmHg/mosm/L = 5944 mmHg of
NSS
6.
7.
So NSS will have a pressure of 5944 mmHg.
But that doesn’t stop there
a. You need to take into account the
correction factor of NaCl.
Correction factor of NaCL = 0.93
so if you place NaCL in water, only 93% of NaCl will
dissociate into Na and Cl. The other 7% will stick as
NaCl. This is because Na is positive and Cl is negative,
they will always have some ionic attraction between the
two.
8. So from 308 mOsm/L, you multiply it to the
correction factor
Table: Magnified bottom part of the above table



This now the total osmolarity but you always
need to take into account the corrected factor
for each ion.
By taking into account the correction factor for
all the ions, the corrected osmolar activity are
presented on the second row.
o You will notice that they are ALMOST
equal with one another.
To get the pressure now, you multiply the
corrected osmolar activity by 19.3 mmHg
Take note:
All three compartments are said to be isotonic with one
another.
You will also notice that the plasma has a higher
osmotic pressure compared to the two, this is due to the
presence of Plasma Proteins.
308 mosm/L x 0.93 = 286 mosm/L
The Great Escoto
4 of 17
Isotonic fluid
 It means that the solution has the same
osmotic pressure /potential NOT the same
concentration.
o It is said to be that the 0.9NaCl (NSS)
is isotonic with plasma, IT DOES NOT
HAVE THE SAME CONCENTRATION
WITH PLASMA because it contains
Na and Cl while plasma contains
NaCL, K, Mg, SO4 etc.
o What is the same between the two is
the ability to attract water or osmotic
potential
 Examples are NSS and PLR
Hypotonic solutions
 The solution has a lower ability to attract
water.
Hypertonic solutions
 The solutions has a higher ability to attract
water
TAKE NOTE:
Dextrose 5% water (D5 water) is NOT isotonic. It is
ISOOSMOTIC.
 It has the same ability to attract water
 It is not the same with isotonic even though it
has the same ability to attract water like
plasma
 If you place cells within D5 water, glucose is an
INEFFECTIVE osmole because glucose will
readily enter the cell.
o once glucose enters the cell, this will
decrease the glucose concentration
of the medium, rendering your fluid
HYPOTONIC.
Sensors that will detect Effective Circulating Volume
1. Vascular low-pressure volume sensors
 Located within the atria and
pulmonary vessels
 They detect venous return
Example:
When you decrease venous return, you decrease the
filling of atria and the pulmonary vessels  this will be
detected by the receptros  activates sympathetics and
ADH  ↑ volume
Increase venous return  increase filling 
sympathetics go down  ANP and BNP are released 
excrete water or ↓ volume

2.
Vascular high-pressure volume sensors
 These are the barorecpetors (aortic
and carotid sinus) and afferent
arterioles
 They detect cardiac output
Example:
When CO is low  ↓ decrease BP  inhibit
baroreceptors  increase sympathetics to heart and
blood vessels  increase BP  increase blood volume
But for kidneys since BP is low  RBF goes down 
GFR goes down  activating JG apparatus  increasing
RAAS  increases volume

Hepatic sensors
 Hepatic blood vessels contain volume
and Na sensors
 Increase Na or volume  decrease
sympathetic activity  increase Na
excretion (we all know that where Na
goes, water follows)
4.
CNS
Average Blood Volume = 5L
Under certain conditions, 5L may not be enough to
perfuse body tissues for the body organs.
Effective circulating volume

The volume that will effectively perfuse tissues

Keep in mind that volume is Na dependent
Extracellular volume = Plasma + interstitial fluid
If you have a 5-10% change in
volume, that will evoke a response
3.
EFFECTIVE CIRCULATING VOLUME
A classic example is Septic Shock
 even if the patient has 5L of blood, if he is
suffering from septic shock, all of the blood
vessels will dilate.
o This will increase the capacitance of
blood vessels
 Although Blood volume is 5L, this will not
ensure that the different organs are properly
perfused so that’s why we have the concept
effective circulating volume.
If you have a 5-10% change in
volume, that will evoke a response



in the hypothalamus contains Na
sensors
this detects the Na content of CSF or
carotid perfusion
increase in Carotid or CSF Na 
increase Natriuretic peptides and
angiotensin II increase Na
excretion
VOLUME EXPANSION
 the body would have to remove excess Na
 Na excretion
 The effects are:
o  renal sympathetic effects
o  ANP, BNP, urodilantin
o  ADH, renin, RAAS
The Great Escoto
5 of 17
VOLUME CONTRACTION
 Because the volume goes down, the body
would have to reabsorb Na
 Na Reabsorption
 the effects are:
o  renal sympathetic effects
o  ANP, BNP, urodilantin
o  ADH, renin, RAAS
Take note: they are just opposites.
VOLUMES AND OSMOLALITIES OF EXTRACELLULAR
AND INTRACELLULAR FLUID IN ABNORMAL STATES
Fluid Compartments
 In calculating intracellular and extracellular
fluid volume:
o Water moves rapidly across cell
membrane
o Cell membranes are almost
completely impermeable to solutes

Solutes are not able to pass
through
C: Adding a hypertonic solution, water inside the cell
will go out
 the Intracellular volume goes down
 ECF volume increases
 The tonicity of both compartments both
increases.
Other than NSS and PLR, we also have other fluids
available in the clinic:
1. Glucose
2. Amino Acids
Sometimes we incorporate medications with the fluid
and that will change the tonicity of the fluid. So all of
these fluids must be adjusted to isotonicty and they
must be administered slowly.
For example:
Common fluids can contain glucose (D5 NSS) or they
may contain Amino Acids for nutritional build up.
Glucose and AA are ineffective osmoles, they readily
enter the cell and we all know that when these
substances enter the cell, they will render the fluid
hypotonic. So we do not administer these substances in
fast drip so the body can excrete excess water.
CLINICAL ABNORMALITIES OF FLUID VOLUME
REGULATION
Diagram: Volume is plotted against osmolarity showing
the intracellular and extracellular volume.
A: Adding an isotonic solution, the volume of the cell
will not change
 volume of the intracellular compartment is the
same
 since you are adding an isotonic solution, the
extracellular fluid volume increases
 the tonicity will be the same
B: Adding a hypotonic solution, water will enter the
cell
 the volume of the cell (intracellular
compartment) increases
 the volume of the ECF increases since you are
adding a hypotonic fluid
 both their tonicity will go down
HYPONATREMIA – we all know that Na basically
detects ECF volume

Hypoosmotic dehydration
o water goes down with decrease Na
o Clinical conditions:

Electrolyte, H2O loss

Diarrhea, vomiting

Diuretics

Addison’s disease

Hypoosmotic overhydration
o Water goes up with decrease Na
o Clinical conditons:

SIADH
You should read on this daw. Why Na is low while water
is increased or decreased.
HYPERNATREMIA

Hyperosmotic dehydration
o Water goes down with increase Na
o Clinical conditions:

DI

Excessive sweating

Hyperosmotic overhydration
o Water goes up with increase Na
o Clinical conditions:

Conn’s syndrome (1o
hyperaldosteronism)

2o hyperaldosteronism
The Great Escoto
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NON ISOTONIC CELL VOLUME REGULATION
 the body has a defense mechanism by which
the cells will regulate its own volume so that it
won’t expand or won’t shrink even if you give
a hypertonic or a hypotonic solution.
Cell Shrinking
 this will happen when you administer a
hypertonic solution because water inside the
cell will go out
 what it will do is to undergo regulatory
volume increase response
o the cell will start to produce its
osmolytes
o when the cell shrinks, you have the
cytoskeleton which will modify the
volume of the cell.
o Once the cell shrinks and the
cytoskeleton is activated, osmolytes
production are activated.
o Osmolytes are located more
intracellularly and exerts osmotic
potential
o water will not go out so water is
maintained & cell volume is more or
less maintained.
Cell Swelling
 this will happen when you administer a
hypotonic solution because water outside the
cell will go in
 the swelling will be detected by cytoskeletal
elements and it will undergo regulatory
volume decrease response
o again the cell will synthesize the
osmolytes but
o the osmolytes will be pumped
extracellularly because you
administer a hypotonic solution
o this will increase osmotic potential
extracellularly preventing water
from entering the cell.
o The volume of the cell is maintained.
Osmolytes
 Ions, amino acids
o Na, Cl, K
o Taurine, glutamate, Ala
 Polyols
o Sorbitol, myoinositol
 Methylamines
o Glycerophosphoryl-choline, betaine
Osmotic demyelinization syndrome
 A condtion in which occurs in patient with
decrease Na and you rapidly correct Na
o So in correcting Na, you need to
slowly adjust it.
How does this happen? (as explained by Dr. Cruz)
When you have a patient with hyponatremia, Na outside
the cell is less so it is hypoosmotic therefore there is a
tendency for water to enter the cell causing the
swelling. But then you activate the regulatory decrease
response synthesizing osmolytes and pumping it out of
the cell. More osmolytes are found extracellularly.
When Na is rapidly increased, the cell will start to
shrink. You do not give proper time to the cell to
synthesize osmolytes intracellularly. So H2O now goes
out causing shrinking of the cell. The more susceptible
cells would be the neurons in the white matter and in
the pons.


Myelin sheath is destroyed
The condition is irreversible.
So in correcting Na especially in hyponatremia, it should
be slow for the cell to synthesize enough osmolytes.
EDEMA
Accumulation of fluid
2 types:
o Intracellular edema/swelling
o Extracellular edema/ swelling
Intracellular edema
 Water accumulates within the cell
 Manifestation is non-pitting edema
o Depression does not persist after
pressing
 Pathology:
o  metabolism
o  nutrition
o  ion pump activity
o  osmosis
o Inflammation
Extracellular edema
 Water accumulates in the interstitial space
 Manifestation is Pitting edema
o Depression persist even after
pressing
 Pathology:
o Plasma leakage
o Failure of the lymphatic drainage
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So here you have your filtration coefficient and Starling
forces. If you will recall, these are the factors that will
affect the amount of water going into the interstitium.
F = Kf x [(Pc+πi)-(Pi+πc)]
F – filtration rate
Kf – filtration coefficient
Pc – capillary hydrostatic pressure
πi – interstitial oncotic pressure
Pi – interstitial hydrostatic pressure
πc – capillary oncotic pressure
Lymphatic drainage
For edema to occur you have four important factors to
take note of and they are highlighted in red. Any
problems with the four will cause edema. For example
changes in your filtration coefficient, capillary
hydrostatic, capillary oncotic pressure and lymphatic
drainage. For each factor you have several examples.
Table: You have the four factors that can cause edema.
Any condition that will cause edema can fall under one
or more categories.
Example:
1. Congestive heart failure
 It can cause edema primarily because you
increase the capillary hydrostatic pressure.
2. Burned Patient
 When you damaged the skin due to burns,
blood vessels are also damaged.
 When BVs are damaged, Plasma proteins are
decreased due to leak out
o Capillary oncotic pressure drops
 Burns is also under the increased Kf because if
BVs are destroyed, capillary permeability is
increased.
SAFETY FACTORS THAT PREVENT EDEMA
The body has some way in protecting us from
edema
3 factors:
o Low compliance of the interstitium
o Increased lymph flow 10-50x
o Washdown on interstitial fluid CHON
1.
Low compliance of the interstitium
 Primarily due to the presence of
these in the interstitial space:
o Negative pressure
o Interstitial gel
o Proteoglycans and collagen
filaments
*let’s look at it one by one*
A. Negative pressure
 The pressure in the interstitium is said to be
-3mmHg
Table: If the pressure is -3mmHg, the volume of the
interstitial compartment is around 11-12L and that is
the amount of fluid present in the interstitial space.
You can equate this in a vacuum seal because the
pressure inside a vacuum seal is negative.

As long as pressure is in the negative side,
small changes in fluid volume are associated
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8 of 17

with large changes in interstitial hydrostatic
pressure
o For as long as the pressure is in 3mmHg, the slightest increase in
water in the interstitial
compartment, drastically increases
the interstitial hydrostatic pressure.
o We all know that increasing the
interstitial hydrostatic pressure
pushes the fluid back to the blood
vessels, preventing edema.
For as long as your pressure is in the negative
range  COMPLIANCE IS LOW
o C= ∆V / ∆P
o Compliance is expansibility so when
you have a negative pressure, you
can’t expand it easily.
B. Interstitial gel
 The function is to prevent the flow of fluid
 Offers elastic resistance to compression
 Compact brush pile
o This will not allow the flow of water
because the gell is compacted
together due to the negative pressure
(like a vacuum seal)
o Water from the upper portion of the
body can’t easily go to the lower
extremities due to compact brush
pile
 The interstitial fluid vol does not change
greatly.
C. Proteglycan Filaments
 Although the gel are compacted together, the
proteoglycan filaments are located in between
the gel that acts as a spaces.
 Modulates the flow of fluid
 Permits the flow of other substances like the
nutrients and metabolites
o Nutrients and metabolites can
readily go through the interstitium
but it will not allow the passage of
water.
Increased Compliance of the Interstitium
What happens when the interstitium becomes positive?
Looking at the graph:
 If the interstitium becomes
positive  there is a
drastic increase in fluid
volume
It’s like a hole in the vacuum seal
allowing air to enter that increases
the pressure within the package
 Compliance will increase
o
You can now
separate the
layers
 Increases the volume
because water enters
 All of the gel present will
be dispersed / the brush
pile is pulled apart
 The spaces in between will
now be occupied with
water
2.
Increased lymph flow 10-50x / Lymphatic
drainage
 If water is allowed to enter the
interstitial compartment, that will
increasing the interstitial hydrostatic
pressure
o And by increasing it, this
will facilitate lympathic
drainage.
 Safety facto is 7mmHg
3.
Washdown on interstitial fluid CHON /
drainage of interstitial proteins
 Once Pi increases (facilitates
lympathic drainage), at the same
time, some of the interstitial CHON
will be carried into the lymphatics
and brought back to the blood
 This decreases the interstitial oncotic
pressure
 Safety factor of 7mmHg

Low compliance of the interstitium
 Negative pressure
 Interstitial gel
 Proteoglycan and collagen fillaments
 3 mmHg
Increased lymph flow 10-50x
 7 mmHg
Washdown on interstitial fluid CHON
 7 mmHg


Looking at the three factors, highlighted in red are the
safety factors. The total safety factor would be 17mmHg.
 For edema to occur, the effective filtering
pressure must EXCEED 17mmHg.
FLUIDS IN THE POTENTIAL SPACES OF THE BODY /
TRANSCELLULAR FLUIDS
Potential Spaces – specialized cavities
 Pleural cavity
 Peritoneal cavity
 Pericardial cavity
 Synovial cavity
The fluid there is serve to prevent/reduce friction.



Fluids exchange between capillaries and the
potential space just like the interstitium
Lymphatics drain fluid from potential space
It also has negative fluid pressure
Table: Shows the negative pressure inside the spaces.
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9 of 17
Just like the interstitium, if these negative pressure
becomes positive:
 Fluid will accumulate
 Example: pleural effusion, ascites, or
tamponade
 The safety factors are their range of
pressures.
2.
ACID-BASE BALANCE
3.
Some Normal Values:
Extracellular concentration of H+ ions in the body 
0.00004 mEq/L
To get the pH  -log of the H+ concentration

So you’ll have a value of 7.4

In the clinics, the range is from 7.35 – 7.45

Intracellular

Extracellular
Respiratory System

reacting from minutes to
hours

2nd most important

Handles H2CO2 or volatile
acid
Renal System

reacting within days (3-5
days)

Most important and most
powerful regulators of pH
because it can handle a
wide variety of acid and
bases
Intracellular Buffers
 H moves in or out of the cell
 Intracellular buffers
1. HCO3
2. PO4
3. Histidine
 Intracellular CHON
1. H + Hgb  HHgb

Hemglobin can acts as
abuffer because H+ can
combine with hemoglobin

pK of hgb = 7.4
pK


Table: different compartments in the body with their H+
ion concentration with their pH.
When you speak of an acid  will donate a proton
When you speak of a base  will accept a proton
Example: H2CO3  H + HCO3

This is your carbonic acid giving in a H+ and
HCO3

Carbonic acid is the conjugate acid of HCO3

HCO3 is the conjugate base of the H2CO3

The reaction is reversible
Control of Hydrogen Ion Concentration
 To regulate the pH, there are three
mechanisms:
1. Chemical Buffer systems

1st to react when pH
becomes deranged

Least potent

Divided into:
dissociation constant
at around this pH value, you have maximum
buffering capacity
Extracellular buffers
 HCO3 buffer system
o More important
 PO4 buffer system
o This is basically a buffer of the renal
tubule and inside the cell
Bicarbonate Buffer System
How do we produce HCO3 now?
1. CO2 combines with H2O with the action of
carbonic anhydrase forming carbonic acid
CO2 + H2O  H2CO3
2. Carbonic acid dissociates into hydrogen and
HCO3
H2CO3  H + HCO3
3. HCO3 combines with Na present in the
extracellular compartment forming
SodiumBicarbonate
Na + HCO3  NaHCO3
4. Combining all of the equations:
CO2 + H2O  H2CO3  H + HCO3
Na + HCO3  NaHCO3
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
By adding acid into the system (lactic acid is
example):
o You increase the H+ concentration
o H+ ion will combine with HCO3,
shifting the reaction to the left
(reactant’s side)
pK

By adding base (specifically NaOH)
o NaOH will react to carbonic acid
o That will shift the reaction to the
product side
Henderson Hasselback equation;
 Compute for pH given a known concentration
of HCO3 and CO2.
 H = K x (0.03mmol/mmHg x PCO2)/[HCO3]
 pK = -log K
o -log H = -log K -log (0.03 x
PCO2)/[HCO3]
o pH = pK -log (0.03 x PCO2)/[HCO3]
o pH = pK +log [HCO3]/(0.03 x PCO2)
o pH = 6.1 +log [HCO3]/(0.03 x
PCO2)
*not required to be memorized but you need to be
familiar with the equation*
In utilizing the Henderson Hasselbach’s eqution you
need:
1. the concentration of HCO3 in the blood
 determined by ABG
2. the concentration of CO2 in the blood
 determined by ABG
Once you have the BG values, you can now compute for
the pH.
The pK for HCO3 buffer system = 6.1


at this pH, there is an equal amount of
protonated and unprotonated species.
o So at 6.1 pK in the HCO3 buffer
system, you have an equal amount of
protonated and unprotonated
species.
Around this pH, this is the maximum buffering
capacity
o So at 6.1 pH, that is for HCO3
o So any changes in pH, the HCO3
buffer system, it will try to bring it
back to 6.1
The normal pH of the body is 7.35 – 7.45:

Remember that the HCO3 buffer system will
try to bring the pH to 6.1 but the pH of our
body is 7.4

This is why the buffer system are the
weakest so it is now the job of the lungs and
the kidneys to bring the pH to 7.35 – 7.45
Phosphate Buffer System

These are:
o H2PO4
o HPO4

They are more important as:
o Intracellular buffer
o Buffer in the renal tubules

pK = 6.8
Example:
 If you add an acid into the system, it will react
into Na2HPO4 producing NaH2PO4 and NaCL
HCl + Na2HPO4  NaH2PO4 + NaCl

If you add a base into the system, it will react
into NaH2PO4 producing NaHPO4 and water
NaOH + NaH2PO4  Na2HPO4 + H2O
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11 of 17
Isohydric Principle
 H = K1 x (HA1/A1) = K2 x (HA2/A2) = K3 x
(HA3/A3)
 This is your H+ that is equal to the
various buffer system in the body
acting simultaneously
 For example K1 will represent
intracellular protein, K2 will be HCO3
buffer & K3 will be the PO4 buffer
system
 If you change your H+ concentration or you
change the pH, all three systems will act
simultaneously
 If you change one system (example the third
system), the other system will adjust as well to
maintain the hydrogen ion concentration
HYDROGEN ION SECRETION
 Via Na-H countertransport / exchanger
o Secretion of H+ is dependent on Na
availability
o Whenever Na enters, H is pumped
out
 To reabsorb HCO3, 1 H+ must be secreted
o The excess 70 mEq of H+ in the renal
tubules would have to be buffered by
the tubular buffers:

H2PO4, HPO4, NH3, urate,
citrate buffers
Respiratory System
 Controls extracellular CO2
o It can only handle H2CO3, a volatile
acid
 Alveolar ventilation modulates PCO2
 50-75% effective
 1-2x buffering power greater than te chemical
buffer system
 It will act within minutes
 When pH is high, this will inhibit the
respiratory center, decreasing ventilation
 When pH is low, it stimulates the respiratory
center, increasing ventilation
Renal System
 Handles wide variety of acids and bases
o Excretes acidic or basic urine
 Around 4320 mEq/day of HCO3 is filtered
o The body would have to reabsorbe
HCO3 (ideally)

To reabsorb HCO3, 1 H+
must be secreted
 Around 4390 mEq/day of H is secreted
o 4320 mEq of H is secreted due to
HCO3 reabsorption

So it is said that at this
point, all of the HCO3
reabsorbed
o 70 mEq of H is excreted as
nonvolatile, titratable acids

These are the excess from
HCO3 reabsorption

This is why our urine is
normally acidic.
In order to maintain acid-base balance:
1. Secretion of H ions
2. Reabsorption of HCO3
3. Generation of new HCO3
Diagram: this will show the HCO3 reabsorption. Take
note that major reabsorption of NaHCO3 happens in the
PCT. For the DCT and CD, it is where acid-base
regulation happens.
1.
2.
3.
4.
When there is a filtered HCO3, we need to
reabsorb it.
Within the cell, you have CO2 and water being
produced
With CA, you produced carbonic acid
Carbonic acid dissociates to HCO3 and H+
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12 of 17
5.
6.
7.
8.
H+ ion will be pumped out
 In the diagram, it is the Na-H antiport
 Another is the H+ pump (as
exemplified by the purple circle with
ATP label)
H+ will combine to the filtered HCO3 forming
H2CO3
H2CO3 will be acted upon by CA producing
water and CO2
CO2 can freely enter the cell and goes again
through the same process
DCT, CT INTERCALATED CELL: NON-HCO3 BUFFER
Filtrate
So in order for us to reabsorb this HCO3, H+ must be
secreted. If H+ is not present, the HCO3 in the filtrate
will not become a carbonic acid nor CO2 therefore, it
can’t enter the cell and excreted.
DCT, CT Alpha AND Beta INTERCALATED CELL: H
AND HCO3 SECRETION
Acidosis (alpha intercalated cells because it
primarily handles H+ secretion)
 During acidosis alpha intercalated cells
increases its activity promoting H+ secretion
1.
2.
3.
4.
5.
1.
Same process as what is discussed previously
Alkalosis (beta intercalated cells because it
primarily handles HCO3)
 During alkalosis, increased activity of beta
intercalated cells promoting HCO3 excretion
1.
2.
3.
In the cell you have CO2 combining with water
forming H2C03
This will dissociate to HCO3 and H+
HCO3 goes to the filtrate and H+ goes into the
blood.
CO2 combines with water forming H2CO3
H2CO3 dissociates into HCO3 and H+
 HCO3 goes into the blood
H+ ion is secreted via Na-H antiport
H+ will now combine with non-HCO3 buffer, in
this case a phosphate buffer (NaHPO4-)
 H+ ion can combine with any of these
as long as it is not HCO3:
i. NH3
ii. Urate
iii. Citrate
When it combine with a non-HCO3 buffer, the
H+ is excreted
 Take note that the HCO3 is added to
the system. So there is a net gain of
HCO3 for every H+ secreted.
 Another thing to take note is that if
your H+ here combines with a HCO3,
you simply reabsorb it, you do not
add it to the system. (di ko gets haha)
DCT, CT INTERCALATED CELL: ALDOSTERONE
EFFECT
1.
2.
Increased Na-pump promoting H+ ion
secretion
Promoting HCO3 reabsorption
a. That is why in hyperaldosteronism,
alkalosis occurs.
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13 of 17
DCT, CT INTERCALATED CELL: NH3 BUFFER
 This is due to the breakdown of amino acid
2.
3.
4.
5.
One in the filtrate, NH3 will combine with H+
so it becomes NH4, ammonium
 Since it is already charged, it can’t
cross the membrane (diffusion
trapping)
In the distal segments, the mechanism are the
same
NH3 can easily cross the cell membrane
 Once in the filtrate it will combine
with H+ forming NH4+
 It will now be excreted
Going down, you’ll have an antiporter
 It will pump NH4 into the cell and out
into the filtrate in exchange for H+
o NH4+ exchanger
GENERATION OF NEW BICARBONATE
1.
2.
3.
4.
5.
6.
Water combines with CO2 forming H2CO3
H2CO3 dissociates to HCO3 and H+
H+ geos out via H+ pump
NH3 can easily cross cell membrane and
combine with H+ ions
a. this will make the NH3 to have a
charge  NH4+ (diffusion trapping)
NH4+ can combine with Cl- to be excreted
Since your hydrogen ion is buffered by a nonHCO3 buffer, a HCO3 is gained into the system.
TAKE NOTE:
In the DCT andCD, as long as you secrete H+ and as long
as it binds to a NON-HCO3 BUFFER, you will gain a NEW
HCO3 into the system.
NH4 PRODUCTION, TRANSPORT, EXCRETION




4
5
In generation of new HCO3, you metabolize
gulatmine
The breakdown of glutamine will produce 2
moles of HCO3 and 2 moles of NH4
NH4+ is pumped out into the filtrate to be
excrted
There will be a net gain of HCO3 into the
system
Titration of H in the tubular lumen
 If H combines with HCO3 (H + HCO3):
o HCO3 is reabsorbed
 If H combines with non-HCO3 buffers
o A new HCO3 is added into the system
/generation of a new HCO3
During Acidosis: Excess H
 All of HCO3 is 100% reabsorbed
 And there will be generation of new HCO3
o This will attempt to correct acid-base
disorder
HYDROGEN ION SECRETION
1.
In early segments, NH3 can:
 Easily go out into the filtrate
 Or pumped out via Na-NH3
exchanger
Stimuli for H+ secretion
1.  PCO2
a. Excess CO2 within the body will
cause respiratory acidosis
2.  extracellular pH
The Great Escoto
14 of 17
3.
Excess aldosterone (we all know that it
powers H+ secretion)
a.  loss of H, NH4, titratable acids
b.  HCO3
During Acidosis:
 Favorable cell-to-tubular fluid H gradient
o More H+ ions in the body compared
to the filtrate favoring H+ secretion
 Allosteric changes in transport CHON
o For example is albumin
 Regulation of number of transporters:
o Na-H antiporter (H+ secretion)
o Na-HCO3 symporter (HCO3
reabsorption)
 ET-1, cortisol
o It will be increased and its effect is to
increase the transporter
Volume Contraction:
 Increase in H+ ion secretion
o Increased Na-H antiport, Na-3HCO3
symport
o RAAS
o Increased intercalated cell secretion
o Changes in Starling forces that favors
Na reabsorption
Volume Expansion:
 Decrease in H+ secretion
o Decreased Na-H antiport, Na-3HCO3
symport
o deccreased intercalated cell secretion
o Changes in Starling forces that
antagonizes Na reabsorption
i. If the solution turns pink, it
is the amount of NaOH
consumed therefore that is
the amount of H+ present
Net Acid excretion =
(NH4 excretion + urinary titratable acid) – HCO3
excretion
In order to maintain acid-base balance:
 net acid excretion must be equal to nonvolatile acid production
o acids other than carbonic acid like
lactic acid etc.
 During acidosis:
o Increased H+ secetion, NH4 excretion
increases and new HCO3 is added to
the blood
 During alkalosis
o No NH4 and titratable acid excretion
 increased HCO3 excretion  no
new HCO3 is generated
ACID-BASE DISORDERS
Simple acid-base disorders
pH = 6.1 +log [HCO3]/(0.03 x PCO2)
QUANTIFYING ACID-BASE SECRETION
What we need to determine in the lab are:
1.
HCO3 Excretion
 V x UHCO3
V = urine flow rate
UHCO3 = urine bicarb concentration

2.
NH4 Excretion
 V x UNH3
V= urine flow rate
UNH3 = urine NH3 concnetration

3.
This measures the removal of HCO3
from the blood or the additional of
H+ in the blood
Measures the amount of new HCO3
added into the blood
Titratable acids
 Non-HCO3 and non-NH4 buffer
excreted like phosphate , citrate,
urate buffers.
 Measured via titration with NaOH
During Acidosis:
 There is excess H+ ion
 Manifestations:
o H > HCO3
o H excreted, acidic urine
o Reabsorption of all filtered HCO3
o  Na-H antiport, 1Na-3HCO3
symport, ET-1, cortisol
o Generation of new HCO3
o  NH4 excretion
o Lungs:  ventilation due to decrease
pH
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15 of 17
During Alkalosis:
 There is excess HCO3
 Manifestations:
o HCO3 > H
o HCO3 excreted, alkaline urine
o  H secretion
o  Na-H antiport, 1Na-3HCO3
symport, ET-1, cortisol
o NH4 and titratable acids are not
excreted
o No new HCO3
o Lungs:  ventilation due to increase
pH
Application:
ABG of:
pH: 7.3  acid
HCO3: 12 mEq/L  acid
PCO2: 25 mmHg  base
1.
2.
3.
COMPLEX ACID-BASE DISORDERS
Acid- base nomogram
This is utilized when you have complex acid-base
disorders. In using this, you must take into account the
pulmonary and renal correction. You don’t use this
immediately because the kidneys will take days to
function in correcting acid-base disorders. You need to
allow pulmonary and renal compensation first before
using this.
The red lines are PCO2, x axis is arterial bood
pH and y axis is the PlasmaHCO3
concentration
Plot the values
When you trace, you will be pointed to
metabolic acidosis
ABG of:
pH: 7.15  acid
HCO3: 7 mEq/L  acid
PCO2: 50 mmHg  acid



In this you have two points.
You need to analyze the ABG
o This is not a simple metabolic
acidosis
An accurate diagnosis is metabolic acidosis
with respiratory component
o You can’t write metabolic acidosis
only because when you will refer this
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16 of 17

patient, the clinician might miss out
the respiratory component
This could be a combination of disease entities
o Example you have diabetic patient
with ketoacidosis and this patient
has COPD which can cause acidosis
ABG of:
pH: 7.40 normal
HCO3: 30 mEq/L  base
PCO2: 60 mmHg  acid
Anion Gap
 It is basically utilized when there is metabolic
acidosis
o When the patient has metabolic
acidosis, looking at the equation for
the anion gap, HCO3 is deranged
(goes down)
o There will be a wide anion gap, it
increases during metabolic acidosis
 Plasma anion gap: 8-10 mEq/L
o So for the anion gap to be normal
when there is low HCO3, Cl needs to
increase or other umeasured anion
o If we have metabolic acidosis and the
anion gap is deranged, Cl is also
decreased, you need to request for
other anions.
When the anion gap increases = > 10mEq/L
 You should now investigate for other
electrolytes
o There could be an increase in anions

PO4, SO4, albumin, organic
anions
o There could be a decrease in cations

Ca, Mg, K
Application:
Diagnosis: Chronic respiratory acidosis with renal
compensation
 If the pH was 7.3  the diagnosis would be
chronic respiratory acidosis with partial renal
compensation
ANION GAP
 Another laboratory procedure
 To maintain electrical neutrality:
o PLASMA CATIONS must be EQUAL to
PLASMA ANIONS
 Normally, when there is acid-base disorders,
what is usually obtained is the level of:
o Na
o Cl
o HCO3
 To get the plasma anion gap, this is cations –
anions
o Na – HCO3 – Cl levels
o Done by obtaining a blood sample:
o Example is: 144 – 24 – 108
= 10 mEq/L
We only request this depending on the condition of the
patient
There is a metabolic acidosis and the anion gap
increases and you are thinking there is a problem in
Calcium so you request for ionized calcium
When you find out that you ionized calcium decreases,
then you should be able to correct calcium, otherwise
tetany will happen.
Or you want to find out K  hypokalemia can cause
arrhythmia, then you should be able to correct the K
levels.
In correcting acid-base disorder, always keep in mind to
address the primary problem first. If you are having
diabetic ketoacidosis, you have to correct sugar level
first.
During alkalosis:
 NH4Cl, lysine monohydrochloride are given
During acidosis:
 NaHCO3, Na-lactate, Na-gluconate are given
We rarely administer NH4Cl and NaHCO3 simply because these two
substances have narrow therapeutic details.
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Far Eastern University
Nicanor Reyes Medical Foundation
Institute of Medicine
1D – Batch 2020
Physiology A – Blood Physiology
(Part 3)
Dr. Endymion Ervin M. Tan
LEUKOCYTES / WBCs
è Formed in the bone marrow
(majority) and some are in lymph
tissues (spleen, lymph nodes,
adenoids, tonsils, etc.)
è 6 types; 2 branches
GRANULOCYTES
AGRANULOCYTES
Basophils
Monocytes
Eosinophils
Lymphocytes
Neutrophils
*ALL THE GRANULOCYTES and
SOME LYMPHOCYTES are
manufactured in the BONE MARROW
*MAJORITY OF LYMPHOCYTES are
manufactured in the LYMPH TISSUES
*according din to kay Guyton*
ARRANGEMENT OF WBC
ACCORDING TO NUMBER
(descending)
1. Neutrophils –marker for acute
infection
2. Lymphocytes – marker for
chronic infection
3. Monocytes – marker for chronic
infection
4. Eosinophils
5. Basophils
Morphogenesis of WBCs
1. All the blood cells came from the
Pluripotent Hematopoietic Stem
Cell
2. Differentiate to MYELOID &
LYMPHOID PROGENITOR CELLS
3. Then it will be destined to become
the granulocytes and
lymphocytes, respectively.
GENERAL CHARACTERISTICS OF
WBCs
• LIFE SPAN
o GRANULOCYTES: 4-8 hrs in
blood and 4-5 days in tissues
o MONOCYTES: 10-20 hrs in the
blood and MONTHS in tissues
*MONOCYTES can RESIDE in
the tissues, grow bigger and
BECOME MACROPHAGES,
even if there is no infection, they
will thrive in the tissues.
• MATURITY
o NEUTROPHILS: mature cells so
once they are in the blood, they
can perform their functions as
a PHAGOCYTOTIC AGENTS
[this is the reason why they are
the markers for acute infection]
o MONOCYTES: not mature
enough to perform their functions
if they are in the bloodstream, IT
SHOULD TAKE SOME TIME TO
GROW AND BECOME
MACROPHAGES
• DIAPEDESIS – squeezing action
of the neutrophils, monocytes,
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macrophage ACROSS THE INTACT
BLOOD VESSEL WALL going to the
CHEMOTACTIC SOURCE
•
CHEMOTAXIS
o Migration of the
macrophages, neutrophils,
etc. to the chemotactic
source/substance.
Chemotactic substances can be
viral/bacterial toxins, products of
inflamed tissues like prostaglandin,
histamine, etc., products of the
Complement (proteins that help the
immune system to fight or destroy
invading organisms) complex,
products of plasma clotting
NEUTROPHILS
Mature
Phagocytic agent
Secretes
PROTEOLYTIC
ENZYME
Secretes
BACTERICIDAL
AGENTS
Less potent; can
digest only 3-8
bacteria
ONLY BACTERIA
LESS DURABLE;
After phagocytosis,
it will die
MACROPHAGES
Immature
Phagocytic agent
Secretes
PROTEOLYTIC
ENZYME
Secretes LIPASES
Secretes
BACTERICIDAL
AGENTS
More potent; can
digest up to 100
bacteria
Bacteria, RBC,
Virus, Fungi,
Parasites (ex.
Malaria, Ascaris,
etc.)
MORE DURABLE;
can stay in the
tissue to perform
another
phagocytosis
Normal Cells
o has smooth surface
o has a PROTEIN COAT to prevent
them from being phagocytose
o NO ANTIBODIES; it is not an
antigen
Abnormal cells/BACTERIA/FOREIGN
CELLS/INVADING ORGANISMS
o rougher surface
o no PROTEIN COAT
o Antibodies are the COATING
OPSONIZATION à abnormal
cells/invading cells/ foreign cells are
COATED WITH ANTIBODIES to
become more palatable and be
phagocytose. **sabi nga ni Dr. Tan,
pinapasarap J**
NEUTROPHIL
o Presence
of 3 to 5 lobes
of nuclei
o Very pinkish
PHAGOCYTOSIS
o cell eating
How do phagocytosis work?
1. The neutrophil will form a
PSEUDOPODIA, an arm that will
embrace the bacteria
2. All the bacteria will be embraced
inside the neutrophil and will be
contained in the PHAGOSOME, or
the DIGESTIVE VESICLE
3. Neutrophil has a lysosome, the
digestive system of the cell, which
will bind to the phagosome
4. The lysosome will secrete an
enzyme, lysozyme, that will
digest/destroy the bacteria inside
5. Debris that is not capable to be
digested will be left, and nutrients
left will be absorbed and will be
used as energy
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**LYSOZYME is an example of
PROTEOLYTIC ENZYME**
PROTEOLYTIC ENZYME à destroys
the protein of the bacteria
Lipases à destroys the fatty cell wall of
bacteria or invasive organisms
*some bacteria causes prolonged
chronic infection like tuberculosis*
Peroxisomes
o A bactericidal agent
o Secretes free oxygen radicals
from hydrogen peroxide that
directly destroys the bacteria
MONOCYTE MACROPHAGE CELL
SYSTEM
o Also known as Reticulum
Endothelial System (RES)
o A working immune system that
protects our body form bact, vi.
etc
Histiocytes
o Also called as Langerhans cell
o Macrophages in the skin
Alveolar Macrophages
o Found in the lungs (ex. Destroys
the TB bacilli)
Gut Associated Lymphoid Tissue
(GALT)
o Destroys the bacteria that
reached the GIT
o If the bacteria escape the gut, it
will go to the liver
Portal vein – main blood supply to the
liver (2/3)
Hepatic artery – 1/3 of the blood supply
to the liver
Kupffer cells – macrophages of the
liver
*if the Kupffer cells FAILED to perform
its functions, all the bacteria will go to
the spleen through the splenic artery
going to the capillaries
Venous sinuses – lined with
macrophages and found in the
capillaries that destroys the bacteria so
the blood going out through the splenic
vein is clean and filtered
Lymph Nodes
o Where the bacteria flowing in the
lymph vessels will pass through
o It has SINUSES that contains
macrophages that will destroy the
flowing bacteria
o Clean filtered blood is the product
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Cardinal Signs of Infection
1. Vasodilation
Ø More blood flow =
increased filtration rate;
increased capillary
hydrostatic pressure so the
plasma will be pushed out
of the blood vessel
(manifests edema,
swelling etc. at the site of
inflammation)
2. Walling-off effect
Ø The fibrinogen will clot the
plasma, so the inflamed
area is tender, hard and
painful.
Ø This will serve as the
protective mechanism to
prevent the spread of
bacteria in the infected
part
Tissue Macrophages – 1st line of
defense
Neutrophil Invasion – 2nd line of
defense
*will cause Neutrophilia –
increase number of neutrophils *normal
count: 60*
How Diapedesis and Chemotaxis
work?
1. Neutrophils are rolling/flowing in
the blood vessel
2. The chemotactic source attracts
the neutrophils
3. There will be an increase in
ICAM-(intracellular adhesion
molecule- 1) and will attach to
the neutrophil
4. SELECTINS would also increase
and binds to the neutrophils [it
has two attachments]
5. The neutrophil would go to the
Blood Vessels
(MARGINATION/PIGMENTING)
6. The BVs will be looser; there will
be a small gap
7. The neutrophil will do the
Diapedesis in the gap that is
made by the Blood Vessel
8. The neutrophil will undergo
Migration/Chemotaxis to the
chemotactic source
2nd Macrophage invasion – 3rd line of
defense
Macrophages will serve as the
FEEDBACK CONTROL releasing
growth factors that will stimulate the
bone marrow
Stimulation of Bone Marrow – 4th line
of defense; the bone marrow will secrete
more cells
PUS – viscous fluid, build up of WBCs
and proteinaceous substances. It will
just be reabsorb by the body after the
infection
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EOSINOPHILS
o 2% only
o They are weak phagocytes
because it only destroys
PARASITES
o Secretes HYDROLYTIC
ENZYMES, REACTIVE Oxygen
SPECIES, MAJOR BASIC
PROTEINS (MOST IMPORTANT
because it directly destroys the
parasites)
o Plays in the important role of
allergic reaction (see basophils
discussion)
Some example are malaria, ascaris, etc.
Leukopenia
o Decrease in the amount of WBCs
o Radiation injuries causes DROP
in the AMOUNT OF WBC
*WBCs are more susceptible to
radiation reaction so the bone
marrow production is affected*
*PAG NAKITA MO ATOMIUM
AUTOMATIC LEUKOPENIA YUN
J*
o Drugs that induces Leukopenia:
o Chloramphenicol antibiotic
o Thiouracil – use to treat
hyperthyrodism
o Barbiturates
Leukemia
BASOPHILS
o Large and heavily granulated
cells
o Function: same as the mast cell
o Releases HEPARIN
(anticoagulant),
histamine, bradykinin, serotonin
that participates in allergic
reaction
o IgE is involved in allergic reaction
o Binding with IgE will tend to
rupture the basophils or mast
cells and secretes the
EOSINOPHIL CHEMOTACTIC
FACTORS
EOSINOPHIL CHEMOTACTIC
FACTORS – attracts the eosinophils
where there is allergic reactions
o Increased number/abnormal
production of WBCs but they are
immature cells/ blast cells
o Myeogenous and Lymphocytic
o Patients can undergo severe
infection due to SURGE OF
ABNORMAL CELLS which are
useless.
*abnormal cells can lodge in the
bones also in the vascular organs
so some patients have the nose
bleedings because it invades the
blood vessel wall causing erotion.
o SEQUELAE: end point of
leukemia
o There will be negative nitrogen
balance because the nutrients will
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be absorbed by the abnormal
cells resulting to being cachectic
Thymus gland à main organ where tcell is being pre-processed; FATE:
NONE, involution, atresia
If the stem cell is destined to be a Tlymphocyte, the t-cell 1 will go to
Thymus for pre-processing assigning it
to different functions.
T cells exhibits EXTREME DIVERSITY
to fight different antigens
T-cell
IMMUNITY
o Has two branches
o Innate Immunity – we
have it when we were born
o Acquired/adaptive
immunity – something
that is needed to be
exposed to before being
protected
Innate Immunity
o These are:
o Digestive enzymes
o Intact skin
o Tissue macrophages
Acquired Immunity
o Vaccinations
o Two types
o T-cell : Cell mediated
immunity
o B-cell : Humoral immunity
B- cell
Cell mediated
immunity
Humoral immunity
Exhibits extreme
diversity
More diverse than
t-cells
Responsible for
transplant rejection
Exhibits
lymphocyte cloning
Exhibits
lymphocyte cloning
Antigens – foreign substances that
would react to the body;
PROTEINACEOUS LONG CHAIN
CARBOHYDRATES substances that
are very potent to reaction when
exposed to the body
Haptens – Incompetent to cause a
disease; small molecular substances
Bursa – organ responsible for preprocessing of B-lymphocytes
Lymphocytes – responsible for the
immunity, the B-cell, T-cell
Mnemonics: Take Care Be Happy
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Early fetal life
to mid fetal
life
Late fetal life
until birth,
now
•
•
T-cell
•
•
•
•
Stem cell is destined to be
a T-cell, goes out of the
bone marrow and go to the
thymus
The thymus will be
producing a lot of T-cells
with great variety
The thymus will release
the T-lymphocyte and will
reside in the lymphoid
tissue
With the presence of
antigen, it will be activated
to become T-lymphocytes
*WHY IS IT CELL
MEDIATED?**
- it started as a whole cell and
ended as a whole cell
B-cell
•
•
Stem cell is destined to be
a B-cell
B-cell will be preprocessed in the fetal
LIVER and bone marrow
•
•
•
LIVER is the
primary organ for
the pre processing
of B-cell
Bone marrow
More versatile than Tcell, around 1000 different
kind.
Starts as B-cell ends
antibodies
B-lymphocytes resides at
the lymphoid tissue and
reacts with an antigen
Will grow into a PLASMA
CELL
It will become the
ANTIBODY
For patients who will undergo transplant,
THE T-cell should be suppressed
because it will destroys the donor’s
organ [STRONG
IMMUNOSUPPRESION]
Lymphocyte Clone - formed when
exposed to a virus/disease to protect the
body or a memory cell [can be a lifelong
protection]
Gene Segments – the bone marrow
and thymus can manufacture a lot of a
different patterns and different
combinations because of this; Scientists
found out that in the body we have
different gene segments so the body will
have different patterns to react to an
antigen
Macrophages has IL-1(interleukin-1)
which is important for the stimulation of
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the bone marrow to produce more
WBCs
B cells (B lymphocytes à lymphoblasts
à plasmablasts à plasma cells à
Antibodies
•
Memory Cells
o When exposed to the
same disease, antigen,
bacteria, virus, you have
an immunity to the disease
o Example: Hepa-B vaccine
“ANTIGEN IS INJECTED
TO STIMULATE THE
PRODCUTION OF
LYMPHOCYTE CLONE”
st
1. 1 dose:
- Latent period: VERY LONG
- Antibody production: NOT
ROBUST
- Duration: VERY SHORT
2. 2nd dose after 1 month
- Latent period: SHORTER
- Antibody production:
ROBUST
- Duration: LONG; or
LIFETIME
That is why in some diseases,
vaccination are given at a schedule of
0,1 and 6 months.
• Antibodies (immunoglobulin)
o IgG, IgM, IgA, IgD,IgE
o The response is not strong so the
COMPLEMENT is needed
Mechanism of Action
1. Can kill and inactivate the foreign
body by AGGLUTINATION; the
binding of antibody & antigen can
clump the antigen, rendering it as
non-infectious
2. PRECIPITATION – it can bind
into the antigen making it a very
big molecule, very heavy so it will
just drop and precipitates,
rendering it as non-infectious
3. NEUTRALIZATION – example:
patient with cobra venom, giving
him anti cobra venom so it will be
neutralized by the antivenin,
rendering the venom noninfectious
4. LYSIS – the antibody can destroy
the antigen. IgA, seminal fluids
because it can kill organisms
IgG
IgM
Most numbered
Biggest
Immunoglobulin
Small, crosses
the placenta
Does not cross
the placenta
Secondary
antigenic
stimulus /
previous
exposure
Primary
antigenic
stimulus / new
exposure
Previous
exposure to
Zika Virus, the
blood should be
Zike virus IgG
positive
First time
exposure to
dengue, the blood
should be Dengue
IgM positive
IgG: Gamit na gamit
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Example:
Dengue IgG is positive, Dengue IgM is
negative: OLD INFECTION
Zika IgM positive, Zika IgG negative:
NEW INFECTION
Dengue IgG positive, Dengue IgM
positive: ACUTE INFECTION ON TOP
OF AN OLD INFECTION
Antibodies
Functions
IgA
Secretory Ig
secreted by the
exocrine gland
(colostrum, saliva,
vaginal fluid,
semen, etc.)
IgD
Least in amount
and the function is
unknown
IgE
CONSTANT PORTION
à tells the PROPERTY and
DIFFUSING CAPABILITY of the
antibody
à MOST IMPORTANT
FUNCTION: binding in to the
COMPLEMENTS
COMPLEMENTS
Ø
Ø
Ø
Ø
Ø
Allergic reaction
High affinity to
basophils and mast
cells
Ø
Proteins that serve in the
antigen-antibody response
Made up of 20 different
proteins in the blood
INACTIVE PROTEINS
Starts from C1, forming
cascade, recruiting more and
more complements from a
small beginning to become a
massive complex for a
robust response
Complements are numbered
base on the sequence on
how they are discovered; but
the cascades are number
according to the number of
complement that would be
recruited first
2 pathways
Classical Pathway
o Stimulated by the antigen
antibody complex
o Starts at C1
Properdin Pathway
o Alternative pathway
o Simulated by MICROBIAL
VARIABLE PORTION
à Binds to DIFFERENT antigens
SURFACES/MICROORGANISMS
o Starts at C3
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•
Lysis/Membrane Attack
Complex(MAC) *MOST
IMPORTANT* : C5b6789
ü This is the one that
destroys the bacteria,
lacking of these will result
to inability to kill the
bacteria and non-resolving
infection
According to
Recruitment
According to
Invention
C1 – 1ST
C1 – 1st
C4
C2
C2
C3
C3
C4
C5
C5
C6
C6
C7
C7
C8
C8
C9 – last
C9 – last
Functions of each complexes
•
Opsonization & Phagocytosis :
C3b
•
Chemotaxis: C5a (anaphylatoxin)
•
Activation of Basophils & Mast
Cells : C3a4a5a
T- cells are like girls: very delicate and
choosy. It needs ANTIGEN
PRESENTING CELLS
o Macrophages
o B-lymphocytes
o Dendritic cells
Different type of T-cells
1. T helper cells
Ø Secretes a lot of
LYMPHOKINES,
GROWTH FACTORS that
will stimulate the
production of B-cells and
T- cells
Ø CD4 cells
2. T suppressor
3. Cytotoxic cells
Ø CD8 cells
Ø Natural killer cells
Ø Has PERFORINS, hole
punching proteins
Ø It will punch holes around
the infected cells, and
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migrate away to kill other
cells. Once holes are
around the cell, fluid will go
around the cell, causing it
to swell and burst (lysis)
Ø It can also destroy the
normal cell but the body
does not allow it so the
thymus produces
abnormal cells (10%) so
the CD8 cells will destroy it
rather than the normal
cells
Ø Additional Info: CD means
Cluster of Differentation J
T-cells need a receptor, (Major
Histocompatibility Complex) MHC PROTEIN
2 types:
1. MHC1 à CD8
2. MHC2 à CD4
*how to remember by Dr.Tan à 4x2 =8
so 4:2 and 8:1 J
CD4 cells will release lymphokines,
colony stimulating factors that help in
the proliferation and differentiation of Bcells, cytotoxic cells, suppressor cells. In
HIV, CD4 cells are the one affected
HIV will destroy CD4 cells causing the
depletion of the entire arm of the
immune system, the patient becomes
very immunocompromised
*We have IMMUNE TOLERANCE (the
body can tolerate our immune system)
so we the body won’t destroy its own
cells. However, losing it will cause
autoimmune diseases like
o Rheumatic fevers – heart valves
and kidneys are affected
o Glomerulonephritis –
streptochocal infection forming
antigen-antibody response that
destroys the kidney
o Myesthenia gravis – affects the
post-synaptic membranes
especially the receptors
o Systemic Lupus Erythematosus –
Rheumatologic disease that can
affect the bones, skin.
Manifestation: butterfly/malar
rashes
IMMUNIZATION
2 types
1. Active Immunity
a. Vaccine will ask your
body to produce
protection
b. Live attenuated (weakened
in force/effect) virus is
given but it will not cause
disease and causes the
body to form protection
against it
c. A dead antigen can also
be administered so the
body will form
immunization
d. LONGER DURATION OF
PROTECTION – may be
lifetime
2. Passive Immunity
a. Immunoglobulin –
preformed protection
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b. The body will not produced
its own protection because
of the administration of
immunoglobulin
c. For IMMEDIATE
protection
ALLERGY AND HYPERSENSITIVITY
A. Atopic allergies
o Drugs: Antihistamines
o IgE mediated
B. Anaphylaxis
o Allergen is inside the
bloodstream
o Triggered when you’ve
eaten something
o Causes
bronchoconstriction etc.
o Production of slow reacting
substances of anaphylaxis
o Drugs: Ephinephrine
C. Urticaria
o Due to histamine
o Hives (pantal in tagalog)
D. Hay Fever
o Pollen/dust allergies
E. Asthma
o Bronchiocronstriction
o Drugs: simulate
sympathetic like
salbutamol(Beta2 agonist)
and irpatropium
(parasympatholitic drug)
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BLOOD PHYSIOLOGY By Dr. Olivar Functions of the BLOOD • Homeostasis (regulates internal environment) • Respiratory (transport of oxygen) • Nutritive (carrier of nutrients) • Excretory (carrier of waste products) • Endocrinology (transporter of secretions) • Helps maintain acid-­‐base balance • Maintenance of water and electrolyte balance and regulation of total osmotic pressure • Immunity to diseases (WBC) • Regulation of body temperature Normal Blood Volume Commonly: Males would have 5 liters Females would have 4.5 liters *Regardless of this, blood should be 60% Plasma, 40% Formed elements. *When centrifuged: -­‐-­‐upper portion is plasma -­‐-­‐white substance a.k.a. “buffy coat” contains WBC and Platelets -­‐-­‐Red portion is the red blood cells Composition of Blood Plasma— water -­‐ 91 – 92% Plasma protein – albumin, globulin, fibrinogen, prothrombin Functions of Plasma Proteins • Maintenance of water balance between the intravascular compartment and extra vascular spaces (proteins serve as solutes that attract plasma inside the blood vessel) Ex. Decreased Plasma Protein con.—higher plasma con.plasma exits into the interstitial space HIGHER TO -­‐-­‐-­‐-­‐-­‐-­‐ LOWER CONCENTRATION Clinical Correlation: Patients with liver diseases manifest with “Edema” because the liver is where proteins are synthesized. With a liver problem, plasma protein may be depleted. In such situation, the plasma will be pushed toward the interstitial space. •
•
•
•
•
•
Imparts viscosity to the blood Source of antibodies Necessary for coagulation Maintains acid-­‐base balance Determines specific gravity of plasma Formation of enzymes; transport of hormones and enzymes Other contents-­‐-­‐-­‐ 1. Water 2. Plasma proteins 3. Blood sugar – glucose 4. Lipids – cholesterol, phospholipids, neutral fats 5. Salts – Na, K, Cl, bicarbonates, phosphates 6. Gases – O2, CO2, Nitrogen 7. Special plasma substances – hormones, enzymes, antibodies RBC, WBC, PLATELETS-­‐ all come from a single cell in the bone marrow called the pluripotent hematopoietic stem cells RED BLOOD CELLS • Not spherical; biconcave discs; 2.5 um thick, 7.5 – 8 um in diameter • Very deformable • Carries hemoglobin in the circulation –1gm of Hgb  1.34 ml of O2 • Non-­‐nucleated in the circulating blood Anemia-­‐ any value lower than normal limit of Hgb and RBC Polycytemia-­‐ any value higher than normal limit of Hgb and RBC RBC count: Hemoglobin: Men: 5-­‐6 x 10 (12)/L Men: 14 – 17 g/dL Women: 4-­‐5 x 10(12)/L Women: 12 – 15 g/dL Infants: 6-­‐5 x 10(12)/L Hematocrit: Men: 0.40 – 0.50 Women: 0.38 – 0.48 RED CELL Production Stage of Life 8 weeks of embryonic life or first 2 months Middle trimester of pregnancy rd
3 trimester of pregnancy 20 years and above Organ Responsible for RED CELL production Yolk sac Liver, spleen, lymph nodes The bone marrow then takes over Bone marrow of skull, vertebrae, ribs, sternum Erythropoiesis-­‐ is the process of red cell production Proerythroblast Early Erythroblast Late Erythroblast Normoblast What happens during intermediate phase? • Hemoglobin is incorporated into the cell. • The nucleus condenses so that it is released from the cell even before the cell is extruded from the bone marrow. • First cell released is called Reticulocyte. Reticulocyte-­‐ still colors blue because of cytoplasmic materials -­‐after 2 days, the cytoplasmic materials are gone and mature non-­‐nucleated erythrocytes are produced *Vit.B12 and Folic Acid are essential for RBC maturation. *Without VitB12 and Folic Acid, • DNA synthesis is impaired • With a problem in DNA synthesis, erythropoiesis proceeds slowly • Intermediate cells are released into the circulation as Macrocytes, which are flimsy and easily rupture. • Structural abnormalities Megaloblastic Anemia-­‐ is described as macrocytic and hyperchromatic Pernicious Anemia-­‐ is a condition characterized by the absence of parietal glands in the stomach which are needed for the secretion of Intrinsic Factors (IF). -­‐Intrinsic factors (IF) aid in the absorption of Vit B12 Absence of IF  malabsorption of B12  B12 deficiency  Pernicious Anemia  Megaloblastic Anemia Sprue-­‐ also causes megaloblastic anemia due to decreased intestinal absorption of Folic acid and Vit B12 Control of RBC Production 1. Stimulated by hypoxia. 2. Inhibited by rise in circulating RBC levels 3. Controlled by circulating hormone called erythropoietin. Example—Living in high altitudes where oxygen is not as abundant as in low lands-­‐-­‐-­‐more RBC is produced. -­‐-­‐Patients with tuberculosis have normal blood levels and oxygen levels in blood, but suffer from impaired oxygen absorption in the lungs. Thus, the body is triggered to produce more blood. Erythropoietin-­‐ is a glycoprotein hormone that controls RBC production by stimulating bone marrow -­‐synthesized by both kidneys (90%) and the liver (10%) -­‐increases production of PROERYTHROBLASTS Destruction of RBC Life span-­‐-­‐-­‐ 120 days Destruction-­‐-­‐-­‐ 1% of red cells is replaced daily Total red cell volume is replaced every 4 months Site-­‐-­‐-­‐ Spleen * The number of red cells in the circulation is determined by the balance between production and destruction. Hypertonic solution-­‐ causes shrinkage of RBC Hypotonic solution-­‐ causes swelling of cell and eventual rupturing Isotonic solution-­‐ no change; equilibrium; 0.9% NaCl; 5% dextrose Hemoglobin Formation I. 2 succinyl Coa + 2 glycine  pyrrole molecule II. 4 pyrroles  protoporphyrin IX III. Protoporphyrin IX + Fe  Heme IV. Heme + globin  Hemoglobin chain (a or B) V. 2 a chains + 2 B chains  Hemoglobin *Each hemoglobin molecule has 4 Fe molecules. One Fe can hold one oxygen at a time. *The primary function of RBC is to transport hemoglobin, which in turn carries oxygen from the lungs to the tissues and the carbon dioxide back from the tissues to the lungs. *97% of oxygen is carried to the tissues in combination with hemoglobin. Only 3% is dissolved in cells. *CO2 may combine with hemoglobin for it to be transported back to the lungs for excretion. Sickle cell anemia • is an abnormality in the B-­‐chain of Hemoglobin • upon exposure to O2, the Hgb forms elongated crystals • prone to hemolysis or easily ruptures IRON • 5 grams in the human body • majority is in the form of Hemoglobin (65%) • 15 – 30 percent ferritin (Storage form in the liver) • 4% myoglobin (hemoglobin in the muscle) • 1% other heme compounds • 0.1 with transferrin • primary source is red meat Absorption of IRON <Duodenum> 1. Liver produces apotransferrinsecreted into the BILEapotransferrin + Fe Transferrin (plasma) blood  transferrin donates Fe to RBCHemoglobin is produced 2. Transferrin I Iexcess Fe Tissues Ferritin Destruction of Hgb • RBC ruptures after 120 days • Hemoglobin is released and broken down to bilirubin • Fe is never wasted. It is liberated and brought back to the iron stores. Women: are prone to IRON deficiency anemia due to menstruation. Should take supplements at least once a day. Anemias— are brought about by deficiency of Hgb • Too rapid loss / too slow production • Blood loss; Fe deficiency Clinical Correlation: When a patient presents with severe palor (anemia), the physician will usually request for a peripheral blood smear. Result: If the RBCs are microcytic hypochromic, the cause of anemia is IRON DEFICIENCY. If the RBCs are microcytic hyperchromic, the cause of anemia is Vit B12 / FOLIC ACID DEFICIENCY. Aplastic Anemia-­‐ is a bone marrow disorder, where all blood cells are not produced Hereditary Spherocytosis-­‐ is a situation where the RBCs are spherical instead of bi-­‐concave *Plasma causes oncotic pressure, while RBC renders viscosity to blood. Anemia’s effect to the heart is INCREASED WORK LOAD. • Anemia causes decrease in viscosity of blood; decrease in resistance to blood flow. • Thus, more blood goes to the tissues and flows back to the heart. • Anemia causes hypoxia. Blood vessels will dilate. Thus, more blood returns to the heart. *Will cause increased heart rate. *Younger individuals can usually tolerate anemia. *Older individuals (60-­‐70) should not be left without treatment because anemia may cause cardiac arrest to individuals with weaker hearts. POLYCYTEMIA nd
2 Degree Polycytemia-­‐ ex. Living in high altitudes, smoking, having pulmonary diseases Polycytemia VERA-­‐ a genetic aberration; increase in RBC does not inhibit further production of erythropoietin -­‐blood viscosity is increased; resistance to blood flow is increased; blood is prone to clotting episodes -­‐treated by performing phlebotomy BLOOD TYPES TYPE A TYPE B TYPE AB TYPE O A agglutinogens B agglutinogens A and B agglutinogens No agglutinogens B agglutinin A agglutinin No agglutinin A and B agglutinin Agglutination is the end point of transfusion reaction Reaction: <Agglutination> <Hemolysis> AntibodyAntigenRBC will clumpWBCs attack RBC Immediate Transfusion Reaction— IgM  immediate hemolysis Delayed Transfusion Reaction— a result of secondary immune response BLOOD COMPATIBILITY Donor Cell-­‐ refers to the antigen Patient’s serum-­‐ refers to antibody Donor’s Cell TYPE A Patient’s Serum TYPE B Result Antigen – A Antigen – B (Orange) Minor reaction= (+) Antibody – B *Blood types are incompatible. Donor’s Cell TYPE O Antibody – A (Red) Major reaction= (+) Patient’s Serum TYPE B Result Antigen – NONE Antigen – B (Orange) Minor reaction= (+) Antibody – AB Antibody – A (Red) Major reaction= (-­‐) *May proceed with transfusion. Patient may suffer slight itchiness as reaction to small amounts of antibodies from Donor cell, which will easily be diluted in Patient’s blood plasma. *Type O is a universal Donor. Donor’s Cell TYPE A Patient’s Serum TYPE AB Result Antigen – A Antigen – AB (Orange) Minor reaction= (+) Antibody – B Antibody – NONE (Red) Major reaction= (-­‐) *May proceed with transfusion. Patient may suffer slight itchiness as reaction to small amounts of antibodies from Donor cell, which will easily be diluted in Patient’s serum. *Type AB is universal recipient. Error in blood transfusion may result in: • Agglutination • Destruction of RBC membrane by phagocytosis or antibodies Hemolysis =Jaundice • Severe hemolysis/decreased amt. of RBCcirculatory shockredistribution of blood to more important organs, ex. Brain Kidneys are bypassedRenal vasoconstrictionhemolyzed cells flow to the kidneys and block the renal tubulesRENAL SHUTDOWN RH BLOOD GROUP-­‐antigens are C, D, E, c, d, e • Rh – (+)-­‐-­‐-­‐-­‐ the sign is shown on the blood type. Example: A+ means Blood type A and RH (+) • The most important factor is the result of the “D” antigen. • Rh antigens are not immediately developed after blood transfusion from RH (+) to RH (-­‐). It takes 2-­‐4 months. After developing antigen, subsequent transfusions will be fatal. • Rh (-­‐) to Rh (+) transfusions do not result in undesirable reaction. Erythroblastosis Fetalis (HDN) st
1 CASE Mother is Rh (-­‐) and Father is Rh (+) Baby Rh (+) • Baby’s blood mixes with mother’s blood • Mother will develop anti-­‐Rh IgG • Mother’s anti-­‐IgG will attack the fetal RBC • Baby suffers from fetal anemia (Baby’s heart may fail) • Blood backflows; increases capillary hydrostatic pressurehydrops, ascites, pleural effusion, and scalp edema. • Spleen and liver are enlarged • There will be blasts in the peripheral smear because immature cells are secreted (erythroblastosis fetalis) • Increased hemolysis of blood resulting in high bilirubin levels • Bilirubin accumulates in the brain (kernicterus) • Commonly the baby dies (prevention is better than cure) Treatment to Hydrops: • Exchange transfusion o Rh (+) blood is removed during birth also to remove the antibodies, then replaced with Rh (-­‐) blood to stop interaction of antibodies with (+) o Then the baby is allowed to produce its own Rh (+) blood • Rho-­‐gam (Rh immunoglobulin) o Rho-­‐gam will coat the fetal RBC so that the maternal blood will not identify it and will not produce antibodies th
th
o Rho-­‐gam is administered on the 28 week or 7 month (during which time the mother’s blood mixes with the baby’s) *First baby is not affected because the sensitization will take several months. st
*Rho-­‐gam should be given on the 1 pregnancy to prevent mother’s sensitization. *Only IgG can penetrate the placenta because of its small size. nd
2 CASE Mother is Rh (+) and Father is Rh (-­‐) Baby Rh (-­‐) • The baby and the mother are unaffected because no reaction will occur. • The baby cannot produce antibodies during this stage. Prepared by: M.A. Pamular BLOOD PHYSIOLOGY
PART 1: RBC’s and Blood groups
Lectured by: Dr. Olivar
Functions of the blood:
1. Keeps the internal environment of the body constant (homeostasis)
2. Transports 02 from the lungs to the tissues and CO2 from the tissues to the lungs
(respiratory)
3. Carries nutritive materials form the intestines to all parts of the body (nutritive)
4. Carries waste products of tissue metabolism to the kidneys (excretory)
5. Transports internal secretions from glands to the tissues on which the effects are
exerted (endocrinology)
6. Helps maintain acid-base balance
7. Maintenance of water and electrolyte balance and in the regulation of total
osmotic pressure
8. Immunity to diseases (WBCs)
9. Regulation of body temperature
I.
Blood volume
A. Normal Blood volume
 A normal 7 kg male will usually have approx. 5 L of blood.
 Women, because of their short stature, will usually have a lower volume
of blood = 4.5 L
 Regardless of the volume, the blood will always be divided into two
major parts:
1. Plasma  60% = 3000 ml
2. Formed elements  40% = 2000 ml
B.
Composition of blood
We can separate the components of the blood by
CENTRIFUGATION.
 The RBCs will be the most dense so it will
settle at the bottom of the haematocrit.
 Middle:
platelets
and
WBCs
(have
intermediate densities) = Buffy coat
 Upper
portion:
Plasma
C.
Regulation of blood volume
When the heart contracts, it creates a pressure inside the
blood vessel = HYDROSTATIC PRESSURE (HP)
 HP tends to push the plasma into the interstitial space
but normally it does not happen because of an opposing
force that keeps the plasma inside the blood vessel
= ONCOTIC PRESSURE


Important factors in the regulation of formed elements:
o Bone marrow production
o Destruction/Wear and tear
II. Composition of blood
A. Formed elements
 Components: RBC, WBC, Platelet
B. Plasma
 Predominantly WATER
 Plasma protein: albumin, globulin, coagulation
factors (fibrinogen, prothrombin), antibodies
 blood sugar: glucose
 lipids: cholesterol, phospholipids, neutral fats
 salts: Na, K, Cl, bicarbonates, phosphates
 gases: O2, CO2, nitrogen
 special plasma substances: hormones,
enzymes, antibodies
 Functions of plasma:
1. Maintain normal balance between the intravascular compartment and
extravascular space (oncotic pressure)

2.
3.
4.
5.
6.
7.
8.
Oncotic pressure is comparable to Osmosis (movement of solvent
form area of lesser solute concentration to an area of higher solute
concentration; going where the solutes are)
 Inside the blood vessel :Plasma CHONs (solute)
 dec. plasma CHONs  dec oncotic pressure  hydrostatic pressure
predominates  plasma will go into the interstitial space  EDEMA
 Liver (produces plasma CHONs): Liver disease  dec plasma CHONs
 edema
 Ex: Cirrhosis of the liver  liver can no longer produce plasma
CHONs
 Kidney (allows CHONs to go to the urine)  dec plasma CHONs 
edema
Viscosity of the blood is primarily determined by the RBCs but somehow,
plasma CHONs also contribute to the viscosity of the blood
Source of antibodies
Necessary for coagulation
Maintenance of acid-base balance
Determines the specific gravity of the plasma (1.028)
Formation of enzymes
Transport of hormones and enzymes
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RED BLOOD CELL




Biconcave discs, 2.5 um thick, 7.5 – 8 um in diameter; 1 um at the center
Very deformable: due to excess cell membrane
Non-nucleated in the circulating blood
Primary function: carry haemoglobin  carries O2 in the circulation (1 gm of Hgb:
1.34 ml of O2)
 During adulthood, in the rare case that the bone marrow fails to produce RBCs,
liver and spleen can produce RBCs again = EXTRAMEDULLARY HEMATOPOIESIS
Ex: Aplastic anemia (bone marrow failure)  Liver and spleen must
produce RBCs in exaggerated way  Enlargement of liver and spleen 
HEPATOSPLENOMEGALY
D. Erythropoiesis: process of RBC production
A. Hematopoiesis: process by which formed elements are produced
o All blood cells originate in the BONE MARROW
o Multipotent/Pluripotent cells  can give rise to different types of cells
o Stem cells are not only seen in the bone marrow. There are also stem cells
present in the umbilical cord (can be harvested during childbirth and stored
in the blood bank for future purposes; could be beneficial if the child would
develop blood disease)
B. Normal values:
o RBC count
1. men: 5-6 x 1012/ L
2. women: 4-5 x 1012/ L
3. infants: 6.5 x 1012/ L
< NV = ANEMIA
> NV = POLYCYTHEMIA
o Hemoglobin
1. men: 14 – 17 g/dL
2. women: 12 – 15 g/dL
o Hematocrit
1. men: 0.40 – 0.50
2. women: 0.38 – 0.48
C.
RBC production: begins IN UTERO
a. Yolk sac of the embryo
st
 Produce RBCs during the 1 few weeks of embryonic life
 nourish the embryo
st
 1 site of hematopoiesis
b. Liver, spleen, lymph nodes
 middle trimester of pregnancy
c. Bone marrow
 3rd trimester of pregnancy – 5 y/o
d. Bone marrow of axial skeleton (skull, vertebral column, ribs, sternum,
pelvic bone)
 20 y/o and above
 Why are the long bones no longer capable of producing RBCs during adulthood?
It is because the long bones become infiltrated with yellow marrow.
 Multipotential/Pluripotential Hemopoietic stem cell: HEMOCYTOBLAST
1. All the cells in the circulating blood are derived from this cell.
 Committed stem cell: PROERYTHROBLAST
1. Intermediate-stage cell
2. They have already become committed to a particular line of cells;
produce specific type of blood cells
3. Formed from COLONY-FORMING UNIT ERYTHROCYTE (CFU-E)
 During the production of the mature RBC, the haemoglobin is incorporated into
the RBC and the nucleus condenses until it is finally extruded from the cell
st
 Reticulocyte: 1 cell released into the circulation
Peripheral blood smear:
feathery edge
E.

(remains blue because they still
contain cytoplasmic and
nuclear remnants)
(after 2 days, they become
reddish, non-nucleated RBCs)
Hemoglobin
The primary function of red blood cells is to transport hemoglobin, which in
turn carries oxygen from the lungs to the tissues and the carbon dioxide back
from the tissues to the lungs
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

Formation of Hgb:
o 2 succinyl CoA + 2 glycine  pyrrole molecule
o 4 pyrroles  protoporphyrin IX
o Protoporphyrin IX + Fe  Heme
o Heme + globin  Hemoglobin chain (alpha or beta)
o 2 alpha chains + 2 beta chains  Hemoglobin A
1. 1 chain = 1 Fe
2. Adult Hgb = 4 Fe
3. 1 Fe = bind to 1 O2 molecule
4. Sickle cell anemia
Abnormal beta chain: valine is substituted to glutamic acid in
each of two beta chains
upon exposure to O2, the Hgb forms, elongated crystals 
spiked ends rupture the cell membrane
hemolysis

Fe in the body exist in the following forms:
o RBC: Hemoglobin (majority)  65%
o Muscle: Myoglobin  4%
o Tissues in GIT (Reticuloendothelial system and liver parenchymal cells):
Ferritin  15 to 30%
o Participate in enzymatic reaction: Cytochrome enzymes


Source of Fe: glandular organs, beef, pork, chicken, oyster
Absorption of Fe from GIT:
Transport of O2 in the blood is primarily due to the combination of Hgb to O2
o 97% of O2 – combine with Hgb
o 3% of O2 – dissolved in plasma and cells
o Attachment of Hgb to O2 is a REVERSIBLE combination
Liver produces apotransferrin  secreted to the bile  duodenum (does
not readily go to the blood):
 If Fe content is adequate, Fe will just be stored in the mucosal cells of
duodenum as FERRITIN (storage form of Fe)
 Fe + Apoferritin  Ferritin
 If Fe is already needed in the bone marrow for the production of RBCs
(when the quantity of Fe in the plasma falls low), Fe in the form of
TRANSFERRIN (transfer form of Fe) will be delivered to the bone marrow
for erythropoiesis
 Fe + Apotransferrin  Transferrin
o
o
o

In the lungs, when the O2 content is VERY HIGH, O2 readily ATTACHES to
Hgb
In the tissues, when the O2 content is VERY LOW, O2 is readily RELEASED
by the Hgb
Transport of CO2 in the blood is predominantly via bicarbonate.
 Iron Metabolism
o RBC released in circulation  120 days  RBCs will be destroyed in the
liver and spleen (RETICULOENDOTHELIAL SYSTEM) by KUPFFER CELLS of
the liver and MACROPHAGES of spleen and bone marrow  Hgb is
released  Liver  release Fe and porphyrin  bilirubin and Fe is brought
back to the bone marrow to be reused again in erythropoiesis
o
o

Hence, we don’t need Fe that much because the Fe used in the
erythropoietic period is just recycled and the mechanism by which our
body eliminates Fe is very limited = It’s harmful to take Fe as a
multivitamin everyday
Fe as multivitamin taken every day  Fe overload Destroy organs
An adult individual, depending on the gender and habit, has 4-6 g. of Fe
3|CKRP
o
 (-) intrinsic factor: For the Vit. B12 to be absorbed, the stomach does
not only produce acid. The parietal cells of the stomach also release an
intrinsic factor which facilitates absorption of Vit. B12. Therefore, if
the intrinsic factor is not present, Vit B12 will not be absorbed
 Treatment: give Vit B12 through SHOT not through tablet; direct to the
blood vessels
Fe supplements are only recommended for females with menstrual
problems (heavy menstrual bleeding) and pregnant women
-
Folic acid Deficiency: SPRUE
 decreased intestinal absorption of folic acid and B12
G. Control of RBC production
o to ensure that there will be enough RBC that would carry O2 from the lungs
to the tissues
o too many RBC  RBCs overcrowd the vessels  impede blood flow


Elimination of Iron:
o Bile
o Urine
o Feces
o Menstruation

Tissue oxygenation
o Primary stimulus for RBC control
o Dec RBC = HYPOXIA
 Dec. blood flow and blood volume
 Inc. altitude and pulmonary diseases
= In people living in high places, they are not anemic and they have
adequate RBC but the amount of O2 is decreased in high altitude
= In people with pulmonary diseases, O2 cannot traverse the
pulmonary system  O2 can’t go to the blood  dec O2 in tissues
o production of RBC is not dependent on the number of RBC
 RBC production can be stimulated when RBC number is low but it can
also be stimulated even if the RBC number is normal as long as the
tissues are hypoxic

Erythropoietin
F. Maturation of RBC
Vitamin B12 (Cyanocobalamin) and Folic acid (Pteroylglutamic acid)
- Essential for synthesis of DNA
- Without them, erythropoiesis will proceed slowly; abnormal and
diminished DNA  failure of nuclear maturation and cell division
- Blast cells are released into the circulation due to slow DNA synthesis =
Macrocytes: rupture easily  MEGALOBLASTIC ANEMIA
“megalo” = big
“blastic” = produce blast cells
“anemia” = RBCs rupture easily
-
Vitamin B12 Deficiency: PERNICIOUS ANEMIA
 atrophic gastric mucosa: stomach is devoid of any cell and gland 
cannot produce intrinsic factor and normal gastric secretions
4|CKRP
o
o
o
90% is produced by the kidney and the remainder is mainly produced by the
liver
Stimulate production of proerythroblast  inc RBC  Inc O2
Cause cells to pass more rapidly through the different erythroblastic stages
than they normally do = speeding up production of new RBCs
I. Anemias: deficiency of Hgb; too rapid loss or too slow production
Blood loss – due to hemorrhage
Iron deficiency anemia
o In PBS, smaller in size and paler in color
o MICROCYTIC HYPOCHROMIC RBCs
 Hypochromic = RBCs contain much less haemoglobin than normal
 Aplastic anemia – bone marrow failure; due to chemotherapy, toxic chemicals,
autoimmune disorders
 Idiopathic aplastic anemia – aplastic anemia cases wherein the cause
is unknown
 Megaloblastic anemia
o Vit B12 and Folic acid deficiency
o MACROCYTIC HYPERCHROMIC RBCs
 Hemolytic anemia
o Hereditary spherocytosis


 When your Hgb synthesis is already normal and O2 transport is already adequate,
the kidney and liver will stop further production of erythropoietin  to inhibit  RBCs are spherical in shape not biconcave
 These cells cannot withstand compression forces because
overcrowding of RBC
they do not have the normal bag-like cell membrane
structure of biconcave discs
H. RBC destruction
 The cell membrane does not have a functional Na-K pump
 1% of red cells replaced daily total red cell volume replaced every 4 months
 Na+ are not pumped out of the cell  H20 continuously
 Site of destruction: SPLEEN
go inside of the cell  Cell becomes spherical (swell) until it
 “The number of red cell in the circulation at any time is determined by the balance
ruptures
between production and destruction ”
o
o



POLYCYTHEMIA = overproduction
ANEMIA = underproduction/over-destruction
Isotonic solution
o 0.9% Nacl; 5% dextrose
o No movement of water
Hypertonic solution
o Greater concentration of solute in the solution than in the RBC
o crenation
Hypotonic solution
o Lower concentration of solute in the solution than in the RBC
o Spherical  rupture  hemolysis
Effects of anemia on the circulatory system:
 Dec viscosity  Dec resistance to flow
o Viscosity of the blood is due to RBCs
o Dec RBC  Dec viscosity  greater blood flow  greater volume of blood
goes to the heart  INCREASE CARDIAC OUTPUT  INCREASE WORKLOAD
(Anemia makes the heart work faster and harder)
o In young people, it’s still okay to have anemia because the heart muscle is
still strong
o In old people, too much pumping of the heart  heart failure
o Since there’s a decreased amount of RBC, the heart needs to pump harder to
supply adequate amount of O2 to the tissues

Polycythemia
o Primary
o Secondary
 Normal number of RBC but
since an individual is living in a
high place, smoking, or has
pulmonary diseases  Tissue
5|CKRP
hypoxia  Inc RBC  Inc viscosity  sluggish flow of blood  high
probability of forming clot within blood vessels which blocks the blood
flow
 Treatment: Therapeutic phlebotomy (every 2 or 3 months,
removal/extraction of blood to decrease the amount of RBCs)
o

Effect of polycythemia in circulatory system
 Increase in blood viscosity  DECREASE rate of venous return to the
heart
 Increase in blood volume  INCREASE rate of venous return to the
heart
 Hence, the effect is NORMAL because the two factors normalize each
other
Polycythemia vera
o Genetic aberration in the hemocytoblastic cells
o Negative inhibition to the liver and kidneys to control production of
erythropoietin does not occur so even if the number of RBCs was already
increased, there is still sustained production of RBC
o It affects not only the RBCs but also WBCs (total blood volume increases)
unlike in secondary polycythemia wherein only the RBCs will increase.


Agglutination process in transfusion reactions
o Immediate: IgM  complement system (release proteolytic enzymes that
ruptures the cell membrane)  HEMOLYSIS
o Delayed: IgG +Ag  AGGLUTINATION  HEMOLYSIS
Blood typing:
ABO BLOOD GROUP

Antigens
o Aka Agglutinogens because they often cause blood cell agglutination
o Ag: A, AB, B, O
o Genetic determination of agglutinogens:


Antibodies
o Aka Agglutinins
o Ab: IgG, IgM
Cross-matching : to know the compatibility of the blood
o Recipient: patient who will receive the blood
o Donor: donates blood to the recipient
o Cross match the CELL (antigen) present in the blood of the donor with the
PLASMA (antibodies) present in the recipient = MAJOR REACTION
o MINOR REACTION: Reaction between the PLASMA of the donor with the
recipient’s CELL
o In a packed RBC, plasma in the blood is removed leaving only the RBCs.
6|CKRP




During haemorrhage, blood transfusion can save the patient’s life but if the blood
is transfused in the wrong way can also lead to the death of the patient.
Error in blood transfusion may result in:
o agglutination
o destruction of RBC membrane by antibodies = hemolysis
o renal shutdown
Acute renal failure occurs whenever there is error in blood transfusion.
Causes of Renal shutdown:
o hemolyzing blood releases toxic substances that cause severe renal arteriolar
vasoconstriction
o circulatory shock  arterial blood pressure falls very low  decreased renal
blood flow and urine output
o increase free hemoglobin  block the renal tubules
RH BLOOD GROUP
CROSSMATCHING
MAJOR
REACTION
MINOR
REACTION
DONOR
RECIPIENT
Cell
-Antigen
Plasma
-Antibodies
Plasma
-Antibodies
Cell
-Antigen
 Case 1: Donor (Type A) and Recipient (Type B)
CROSSMATCHING
MAJOR
REACTION
MINOR
REACTION
DONOR
RECIPIENT
RESULTS
A antigen
Anti -A
Reactive
(Agglutination)
Anti-B
B-antigen
Reactive
 Case 2: Donor (Type O) and Recipient (Type B)
CROSSDONOR
RECIPIENT
RESULTS
MATCHING
MAJOR
No antigen
Anti –A
Non-Reactive
REACTION
MINOR
Anti-A and
B-antigen
Reactive
REACTION
Anti-B
 Even if the minor reaction is reactive, the amount of blood donated (Blood bag:
~250 cc) is much lesser than the blood present in the patient’s body (~3 L) so the
plasma of the recipient will just be degraded; manifested by some reactions like
itching.
 Type O = UNIVERSAL DONOR
 Type AB = UNIVERSAL RECIPIENT (it does not contain antibodies)


Rh Antigens: C D E c d e
Rh + if the patient has D antigen (type D antigen is more widely prevalent and
more antigenic than other Rh antigens)

Transfusion reactions:
o ABO is IMMEDIATE because the antibodies are IgM
o Rh is DELAYED because the antibodies are IgG

Formation of Anti-Rh agglutinins
o Usually occurs when an Rh (-) individual receives a blood that is Rh (+)
o Initially, nothing will happen to the recipient because the generation of
antibodies is delayed.
o (+) anti- Rh will develop in 2-4 months
o After 2-4 months and the recipient receive an Rh (+) blood again 
Agglutination = Fatal because antibodies have already formed

Hemolytic disease of the newborn:
o
If the baby is Rh (+) and the mother is Rh (-), the blood of the baby can mix
with the blood of the mother and the mother will develop an immune
response to produce antibodies against the fetal RBCs
7|CKRP
o
If the fetal RBCs are destroyed by the maternal antibodies 
ERYTHROBLASTOSIS FETALIS
 “Erythroblastosis” – because of rapid production of red cells, many
early forms of RBCs like nucleated blastic forms go into the circulation
o
o
o
o


Components of Erythroblastosis fetalis:
o The baby develops ANEMIA  Inc. workload  heart failure
o Severe anemia  Backflow of blood  dec blood in the tissues
o Congestion relatively around the heart, abdomen  FETAL HYDROP
o In Anemia (hematopoietic tissues attempt to replaced hemolyzed RBCs) 
Enlarged spleen and liver  Extramedullary hematopoiesis  Inc blood 
bilirubin is produced  bilirubin is deposited in the brain
 Kernicterus – permanent mental impairment or damage to motor
areas of the brain because of precipitation of bilirubin in the neuronal
cells causing destruction
o Inc capillary hydrostatic pressure  hydrops, ascites, pleural effusion, scalp
edema
Management of Rh Incompatibility
1. Rho-gam
o Rh immunoglobulin globin – Anti-D antibody
o Incidence of erythroblastosis fetalis has decreased a lot because of RHOGAM
o Before it was introduced, Rh (-) pregnant women have 99% chance of
delivering a newborn with haemolytic disease, manifesting anemia and
erythroblastosis fetalis
o Rh (+) blood is given to a donor (usually male) who is Rh (-)  production of
antibodies  antibodies will be taken = Rho-gam
o Male donors of Rho-gam would no longer have a chance to receive Rh (+)
blood again because they are already sensitized to Rh (+)
o Donors usually have high circulating levels of Anti-D
o
Rho-gam covers fetal RBCs and prevents the fetal RBCs to be recognized by
the maternal immune system
Routine Antenatal Prophylaxis:
th
 Rho-gam is given to pregnant women at around 28 week of
pregnancy, intramuscular (mixing of the blood of the mother and baby
th
usually occur around the 28 week of pregnancy) - a single dose of
300 ug
 The effectivity of Rho-gam is only 12 weeks so if the mother have not
nd
yet delivered by 40 weeks, the 2 dose of Anti-D Ig should be given
Postnatal prophylaxis:
nd
 If the mother had already delivered before 40 weeks and the 2 dose
nd
is not yet given, the 2 dose (single dose of 300 ug) should be given
within 72 hours following the delivery of an Rh (+) infant (if the
nd
newborn is found to be Rh – then there’s no point of giving the 2
dose)
The first thing to do upon discovering that the pregnant woman is Rh (-) is to
get the blood type of the partner because if the partner is also Rh (-), Rhoth
gam is not given at 28 week
Rho-gam is given during the first pregnancy because even if the development
st
of the antibodies is delayed and the 1 pregnancy is not affected, the mother
should not be immunized and should not develop antibodies that might react
nd
during the 2 pregnancy
2. Exchange transfusion
o Getting the blood of the baby and transfuse an Rh (-) blood to prevent
destruction and when the antibodies have already been removed then the
transfusion is stopped
o The baby will still produce Rh (+) blood but the main purpose of exchange
transfusion is to remove the antibodies

How would we know if the baby is Rh (+) while an Rh (-) mother is still pregnant?
o Invasive: pierce through the uterus and get blood form the umbilical cord;
but there are many complication possible through this method
o So, we don’t necessarily have to do the invasive method as long as we know
that the mother is Rh (-) and the partner is Rh (+) because there is a high
chance that the baby will be Rh (+)

Why are we not as concerned with ABO blood reaction as Rh reactions?
o It is not a concern because in ABO blood groups, the antibodies are IgM
which are too large to cross the placenta; In Rh blood groups it is IgG
8|CKRP
BLOOD PHYSIOLOGY
o
PART 2: Platelets, Hemostasis, and Blood Coagulation
Lectured by: Dr. Olivar

Platelets/ Thrombocytes
o Small, non-nucleated, colorless bodies, ranging in size from 1-4 um
o Formed in the bone marrow from megakaryocytes
o Normal value: ~ 150,000 – 300,000
o Half-life in the blood: 8-12 days
o Thrombocytopenia – lower than the normal values
o Thrombocytosis – higher than the normal values
o The primary function is to achieve HEMOSTASIS
 Formation of the platelet plug
 Participates in blood coagulation
 Release thromboxane A2 and serotonin  Local vasoconstriction
 Release thrombostenin  Clot retraction
o Functional characteristics:
 Actin and myosin molecules  contractile protein
 Thrombosthenin  contractile protein
 RER and Golgi complex  synthesize enzymes and store large
quantities of Ca
 Mitochondria  ATP and ADP
 Prostaglandins  local hormone that cause many vascular and other
local tissue reactions
 Fibrin-stabilizing factor  blood coagulation
 Growth factor  cellular growth that will eventually help repair
damaged vascular walls
 Glycoproteins  in cell membrane; adherence to injured areas of
vessel wall
 Phospholipid  in cell membrane; activate multiple stages in bloodclotting process
Platelets secrete thromboxane A2 and serotonin which helps in the
vasoconstriction
B. PLATELET PLUG FORMATION
o Whenever the collagen on the blood vessels is exposed due to damage in the
blood vessels  platelets are attracted to the area  platelet plug
o Platelets + Collagen fibers
 Swell
 Numerous pseudopods protruding
 Release of granules with multiple active factors
 Sticky (to adhere to collagen and von Willebrand factor)
 Secrete ADP
 Form thromboxane A2
o If the damage is only small, the platelet plug formation is already enough 
hemostasis
o Importance: closing minute ruptures in very small blood vessels that occur
many thousand of times daily
o Dec platelet or Adequate amount of platelet but the quality is poor 
Manifestations of multiple lesions: Purpura (bigger) and Petechiae
o IDIOPATHIC THROMBOCYTOPENIC PURPURA – dec platelet; autoimmune
disease; have several hematoma in the body
C. BLOOD COAGULATION
o Occurs during severe trauma: 15 – 20 seconds
o Minor trauma: 1-2 minutes
o Procoagulant: promote coagulation; predominated in blood stream
o Anticoagulant: inhibit coagulation; dominate and activated in damaged tissue

Mechanism of coagulation:
HEMOSTASIS
- prevention of blood loss

3 mechanisms:
o Local vasoconstriction
o Platelet plug
o Blood coagulation
o Eventual growth of fibrous tissue into the blood clot to close the hole in the
vessel permanently
A. LOCAL VASOCONSTRICTION
o a reflex response from local myogenic contraction of the blood vessel
st
o 1 line in hemostasis
o
o
Formation of prothrombin activator or prothrombin converting enzyme
 Rate-limiting factor
Prothrombin  Thrombin
9|CKRP
o
o

 with sufficient amount of CA++
 Prothrombin is formed by the liver
 Vit K: required by the liver for normal production of prothrombin and
other clotting factors
Fibrinogen  Fibrinogen monomer (not a stable clot due to weak non
covalent hydrogen bond)  polymerization through a coagulation factor
called factor XIII  Fibrin polymer (covalent bonds and multiple crosslinkages)
 Clot is composed of meshwork of fibrin fibers with trapped RBCs,
platelets and plasma
 Fibrinogen is also formed by the liver
Clot retraction
 Activation of thrombostenin, actin, and myosin
 Edges of broken blood vessels are pulled together  Hemostasis
Initiation of clotting process:
o Extrinsic pathway
 trauma to the vascular wall and adjacent tissues
o Intrinsic pathway (true pathways by which you can actually stimulate the clot
to form)
 contact of the blood with damaged endothelial cells / collagen
 trauma to the blood
 most are inactive forms of proteolytic enzymes
 concerted to active forms  successive, cascading reaction of clotting process

 common pathway: formation of prothrombin activator
Extrinsic pathway (coagulation is easily formed)
1. Trauma in the vascular wall or tissue  release of tissue factor (Factor III Thromboplastin)
o With PHOSPHOLIPIDS in the membrane
o With LIPOPROTEIN COMPLEX – proteolytic enzyme
2. Factor VII  activated Factor VII
10 | C K R P
3. Thromboplastin (lipoprotein complex) + activated Factor VII + presence of
Ca++: Factor X  activated Factor X
4. activated Factor X + thromboplastin (phospholipid) + Factor V: Prothrombin
activator
5. Platelet phospholipid + presence of Ca++: Prothrombin  Thrombin
6. Inactive Factor V + Thrombin  Acitvated Factor V (accelerator of Prothrombin
activation)
7. Fibrinogen  Fibrin
* It is the Factor Xa that is considered as the Prothrombin activator


Roles of Ca++ and platelets:
o serve as cofactor for the coagulation pathways
o Even if the coagulation factors are adequate in number, but the platelet
count is decreased or platelets have poor quality or the Ca++ is decreased 
clot will not be produced
o Principle behind anticoagulants used in laboratory:
 Citrate (blue top): de-ionizes Ca++
 Oxalate (gray top): precipitates Ca++
 Anticoagulants remove Ca++ from the blood sample
 Reducing the Ca++ concentration below the threshold level for clotting

Clot retraction
Intrinsic pathway (coagulation proceeds much slower)
1. Blood trauma or exposure of blood to collagen: Factor XII  Factor XIIa
o Simultaneously, platelets are damaged  release of platelet
phospholipids w/ platelet factor 3
2. Factor XI  Factor XIa
o Requires HMW (high molecular weight) Kininogen
o Accelerated by Prekallikrein
3. Factor IX  Factor IXa
4. Factor IXa + Factor VIII + platelet phospholipids: Factor X  Factor Xa
o Platelet phospholipids are from the traumatized platelets
o Factor VIII: ANTIHEMOPHILIC FACTOR
o Hemophilia: absence of factor VIII
5. Factor Xa + Factor V + Platelet phospholipid  Prothrombin activator
6. Prothrombin  Thrombin
7. Fibrinogen  FIbrin
o
o

“As the clot retracts, the edges of the broken blood vessel are pulled
together, thus possibly or probably contributing to the ultimate state of
hemostasis ”
Platelets contact  vessels are pulled together  re-epithelize 
hemostasis
Lysis of blood clot:
o Plasminogen/Profibrinolysin (inactive form)  Plasmin/Fibrinolysin
o by Tissue plasminogen activator (t-PA) - released by the endothelial cells of
the damaged blood vessel
o In commercial substances called Streptokinase which are given to patients
that suffered from heart attack or myocardial infarction (blood clot blocked
one of the major coronaries that supplies the heart)  lysis of the clot and
normal perfusion is maintained due to PLASMIN and not streptokinase
11 | C K R P
o
o

Plasmin dissolved the clot; Streptokinase immediately converts plasminogen
to plasmin
Plasmin can only lyse/dissolve the clot if the clot had not yet stabilized. If the
clot is already stabilized, even if Streptokinase is given and plasmin is
produced  clot would no longer be dissolved

Functions of Plasmin:
o digest fibrin fibers
o digest fibrinogen, Factor V, VIII, XII and prothrombin
o “to remove clots from the vessels that eventually would become occluded
were there’s no way to clean them”

Prevention of Blood Clotting in the Normal Vascular System – The Intravascular
Anticoagulants:
o endothelial surface factors
 smoothness of the endothelial cell surface  prevent contact
activation of the intrinsic clotting system
 glycocalyx  prevents clotting factors from attaching
 thrombomodulin  binds thrombin  thrombomodulinthrombin complex activates protein C  inactivates Factor Va
and VIIIa; present only in an intact endothelium
o anti-thrombin action of fibrin and anti-thrombin III
 85-90% of thrombin becomes absorbed to the fibrin fibers
 anti-thrombin III: blocks the effect of thrombin to fibrinogen
and inactivates them
o Heparin
 By itself it has no or little anticoagulant properties but when
combined with antithrombin III  greatly increases the
effectiveness in removing thrombin
 Formed by basophilic mast cells
2.
Coagulation Disorders
A. Coagulation deficiencies
1. Bleeding caused by Vit K deficiency
 Vit K is continuously synthesized by intestinal bacteria
 Liver produces Factors IX, X, VII, II, protein C through
carboxylation (liver carboxylase) aided by Vit K
 Once the coagulation factors are already carboxylated  Vit K
becomes inactive
 Vitamin K epoxide reductase complex 1 (VCOR c1)  reduces
Vit K back to its active form
 One of the fat soluble vitamins: can only be absorbed in the
presence of fat
 Fats cannot be absorbed in the intestine without bile because
bile emulsifies fat
3.
Vit K deficiency may be due to failure of the liver to secrete bile
or obstruction of bile duct caused by liver diseases
 If a patient has gallstones  removal of gall bladder  no Vit K
deficiency because bile is secreted from the liver and goes
directly to the intestines; gall bladder is just a storage of bile
 When the common bile duct is cut  bile will not be delivered
 If the common bile duct is accidentally cut during surgery,
duodenum is attached to the liver so that there will be supply of
bile
 In newborn, initially they don’t have intestinal bacterial flora 
Vit K injection is administered
Hemophilia
 sex-linked disease: only manifested in males but from the
chromosomes of female carriers
 85%: absence of Factor VIII = HEMOPHILIA A or CLASSIC
HEMOPHILIA
 15%: absence of Factor IX
 Treatment: Recombinant Factor VIII
Thrombocytopenia
 Presence of very low number of platelets in the circulating
blood
 Treatment: fresh whole blood transfusion with large numbers
of platelets and splenectomy
B. Coagulation excess
 Artherosclerotic plaque  Hypertension (dec diameter of blood vessels)
 Rupture in the lumen of blood vessels  collagen is exposed  abnormal
thrombus formation  myocardial infarction
 Treatment: genetically-engineered T-PA  dissolve intravascular clot
1.
2.
Thrombus
 an abnormal clot that develops in a blood vessel
Emboli
 freely flowing clots
 due to roughened endothelial surface of vessel
12 | C K R P







3.
4.
o
o
o
exemplified by formation of clot coming from the deep veins of
the leg  Pulmonary embolism
left side of the heart  Stroke
due to slow blood flow  clot forms and settles in the valves 
clot is thrown by the blood flow into distal areas  Embolus 
goes up to block pulmonary capillaries  PULMONARY
EMBOLISM
It usually occurs in capillaries rather that in arteries because of
the small diameter of capillaries
Theoretically (under normal condition), it is not possible to see
a clot that originated from the deep vein of the leg go into the
left side of the heart because once it has blocked the pulmonary
capillaries it can no longer go on and proceed to the left side of
the heart
However it is still possible when there is communication
between the chambers of the heart = Ventricular septal defect
It is also possible in tetralogy of fallot wherein the right
ventricular pressure is greater than the left; bidirectional flow
 Blood will flow from right to left
Infarct
 tissue devoid of blood supply
Disseminated Intravascular Coagulation
clotting mechanism becomes activated in widespread areas of the
circulation
Sepsis
 Bacteria release toxins (endotoxins)  activate blood clotting
mechanisms
 Treatment: antibiotics
Abruptio placenta
 If there is clot, plasmin will dissolve it  placenta and bacteria
will produce clot again  it will be dissolved again by the
placenta  coagulation factors are already consumed 
CONSUMPTIVE coagulopathy
 Treatment: Antibiotic or removal of placenta

Anticoagulants for clinical use:
1. Heparin
o Mode of action: potentiates the action of antithrombin III
o Heparin-antithrombin III complex blocks factors XII, XI, IX, X and II
o Antidote: protamine sulphate
o Action lasts for 1.5 to 4 hrs and then destroyed in the blood by
HEPARINASE
2. Coumarin/ warfarin
o Mechanism of action: blocks the action of vitamin K
o Inactivates VCOR C1  Vit K will not be reduced back to its active form
 Coagulation factors will not be activated

Blood coagulation tests
1. Bleeding time
o pierce the tip of the finger or lobe of the ear
o bleeding ordinarily lasts for 1 to 6 minutes
o Prolonged bleeding time: Lack of any one of several of the clotting
factors and lack of platelets.
o Inaccurate because it is operator-dependent
13 | C K R P
o
TEST for QUALITY of PLATELETS: if platelets are of good quality, they will
perform platelet plug formation  bleeding will stop
2. Clotting time
o Collect blood in a chemically clean glass test tube and then to tip the
tube back and forth about every 30 seconds until the blood has clotted
o time needed for blood to clot
o NV: 6 - 10 minutes
o test for clotting factors
3. Prothrombin time
o test for quantity of prothrombin in the blood (E)
o NV: 12 seconds
4. Partial thrombolastin time
o Test the intrinsic pathway of coagulation
God looks down from heaven on the entire human race to see if
anyone is truly wise. And the truly wise person is the one who seeks
Him.
= Psalm 53:2=
14 | C K R P
BLOOD PHYSIOLOGY
PART 1: RBC’s and Blood groups
Lectured by: Dr. Olivar
Functions of the blood:
1. Keeps the internal environment of the body constant (homeostasis)
2. Transports 02 from the lungs to the tissues and CO2 from the tissues to the lungs
(respiratory)
3. Carries nutritive materials form the intestines to all parts of the body (nutritive)
4. Carries waste products of tissue metabolism to the kidneys (excretory)
5. Transports internal secretions from glands to the tissues on which the effects are
exerted (endocrinology)
6. Helps maintain acid-base balance
7. Maintenance of water and electrolyte balance and in the regulation of total
osmotic pressure
8. Immunity to diseases (WBCs)
9. Regulation of body temperature
I.
Blood volume
A. Normal Blood volume
 A normal 7 kg male will usually have approx. 5 L of blood.
 Women, because of their short stature, will usually have a lower volume
of blood = 4.5 L
 Regardless of the volume, the blood will always be divided into two
major parts:
1. Plasma  60% = 3000 ml
2. Formed elements  40% = 2000 ml
B.
Composition of blood
We can separate the components of the blood by
CENTRIFUGATION.
 The RBCs will be the most dense so it will
settle at the bottom of the haematocrit.
 Middle:
platelets
and
WBCs
(have
intermediate densities) = Buffy coat
 Upper
portion:
Plasma
C.
Regulation of blood volume
When the heart contracts, it creates a pressure inside the
blood vessel = HYDROSTATIC PRESSURE (HP)
 HP tends to push the plasma into the interstitial space
but normally it does not happen because of an opposing
force that keeps the plasma inside the blood vessel
= ONCOTIC PRESSURE


Important factors in the regulation of formed elements:
o Bone marrow production
o Destruction/Wear and tear
II. Composition of blood
A. Formed elements
 Components: RBC, WBC, Platelet
B. Plasma
 Predominantly WATER
 Plasma protein: albumin, globulin, coagulation
factors (fibrinogen, prothrombin), antibodies
 blood sugar: glucose
 lipids: cholesterol, phospholipids, neutral fats
 salts: Na, K, Cl, bicarbonates, phosphates
 gases: O2, CO2, nitrogen
 special plasma substances: hormones,
enzymes, antibodies
 Functions of plasma:
1. Maintain normal balance between the intravascular compartment and
extravascular space (oncotic pressure)

2.
3.
4.
5.
6.
7.
8.
Oncotic pressure is comparable to Osmosis (movement of solvent
form area of lesser solute concentration to an area of higher solute
concentration; going where the solutes are)
 Inside the blood vessel :Plasma CHONs (solute)
 dec. plasma CHONs  dec oncotic pressure  hydrostatic pressure
predominates  plasma will go into the interstitial space  EDEMA
 Liver (produces plasma CHONs): Liver disease  dec plasma CHONs
 edema
 Ex: Cirrhosis of the liver  liver can no longer produce plasma
CHONs
 Kidney (allows CHONs to go to the urine)  dec plasma CHONs 
edema
Viscosity of the blood is primarily determined by the RBCs but somehow,
plasma CHONs also contribute to the viscosity of the blood
Source of antibodies
Necessary for coagulation
Maintenance of acid-base balance
Determines the specific gravity of the plasma (1.028)
Formation of enzymes
Transport of hormones and enzymes
1|CKRP
RED BLOOD CELL




Biconcave discs, 2.5 um thick, 7.5 – 8 um in diameter; 1 um at the center
Very deformable: due to excess cell membrane
Non-nucleated in the circulating blood
Primary function: carry haemoglobin  carries O2 in the circulation (1 gm of Hgb:
1.34 ml of O2)
 During adulthood, in the rare case that the bone marrow fails to produce RBCs,
liver and spleen can produce RBCs again = EXTRAMEDULLARY HEMATOPOIESIS
Ex: Aplastic anemia (bone marrow failure)  Liver and spleen must
produce RBCs in exaggerated way  Enlargement of liver and spleen 
HEPATOSPLENOMEGALY
D. Erythropoiesis: process of RBC production
A. Hematopoiesis: process by which formed elements are produced
o All blood cells originate in the BONE MARROW
o Multipotent/Pluripotent cells  can give rise to different types of cells
o Stem cells are not only seen in the bone marrow. There are also stem cells
present in the umbilical cord (can be harvested during childbirth and stored
in the blood bank for future purposes; could be beneficial if the child would
develop blood disease)
B. Normal values:
o RBC count
1. men: 5-6 x 1012/ L
2. women: 4-5 x 1012/ L
3. infants: 6.5 x 1012/ L
< NV = ANEMIA
> NV = POLYCYTHEMIA
o Hemoglobin
1. men: 14 – 17 g/dL
2. women: 12 – 15 g/dL
o Hematocrit
1. men: 0.40 – 0.50
2. women: 0.38 – 0.48
C.
RBC production: begins IN UTERO
a. Yolk sac of the embryo
st
 Produce RBCs during the 1 few weeks of embryonic life
 nourish the embryo
st
 1 site of hematopoiesis
b. Liver, spleen, lymph nodes
 middle trimester of pregnancy
c. Bone marrow
 3rd trimester of pregnancy – 5 y/o
d. Bone marrow of axial skeleton (skull, vertebral column, ribs, sternum,
pelvic bone)
 20 y/o and above
 Why are the long bones no longer capable of producing RBCs during adulthood?
It is because the long bones become infiltrated with yellow marrow.
 Multipotential/Pluripotential Hemopoietic stem cell: HEMOCYTOBLAST
1. All the cells in the circulating blood are derived from this cell.
 Committed stem cell: PROERYTHROBLAST
1. Intermediate-stage cell
2. They have already become committed to a particular line of cells;
produce specific type of blood cells
3. Formed from COLONY-FORMING UNIT ERYTHROCYTE (CFU-E)
 During the production of the mature RBC, the haemoglobin is incorporated into
the RBC and the nucleus condenses until it is finally extruded from the cell
st
 Reticulocyte: 1 cell released into the circulation
Peripheral blood smear:
feathery edge
E.

(remains blue because they still
contain cytoplasmic and
nuclear remnants)
(after 2 days, they become
reddish, non-nucleated RBCs)
Hemoglobin
The primary function of red blood cells is to transport hemoglobin, which in
turn carries oxygen from the lungs to the tissues and the carbon dioxide back
from the tissues to the lungs
2|CKRP


Formation of Hgb:
o 2 succinyl CoA + 2 glycine  pyrrole molecule
o 4 pyrroles  protoporphyrin IX
o Protoporphyrin IX + Fe  Heme
o Heme + globin  Hemoglobin chain (alpha or beta)
o 2 alpha chains + 2 beta chains  Hemoglobin A
1. 1 chain = 1 Fe
2. Adult Hgb = 4 Fe
3. 1 Fe = bind to 1 O2 molecule
4. Sickle cell anemia
Abnormal beta chain: valine is substituted to glutamic acid in
each of two beta chains
upon exposure to O2, the Hgb forms, elongated crystals 
spiked ends rupture the cell membrane
hemolysis

Fe in the body exist in the following forms:
o RBC: Hemoglobin (majority)  65%
o Muscle: Myoglobin  4%
o Tissues in GIT (Reticuloendothelial system and liver parenchymal cells):
Ferritin  15 to 30%
o Participate in enzymatic reaction: Cytochrome enzymes


Source of Fe: glandular organs, beef, pork, chicken, oyster
Absorption of Fe from GIT:
Transport of O2 in the blood is primarily due to the combination of Hgb to O2
o 97% of O2 – combine with Hgb
o 3% of O2 – dissolved in plasma and cells
o Attachment of Hgb to O2 is a REVERSIBLE combination
Liver produces apotransferrin  secreted to the bile  duodenum (does
not readily go to the blood):
 If Fe content is adequate, Fe will just be stored in the mucosal cells of
duodenum as FERRITIN (storage form of Fe)
 Fe + Apoferritin  Ferritin
 If Fe is already needed in the bone marrow for the production of RBCs
(when the quantity of Fe in the plasma falls low), Fe in the form of
TRANSFERRIN (transfer form of Fe) will be delivered to the bone marrow
for erythropoiesis
 Fe + Apotransferrin  Transferrin
o
o
o

In the lungs, when the O2 content is VERY HIGH, O2 readily ATTACHES to
Hgb
In the tissues, when the O2 content is VERY LOW, O2 is readily RELEASED
by the Hgb
Transport of CO2 in the blood is predominantly via bicarbonate.
 Iron Metabolism
o RBC released in circulation  120 days  RBCs will be destroyed in the
liver and spleen (RETICULOENDOTHELIAL SYSTEM) by KUPFFER CELLS of
the liver and MACROPHAGES of spleen and bone marrow  Hgb is
released  Liver  release Fe and porphyrin  bilirubin and Fe is brought
back to the bone marrow to be reused again in erythropoiesis
o
o

Hence, we don’t need Fe that much because the Fe used in the
erythropoietic period is just recycled and the mechanism by which our
body eliminates Fe is very limited = It’s harmful to take Fe as a
multivitamin everyday
Fe as multivitamin taken every day  Fe overload Destroy organs
An adult individual, depending on the gender and habit, has 4-6 g. of Fe
3|CKRP
o
 (-) intrinsic factor: For the Vit. B12 to be absorbed, the stomach does
not only produce acid. The parietal cells of the stomach also release an
intrinsic factor which facilitates absorption of Vit. B12. Therefore, if
the intrinsic factor is not present, Vit B12 will not be absorbed
 Treatment: give Vit B12 through SHOT not through tablet; direct to the
blood vessels
Fe supplements are only recommended for females with menstrual
problems (heavy menstrual bleeding) and pregnant women
-
Folic acid Deficiency: SPRUE
 decreased intestinal absorption of folic acid and B12
G. Control of RBC production
o to ensure that there will be enough RBC that would carry O2 from the lungs
to the tissues
o too many RBC  RBCs overcrowd the vessels  impede blood flow


Elimination of Iron:
o Bile
o Urine
o Feces
o Menstruation

Tissue oxygenation
o Primary stimulus for RBC control
o Dec RBC = HYPOXIA
 Dec. blood flow and blood volume
 Inc. altitude and pulmonary diseases
= In people living in high places, they are not anemic and they have
adequate RBC but the amount of O2 is decreased in high altitude
= In people with pulmonary diseases, O2 cannot traverse the
pulmonary system  O2 can’t go to the blood  dec O2 in tissues
o production of RBC is not dependent on the number of RBC
 RBC production can be stimulated when RBC number is low but it can
also be stimulated even if the RBC number is normal as long as the
tissues are hypoxic

Erythropoietin
F. Maturation of RBC
Vitamin B12 (Cyanocobalamin) and Folic acid (Pteroylglutamic acid)
- Essential for synthesis of DNA
- Without them, erythropoiesis will proceed slowly; abnormal and
diminished DNA  failure of nuclear maturation and cell division
- Blast cells are released into the circulation due to slow DNA synthesis =
Macrocytes: rupture easily  MEGALOBLASTIC ANEMIA
“megalo” = big
“blastic” = produce blast cells
“anemia” = RBCs rupture easily
-
Vitamin B12 Deficiency: PERNICIOUS ANEMIA
 atrophic gastric mucosa: stomach is devoid of any cell and gland 
cannot produce intrinsic factor and normal gastric secretions
4|CKRP
o
o
o
90% is produced by the kidney and the remainder is mainly produced by the
liver
Stimulate production of proerythroblast  inc RBC  Inc O2
Cause cells to pass more rapidly through the different erythroblastic stages
than they normally do = speeding up production of new RBCs
I. Anemias: deficiency of Hgb; too rapid loss or too slow production
Blood loss – due to hemorrhage
Iron deficiency anemia
o In PBS, smaller in size and paler in color
o MICROCYTIC HYPOCHROMIC RBCs
 Hypochromic = RBCs contain much less haemoglobin than normal
 Aplastic anemia – bone marrow failure; due to chemotherapy, toxic chemicals,
autoimmune disorders
 Idiopathic aplastic anemia – aplastic anemia cases wherein the cause
is unknown
 Megaloblastic anemia
o Vit B12 and Folic acid deficiency
o MACROCYTIC HYPERCHROMIC RBCs
 Hemolytic anemia
o Hereditary spherocytosis


 When your Hgb synthesis is already normal and O2 transport is already adequate,
the kidney and liver will stop further production of erythropoietin  to inhibit  RBCs are spherical in shape not biconcave
 These cells cannot withstand compression forces because
overcrowding of RBC
they do not have the normal bag-like cell membrane
structure of biconcave discs
H. RBC destruction
 The cell membrane does not have a functional Na-K pump
 1% of red cells replaced daily total red cell volume replaced every 4 months
 Na+ are not pumped out of the cell  H20 continuously
 Site of destruction: SPLEEN
go inside of the cell  Cell becomes spherical (swell) until it
 “The number of red cell in the circulation at any time is determined by the balance
ruptures
between production and destruction ”
o
o



POLYCYTHEMIA = overproduction
ANEMIA = underproduction/over-destruction
Isotonic solution
o 0.9% Nacl; 5% dextrose
o No movement of water
Hypertonic solution
o Greater concentration of solute in the solution than in the RBC
o crenation
Hypotonic solution
o Lower concentration of solute in the solution than in the RBC
o Spherical  rupture  hemolysis
Effects of anemia on the circulatory system:
 Dec viscosity  Dec resistance to flow
o Viscosity of the blood is due to RBCs
o Dec RBC  Dec viscosity  greater blood flow  greater volume of blood
goes to the heart  INCREASE CARDIAC OUTPUT  INCREASE WORKLOAD
(Anemia makes the heart work faster and harder)
o In young people, it’s still okay to have anemia because the heart muscle is
still strong
o In old people, too much pumping of the heart  heart failure
o Since there’s a decreased amount of RBC, the heart needs to pump harder to
supply adequate amount of O2 to the tissues

Polycythemia
o Primary
o Secondary
 Normal number of RBC but
since an individual is living in a
high place, smoking, or has
pulmonary diseases  Tissue
5|CKRP
hypoxia  Inc RBC  Inc viscosity  sluggish flow of blood  high
probability of forming clot within blood vessels which blocks the blood
flow
 Treatment: Therapeutic phlebotomy (every 2 or 3 months,
removal/extraction of blood to decrease the amount of RBCs)
o

Effect of polycythemia in circulatory system
 Increase in blood viscosity  DECREASE rate of venous return to the
heart
 Increase in blood volume  INCREASE rate of venous return to the
heart
 Hence, the effect is NORMAL because the two factors normalize each
other
Polycythemia vera
o Genetic aberration in the hemocytoblastic cells
o Negative inhibition to the liver and kidneys to control production of
erythropoietin does not occur so even if the number of RBCs was already
increased, there is still sustained production of RBC
o It affects not only the RBCs but also WBCs (total blood volume increases)
unlike in secondary polycythemia wherein only the RBCs will increase.


Agglutination process in transfusion reactions
o Immediate: IgM  complement system (release proteolytic enzymes that
ruptures the cell membrane)  HEMOLYSIS
o Delayed: IgG +Ag  AGGLUTINATION  HEMOLYSIS
Blood typing:
ABO BLOOD GROUP

Antigens
o Aka Agglutinogens because they often cause blood cell agglutination
o Ag: A, AB, B, O
o Genetic determination of agglutinogens:


Antibodies
o Aka Agglutinins
o Ab: IgG, IgM
Cross-matching : to know the compatibility of the blood
o Recipient: patient who will receive the blood
o Donor: donates blood to the recipient
o Cross match the CELL (antigen) present in the blood of the donor with the
PLASMA (antibodies) present in the recipient = MAJOR REACTION
o MINOR REACTION: Reaction between the PLASMA of the donor with the
recipient’s CELL
o In a packed RBC, plasma in the blood is removed leaving only the RBCs.
6|CKRP




During haemorrhage, blood transfusion can save the patient’s life but if the blood
is transfused in the wrong way can also lead to the death of the patient.
Error in blood transfusion may result in:
o agglutination
o destruction of RBC membrane by antibodies = hemolysis
o renal shutdown
Acute renal failure occurs whenever there is error in blood transfusion.
Causes of Renal shutdown:
o hemolyzing blood releases toxic substances that cause severe renal arteriolar
vasoconstriction
o circulatory shock  arterial blood pressure falls very low  decreased renal
blood flow and urine output
o increase free hemoglobin  block the renal tubules
RH BLOOD GROUP
CROSSMATCHING
MAJOR
REACTION
MINOR
REACTION
DONOR
RECIPIENT
Cell
-Antigen
Plasma
-Antibodies
Plasma
-Antibodies
Cell
-Antigen
 Case 1: Donor (Type A) and Recipient (Type B)
CROSSMATCHING
MAJOR
REACTION
MINOR
REACTION
DONOR
RECIPIENT
RESULTS
A antigen
Anti -A
Reactive
(Agglutination)
Anti-B
B-antigen
Reactive
 Case 2: Donor (Type O) and Recipient (Type B)
CROSSDONOR
RECIPIENT
RESULTS
MATCHING
MAJOR
No antigen
Anti –A
Non-Reactive
REACTION
MINOR
Anti-A and
B-antigen
Reactive
REACTION
Anti-B
 Even if the minor reaction is reactive, the amount of blood donated (Blood bag:
~250 cc) is much lesser than the blood present in the patient’s body (~3 L) so the
plasma of the recipient will just be degraded; manifested by some reactions like
itching.
 Type O = UNIVERSAL DONOR
 Type AB = UNIVERSAL RECIPIENT (it does not contain antibodies)


Rh Antigens: C D E c d e
Rh + if the patient has D antigen (type D antigen is more widely prevalent and
more antigenic than other Rh antigens)

Transfusion reactions:
o ABO is IMMEDIATE because the antibodies are IgM
o Rh is DELAYED because the antibodies are IgG

Formation of Anti-Rh agglutinins
o Usually occurs when an Rh (-) individual receives a blood that is Rh (+)
o Initially, nothing will happen to the recipient because the generation of
antibodies is delayed.
o (+) anti- Rh will develop in 2-4 months
o After 2-4 months and the recipient receive an Rh (+) blood again 
Agglutination = Fatal because antibodies have already formed

Hemolytic disease of the newborn:
o
If the baby is Rh (+) and the mother is Rh (-), the blood of the baby can mix
with the blood of the mother and the mother will develop an immune
response to produce antibodies against the fetal RBCs
7|CKRP
o
If the fetal RBCs are destroyed by the maternal antibodies 
ERYTHROBLASTOSIS FETALIS
 “Erythroblastosis” – because of rapid production of red cells, many
early forms of RBCs like nucleated blastic forms go into the circulation
o
o
o
o


Components of Erythroblastosis fetalis:
o The baby develops ANEMIA  Inc. workload  heart failure
o Severe anemia  Backflow of blood  dec blood in the tissues
o Congestion relatively around the heart, abdomen  FETAL HYDROP
o In Anemia (hematopoietic tissues attempt to replaced hemolyzed RBCs) 
Enlarged spleen and liver  Extramedullary hematopoiesis  Inc blood 
bilirubin is produced  bilirubin is deposited in the brain
 Kernicterus – permanent mental impairment or damage to motor
areas of the brain because of precipitation of bilirubin in the neuronal
cells causing destruction
o Inc capillary hydrostatic pressure  hydrops, ascites, pleural effusion, scalp
edema
Management of Rh Incompatibility
1. Rho-gam
o Rh immunoglobulin globin – Anti-D antibody
o Incidence of erythroblastosis fetalis has decreased a lot because of RHOGAM
o Before it was introduced, Rh (-) pregnant women have 99% chance of
delivering a newborn with haemolytic disease, manifesting anemia and
erythroblastosis fetalis
o Rh (+) blood is given to a donor (usually male) who is Rh (-)  production of
antibodies  antibodies will be taken = Rho-gam
o Male donors of Rho-gam would no longer have a chance to receive Rh (+)
blood again because they are already sensitized to Rh (+)
o Donors usually have high circulating levels of Anti-D
o
Rho-gam covers fetal RBCs and prevents the fetal RBCs to be recognized by
the maternal immune system
Routine Antenatal Prophylaxis:
th
 Rho-gam is given to pregnant women at around 28 week of
pregnancy, intramuscular (mixing of the blood of the mother and baby
th
usually occur around the 28 week of pregnancy) - a single dose of
300 ug
 The effectivity of Rho-gam is only 12 weeks so if the mother have not
nd
yet delivered by 40 weeks, the 2 dose of Anti-D Ig should be given
Postnatal prophylaxis:
nd
 If the mother had already delivered before 40 weeks and the 2 dose
nd
is not yet given, the 2 dose (single dose of 300 ug) should be given
within 72 hours following the delivery of an Rh (+) infant (if the
nd
newborn is found to be Rh – then there’s no point of giving the 2
dose)
The first thing to do upon discovering that the pregnant woman is Rh (-) is to
get the blood type of the partner because if the partner is also Rh (-), Rhoth
gam is not given at 28 week
Rho-gam is given during the first pregnancy because even if the development
st
of the antibodies is delayed and the 1 pregnancy is not affected, the mother
should not be immunized and should not develop antibodies that might react
nd
during the 2 pregnancy
2. Exchange transfusion
o Getting the blood of the baby and transfuse an Rh (-) blood to prevent
destruction and when the antibodies have already been removed then the
transfusion is stopped
o The baby will still produce Rh (+) blood but the main purpose of exchange
transfusion is to remove the antibodies

How would we know if the baby is Rh (+) while an Rh (-) mother is still pregnant?
o Invasive: pierce through the uterus and get blood form the umbilical cord;
but there are many complication possible through this method
o So, we don’t necessarily have to do the invasive method as long as we know
that the mother is Rh (-) and the partner is Rh (+) because there is a high
chance that the baby will be Rh (+)

Why are we not as concerned with ABO blood reaction as Rh reactions?
o It is not a concern because in ABO blood groups, the antibodies are IgM
which are too large to cross the placenta; In Rh blood groups it is IgG
8|CKRP
BLOOD PHYSIOLOGY
o
PART 2: Platelets, Hemostasis, and Blood Coagulation
Lectured by: Dr. Olivar

Platelets/ Thrombocytes
o Small, non-nucleated, colorless bodies, ranging in size from 1-4 um
o Formed in the bone marrow from megakaryocytes
o Normal value: ~ 150,000 – 300,000
o Half-life in the blood: 8-12 days
o Thrombocytopenia – lower than the normal values
o Thrombocytosis – higher than the normal values
o The primary function is to achieve HEMOSTASIS
 Formation of the platelet plug
 Participates in blood coagulation
 Release thromboxane A2 and serotonin  Local vasoconstriction
 Release thrombostenin  Clot retraction
o Functional characteristics:
 Actin and myosin molecules  contractile protein
 Thrombosthenin  contractile protein
 RER and Golgi complex  synthesize enzymes and store large
quantities of Ca
 Mitochondria  ATP and ADP
 Prostaglandins  local hormone that cause many vascular and other
local tissue reactions
 Fibrin-stabilizing factor  blood coagulation
 Growth factor  cellular growth that will eventually help repair
damaged vascular walls
 Glycoproteins  in cell membrane; adherence to injured areas of
vessel wall
 Phospholipid  in cell membrane; activate multiple stages in bloodclotting process
Platelets secrete thromboxane A2 and serotonin which helps in the
vasoconstriction
B. PLATELET PLUG FORMATION
o Whenever the collagen on the blood vessels is exposed due to damage in the
blood vessels  platelets are attracted to the area  platelet plug
o Platelets + Collagen fibers
 Swell
 Numerous pseudopods protruding
 Release of granules with multiple active factors
 Sticky (to adhere to collagen and von Willebrand factor)
 Secrete ADP
 Form thromboxane A2
o If the damage is only small, the platelet plug formation is already enough 
hemostasis
o Importance: closing minute ruptures in very small blood vessels that occur
many thousand of times daily
o Dec platelet or Adequate amount of platelet but the quality is poor 
Manifestations of multiple lesions: Purpura (bigger) and Petechiae
o IDIOPATHIC THROMBOCYTOPENIC PURPURA – dec platelet; autoimmune
disease; have several hematoma in the body
C. BLOOD COAGULATION
o Occurs during severe trauma: 15 – 20 seconds
o Minor trauma: 1-2 minutes
o Procoagulant: promote coagulation; predominated in blood stream
o Anticoagulant: inhibit coagulation; dominate and activated in damaged tissue

Mechanism of coagulation:
HEMOSTASIS
- prevention of blood loss

3 mechanisms:
o Local vasoconstriction
o Platelet plug
o Blood coagulation
o Eventual growth of fibrous tissue into the blood clot to close the hole in the
vessel permanently
A. LOCAL VASOCONSTRICTION
o a reflex response from local myogenic contraction of the blood vessel
st
o 1 line in hemostasis
o
o
Formation of prothrombin activator or prothrombin converting enzyme
 Rate-limiting factor
Prothrombin  Thrombin
9|CKRP
o
o

 with sufficient amount of CA++
 Prothrombin is formed by the liver
 Vit K: required by the liver for normal production of prothrombin and
other clotting factors
Fibrinogen  Fibrinogen monomer (not a stable clot due to weak non
covalent hydrogen bond)  polymerization through a coagulation factor
called factor XIII  Fibrin polymer (covalent bonds and multiple crosslinkages)
 Clot is composed of meshwork of fibrin fibers with trapped RBCs,
platelets and plasma
 Fibrinogen is also formed by the liver
Clot retraction
 Activation of thrombostenin, actin, and myosin
 Edges of broken blood vessels are pulled together  Hemostasis
Initiation of clotting process:
o Extrinsic pathway
 trauma to the vascular wall and adjacent tissues
o Intrinsic pathway (true pathways by which you can actually stimulate the clot
to form)
 contact of the blood with damaged endothelial cells / collagen
 trauma to the blood
 most are inactive forms of proteolytic enzymes
 concerted to active forms  successive, cascading reaction of clotting process

 common pathway: formation of prothrombin activator
Extrinsic pathway (coagulation is easily formed)
1. Trauma in the vascular wall or tissue  release of tissue factor (Factor III Thromboplastin)
o With PHOSPHOLIPIDS in the membrane
o With LIPOPROTEIN COMPLEX – proteolytic enzyme
2. Factor VII  activated Factor VII
10 | C K R P
3. Thromboplastin (lipoprotein complex) + activated Factor VII + presence of
Ca++: Factor X  activated Factor X
4. activated Factor X + thromboplastin (phospholipid) + Factor V: Prothrombin
activator
5. Platelet phospholipid + presence of Ca++: Prothrombin  Thrombin
6. Inactive Factor V + Thrombin  Acitvated Factor V (accelerator of Prothrombin
activation)
7. Fibrinogen  Fibrin
* It is the Factor Xa that is considered as the Prothrombin activator


Roles of Ca++ and platelets:
o serve as cofactor for the coagulation pathways
o Even if the coagulation factors are adequate in number, but the platelet
count is decreased or platelets have poor quality or the Ca++ is decreased 
clot will not be produced
o Principle behind anticoagulants used in laboratory:
 Citrate (blue top): de-ionizes Ca++
 Oxalate (gray top): precipitates Ca++
 Anticoagulants remove Ca++ from the blood sample
 Reducing the Ca++ concentration below the threshold level for clotting

Clot retraction
Intrinsic pathway (coagulation proceeds much slower)
1. Blood trauma or exposure of blood to collagen: Factor XII  Factor XIIa
o Simultaneously, platelets are damaged  release of platelet
phospholipids w/ platelet factor 3
2. Factor XI  Factor XIa
o Requires HMW (high molecular weight) Kininogen
o Accelerated by Prekallikrein
3. Factor IX  Factor IXa
4. Factor IXa + Factor VIII + platelet phospholipids: Factor X  Factor Xa
o Platelet phospholipids are from the traumatized platelets
o Factor VIII: ANTIHEMOPHILIC FACTOR
o Hemophilia: absence of factor VIII
5. Factor Xa + Factor V + Platelet phospholipid  Prothrombin activator
6. Prothrombin  Thrombin
7. Fibrinogen  FIbrin
o
o

“As the clot retracts, the edges of the broken blood vessel are pulled
together, thus possibly or probably contributing to the ultimate state of
hemostasis ”
Platelets contact  vessels are pulled together  re-epithelize 
hemostasis
Lysis of blood clot:
o Plasminogen/Profibrinolysin (inactive form)  Plasmin/Fibrinolysin
o by Tissue plasminogen activator (t-PA) - released by the endothelial cells of
the damaged blood vessel
o In commercial substances called Streptokinase which are given to patients
that suffered from heart attack or myocardial infarction (blood clot blocked
one of the major coronaries that supplies the heart)  lysis of the clot and
normal perfusion is maintained due to PLASMIN and not streptokinase
11 | C K R P
o
o

Plasmin dissolved the clot; Streptokinase immediately converts plasminogen
to plasmin
Plasmin can only lyse/dissolve the clot if the clot had not yet stabilized. If the
clot is already stabilized, even if Streptokinase is given and plasmin is
produced  clot would no longer be dissolved

Functions of Plasmin:
o digest fibrin fibers
o digest fibrinogen, Factor V, VIII, XII and prothrombin
o “to remove clots from the vessels that eventually would become occluded
were there’s no way to clean them”

Prevention of Blood Clotting in the Normal Vascular System – The Intravascular
Anticoagulants:
o endothelial surface factors
 smoothness of the endothelial cell surface  prevent contact
activation of the intrinsic clotting system
 glycocalyx  prevents clotting factors from attaching
 thrombomodulin  binds thrombin  thrombomodulinthrombin complex activates protein C  inactivates Factor Va
and VIIIa; present only in an intact endothelium
o anti-thrombin action of fibrin and anti-thrombin III
 85-90% of thrombin becomes absorbed to the fibrin fibers
 anti-thrombin III: blocks the effect of thrombin to fibrinogen
and inactivates them
o Heparin
 By itself it has no or little anticoagulant properties but when
combined with antithrombin III  greatly increases the
effectiveness in removing thrombin
 Formed by basophilic mast cells
2.
Coagulation Disorders
A. Coagulation deficiencies
1. Bleeding caused by Vit K deficiency
 Vit K is continuously synthesized by intestinal bacteria
 Liver produces Factors IX, X, VII, II, protein C through
carboxylation (liver carboxylase) aided by Vit K
 Once the coagulation factors are already carboxylated  Vit K
becomes inactive
 Vitamin K epoxide reductase complex 1 (VCOR c1)  reduces
Vit K back to its active form
 One of the fat soluble vitamins: can only be absorbed in the
presence of fat
 Fats cannot be absorbed in the intestine without bile because
bile emulsifies fat
3.
Vit K deficiency may be due to failure of the liver to secrete bile
or obstruction of bile duct caused by liver diseases
 If a patient has gallstones  removal of gall bladder  no Vit K
deficiency because bile is secreted from the liver and goes
directly to the intestines; gall bladder is just a storage of bile
 When the common bile duct is cut  bile will not be delivered
 If the common bile duct is accidentally cut during surgery,
duodenum is attached to the liver so that there will be supply of
bile
 In newborn, initially they don’t have intestinal bacterial flora 
Vit K injection is administered
Hemophilia
 sex-linked disease: only manifested in males but from the
chromosomes of female carriers
 85%: absence of Factor VIII = HEMOPHILIA A or CLASSIC
HEMOPHILIA
 15%: absence of Factor IX
 Treatment: Recombinant Factor VIII
Thrombocytopenia
 Presence of very low number of platelets in the circulating
blood
 Treatment: fresh whole blood transfusion with large numbers
of platelets and splenectomy
B. Coagulation excess
 Artherosclerotic plaque  Hypertension (dec diameter of blood vessels)
 Rupture in the lumen of blood vessels  collagen is exposed  abnormal
thrombus formation  myocardial infarction
 Treatment: genetically-engineered T-PA  dissolve intravascular clot
1.
2.
Thrombus
 an abnormal clot that develops in a blood vessel
Emboli
 freely flowing clots
 due to roughened endothelial surface of vessel
12 | C K R P







3.
4.
o
o
o
exemplified by formation of clot coming from the deep veins of
the leg  Pulmonary embolism
left side of the heart  Stroke
due to slow blood flow  clot forms and settles in the valves 
clot is thrown by the blood flow into distal areas  Embolus 
goes up to block pulmonary capillaries  PULMONARY
EMBOLISM
It usually occurs in capillaries rather that in arteries because of
the small diameter of capillaries
Theoretically (under normal condition), it is not possible to see
a clot that originated from the deep vein of the leg go into the
left side of the heart because once it has blocked the pulmonary
capillaries it can no longer go on and proceed to the left side of
the heart
However it is still possible when there is communication
between the chambers of the heart = Ventricular septal defect
It is also possible in tetralogy of fallot wherein the right
ventricular pressure is greater than the left; bidirectional flow
 Blood will flow from right to left
Infarct
 tissue devoid of blood supply
Disseminated Intravascular Coagulation
clotting mechanism becomes activated in widespread areas of the
circulation
Sepsis
 Bacteria release toxins (endotoxins)  activate blood clotting
mechanisms
 Treatment: antibiotics
Abruptio placenta
 If there is clot, plasmin will dissolve it  placenta and bacteria
will produce clot again  it will be dissolved again by the
placenta  coagulation factors are already consumed 
CONSUMPTIVE coagulopathy
 Treatment: Antibiotic or removal of placenta

Anticoagulants for clinical use:
1. Heparin
o Mode of action: potentiates the action of antithrombin III
o Heparin-antithrombin III complex blocks factors XII, XI, IX, X and II
o Antidote: protamine sulphate
o Action lasts for 1.5 to 4 hrs and then destroyed in the blood by
HEPARINASE
2. Coumarin/ warfarin
o Mechanism of action: blocks the action of vitamin K
o Inactivates VCOR C1  Vit K will not be reduced back to its active form
 Coagulation factors will not be activated

Blood coagulation tests
1. Bleeding time
o pierce the tip of the finger or lobe of the ear
o bleeding ordinarily lasts for 1 to 6 minutes
o Prolonged bleeding time: Lack of any one of several of the clotting
factors and lack of platelets.
o Inaccurate because it is operator-dependent
13 | C K R P
o
TEST for QUALITY of PLATELETS: if platelets are of good quality, they will
perform platelet plug formation  bleeding will stop
2. Clotting time
o Collect blood in a chemically clean glass test tube and then to tip the
tube back and forth about every 30 seconds until the blood has clotted
o time needed for blood to clot
o NV: 6 - 10 minutes
o test for clotting factors
3. Prothrombin time
o test for quantity of prothrombin in the blood (E)
o NV: 12 seconds
4. Partial thrombolastin time
o Test the intrinsic pathway of coagulation
God looks down from heaven on the entire human race to see if
anyone is truly wise. And the truly wise person is the one who seeks
Him.
= Psalm 53:2=
14 | C K R P
PHYSIOLOGY – A
Blood Physiology pt. 1
Dr. Joseph U. Olivar (JUO)
I. Functions of the Blood
1. Keeps the internal environment of the body constant
(Homeostasis)
2. Transport O2 from lungs to the tissues and CO2 from the
tissues to the lungs (Respiratory)
3. Carries nutritive materials from intestines to all parts of the
body (Nutritive)
4. Carries waste products of tissue metabolism to the
kidneys (Excretory)
5. Transports Internal secretions from endocrine glands to
the tissues on which the effects are exerted
(Endocrinology)
6. Acid base balance maintenance
7. Water and electrolyte balance and total osmotic pressure
regulation
8. Immunity to diseases
9. Body temperature regulation
II. Normal Blood volume

Commonly: Males- 5 liters, Females- 4.5 liters

Composition: 60% Plasma, 40% Formed elements

Centrifuged:
o Upper portion- Plasma
o Buffy coat/ White substance- contains WBC and
Platelets
o Bottom – RBC, most dense
III. Composition of Blood
A. Plasma

Water: 91-92%

Plasma proteins
o Albumin: responsible for maintaining osmotic
pressure, transport of bilirubin and other drugs
o Alpha Globulin & Beta Globulin: antibodies;
some are transport proteins
o Y- Globulin: immunoglobulins
o Fibrinogen: participates in blood coagulation
o Complement proteins: important inflammation &
destruction of organisms

Blood sugar: Glucose

Lipids: Cholesterol, Phospholipids, Neutral fats

Salts: Na, K, Cl, HCO3, Phosphates

Gases: O2, CO2, Nitrogen

Special Plasma Substances: Hormones, Enzymes,
Antibodies
Functions of Plasma
1.
Maintenance of Water balance between
intravascular compartment and extravascular
spaces (Proteins serves as solutes that
maintains plasma inside blood vessel)
Example: ↓Plasma proteins inside blood
vessel = Higher PP in the interstitial space,
Plasma will exit in the interstitial spaces
(Osmosis)
Clinical Correlation: Edema (due to
depleted plasma proteins secondary to liver
disease)
Galolo, Matias, Viacrusis, Zaragoza
MD-1C 2019
Lec 10 - 20 Aug 2015
2.
3.
4.
5.
6.
7.
Contributes mainly in the Blood viscosity
Source of Antibodies
Necessary for coagulation
Maintains acid-base balance
Determines specific gravity of plasma
Formation of enzymes; transport
hormones and enzymes
of
B. Buffy Coat

Thin gray- white layer between plasma and hematocrit

Makes up 1 % of blood sample

Leukocytes and platelets
C. Serum

Liquid portion of clotted blood

Contains growth factors and other proteins released
from platelets
D. Formed Elements

RBCs (Erythrocytes)

WBCs (Leukocytes)

Platelets ( Thromobocytes)
o Came from same pluripotent hematopoietic
stem cell







IV. Erythrocytes (RBC)
50% protein , 40 % lipids, 10 % carbohydrates
Biconcave, non- nucleated, not spherical, 2.5um thick, 7.58um in diameter, 0.74 thick at center
Pliable/very deformable
Carries hemoglobin (Hgb) in the circulation (primary
function)
o 1gm of Hgb →1.34 ml of O2
Non-nucleated in the circulating blood
o RBC Count
12
1. Men: 5-6 x 10 /L
12
2. Women: 4-5 x10 /L
12
3. Infants: 6.5x10 /L
o Hgb Normal Values
1. Men- 14 to 17g/dl
2. Women- 12 to 15 g/dl
o Hematocrit (Hct) Normal Values
1. Men- 0.40 to 0.50
2. Women- 0.38 to 0.48
Anemia: Any value lower than normal limit of RBC and
Hgb
Polycythemia: Any value higher than limit of RBC and
Hgb
RBC Formation

Genesis of red blood cells in various parts of the body as a
person progresses through different life stages

Extramedullary hematopoiesis
o The body attempts to maintain erythrogenesis in
response to an alteration in the normal production of
RBC
Page 1 of 7
PHYSIOLOGY – A
Blood Physiology pt. 1
Dr. Joseph U. Olivar (JUO)

Table 1. Red cell production
Stage Of Life
Organ Responsible For
Red Cell Production
8 weeks of
embryonic life or
first 2 months
Yolk sac (primitive ad nucleated
RBC are produced)
Middle trimester of
pregnancy
Liver- main organ for production of
RBC
Spleen
Lymph node
rd
3 trimester of
pregnancy and after
birth
Bone marrow takes over
20 years and above
Vertebrae, ribs, sternum, ilia, bone
marrow of the skull
Figure 1. Relative rate od RBC prod in bone marrows at
different ages.



Lec 10 - 20 Aug 2015
Pluripotential hematopoietic stem cell
o all the cells of the circulating blood are eventually
derived
Proerythroblast
o committed stem cell to become RBC
Basophil erythroblast
o “first generation cells”
o Contains basic dyes
Reticulocyte
o first cell to release in the circulation
o After 2 days the cytoplasmic materials are gone
and mature non-nucleated erythrocytes are
produced.
o During this stage the cell pass from the bone
marrow into the blood capillaries by diapedesis.

Erythrocyte
o no nucleus  nucleus extruded

Erythropoiesis
o
process of red cell production
RBC Maturation

Vitamin B12 and Folic Acid (Pteroylglutamic Acid)
o Important for final maturation of RBC
o essential for the synthesis of DNA(required for the
formation of thymidine triphosphate)
o Lack of VitB12 and Folic acid
1. abnormal DNA
2. failure of nuclear maturation and cell division
3. erythropoiesis proceeds slowly
4. macrocytes
5. structural abnormalities

Pernicious Anemia
o Poor absorption of Vit B12 in the GI Tract
o Atrophic mucosa that fails to produce normal gastric
secretion
o Lack of intrinsic factor
Absence of IF  malabsorption of B12  B12
deficiency  Pernicious Anemia Megaloblastic
Anemia

Sprue
o  intestinal absorption of folic acid and vitamin B12
Control Of Red Cell Production
1. Stimulation by Hypoxia

anemia

↓ Blood flow

Poor blood flow

↓ Altitude

Pulmonary diseases
2. Inhibition by rise in circulating RBCs
3. Control by circulating hormone called erythropoietin

Synthesized by both kidneys (90%) and liver
(10%)

principal stimulus for RBC production

increases production of proerythroblast
Figure 2. Stages in RBC formation.
Galolo, Matias, Viacrusis, Zaragoza
MD-1C 2019
Page 2 of 7
PHYSIOLOGY – A
Blood Physiology pt. 1
Dr. Joseph U. Olivar (JUO)
Ensures an adequate number of red cells is
always available to provide sufficient
transport of oxygen
Cells must not become too numerous that
they impede blood flow




Example:

Living in high altitudes where oxygen is not as
abundant as in low lands  more RBC is produced

Patients with TB have normal blood levels and oxygen
levels in blood but suffer from impaired oxygen
absorption in the lungs. Thus, the body triggered to
produce more blood
Note: Tissue Oxygenation—most essential regulator of RBC
production



RBC Destruction

Life Span: 120 days

Destruction: 1% red cells replaced daily
o Total red cell volume replaced every 4 months

Site of destruction: Spleen

Hypertonic solution: causes shrinkage of RBC

Hypotonic solution- causes swelling and rupturing

Isotonic solution- no change; equilibrium; 0.9% NaCl, 5%
Dextrose
Lec 10 - 20 Aug 2015
15-30% in the form of ferritin (storage form in the liver)
4% in the form of myoglobin (hemoglobin in the muscle)
1% other heme compounds
Primary source is from the diet: Organ meat, Red meat,
Oysters
Diet: 1mg of Fe/day
Figure 4. Absorption of Iron from GIT


Formation of Hgb


Liver secretes apotransferrin into the bile, which flows
through the bile duct into the duodenum. In the Duodenum
apotransferrin binds with Iron to form transferrin and is
released into the blood
Apotransferrin from the liver combines with in the small
intestine and they are usually absorbed in the duodenum.
Cases:
o Iron Replete

Person has plenty of Iron in the blood
(Iron is stored in the intestinal mucosa)
o Hemoglobin content is Depleted or Person is
anemic

Iron is immediately combined to form
transferrin and transferrin readily
donates Iron to form hemoglobin
o Iron supplementation

only needed by persons who need it ex.
Anemic
Women are prone to Fe deficiency anemia due to
menstruation
Elimination of Iron
Figure 3. Hemoglobin formation.


The primary function of red blood cells is to transport Hgb
which in turn carries oxygen from the lungs to the tissues
and the carbon dioxide back from the tissues to the lungs
There are 4 iron molecule in 1 Hemoglobin (2 beta, 2
alpha)
Iron




Essential for the formation of hemoglobin and other
essential elements
There are 4 Fe in one adult Hemoglobin
Approximately 4-6 grams in the human body
Majority is in the form of hemoglobin (65% or 2/3)
Galolo, Matias, Viacrusis, Zaragoza
MD-1C 2019


Only 1mg of Iron is eliminated per day
Elimination via:
o
Stool: trace amounts are lost in the bile
o
Urine
o Sweat
o Menstruation
Clinical Correlations

Underproduction/ Over Desctruction of RBC= Anemia

Over production of RBC= Polycytemia

A person found in the emergency room
complains of difficulty in breathing presents with
severe palor (anemia)
Page 3 of 7
PHYSIOLOGY – A
Blood Physiology pt. 1
Dr. Joseph U. Olivar (JUO)
o
For you to correct the anemia you have
to find the cause
o Physician will usually request a
peripheral blood smear (PBS)
Results:
o Iron Deficiency= RBC’s are Microcytic
Hypochromic
o Vit. B12/ Folic Acid Deficiency= RBC’s
are Macrocytic Hyperchromic
Anemia

Deficiency of RBC

Too rapid loss/ slow production of RBC

Blood loss/ Fe deficiency
1. Aplastic Anemia

Bone marrow disorder (Cannot produce blood
cells)
2. Megaloblastic Anemia

Macrocytic and Hyperchromatic (Vit. B12 & Folic
acid Deficiency)

Pernicious Anemia
o
condition characterized by absence of
parietal glands in the stomach, which is
needed for the secretion of Intrinsic
Factors (IF helps in the absorption of Vit.
B12)

Sprue
o due to decrease intestinal absorption/
malabsorption of Folic Acid and Vit. B12
3. Hemolytic Anemia

RBC’s rupture prematurely

Hereditary Spherocytosis
o RBC’s are spherical because SodiumPotassium Pump is not functioning.
+ +
+
o Function of Na -K Pump is to bring Na
out of the cell’s membrane. In Hereditary
+
Spherocytosis Na stays inside the cell
causing more water to go into the cell,
causing the spherical shape of the cell.
4. Sickle Cell Anemia

RBC’s are sickle shaped

Abnormal type of hemoglobin: Hemoglobin S

Prone to hemolysis
Effects of Anemia on Circulatory System
1. Decreased viscosity of blood; Decreased resistance =
rapid blood flow
2. Hypoxia; Vasodilation of Blood Vessels=more blood
goes to the heart
3. Will cause increased heart rate/ increased workload
on the heart
Note:

Younger individuals can tolerate anemia

Older individuals (60-70) should not be left without
treatment because anemia may cause cardiac arrest
to individuals with weaker hearts.
Galolo, Matias, Viacrusis, Zaragoza
MD-1C 2019
Lec 10 - 20 Aug 2015
Polycythemia

Over Production of RBC
o Second Degree Polycythemia

Normal individual but situation dictates
to produce more RBC

Ex: Living in high altitudes, smoking,
having pulmonary diseases
o Polycythemia Vera

genetic aberration

No inhibition of erythropoietin

No inhibition of hemoglobin production

Increase in RBC does not inhibit
production
3

Blood count: 7to 8 Million/mm

Blood viscosity is increased; resistance
is increases= sluggish blood flow

Prone to clotting

Decreased heart workload

Treated
by
frequent
Phlebotomy
(Removal of 500cc of blood every other
month)
A.
V. The ABO System
Inheritance of the ABO Blood groups

An individual inherits one ABO gene from each
parent and that these two genes determine which
ABO antigens are present on the RBC membrane

ABO is codominant in expression

O gene is considered a silent gene or an
amorph as no detectable antigen is produced in
response to inheritance of these gene

An individual who has a phenotype A can have a
genotype AA or AO. An individual who has a
phenotype B can have a genotype BB or BO. In
case of O individual, both phenotype and
genotype are the same (OO) because that
individual would have to be homozygous for the
O gene. The phenotype and genotype are also
the same in an AB individual because of the
inheritance of both A and B gene. (Harmening,
2005)
Figure 4. Blood type Punnett Square for offspring
Page 4 of 7
PHYSIOLOGY – A
Blood Physiology pt. 1
Dr. Joseph U. Olivar (JUO)
Lec 10 - 20 Aug 2015
VI. Blood Typing / Blood Matching
B.
ABO Antibodies – Agglutinins

Present in serum/plasma

naturally occuring antibodies directed against A
and/or B antigen(s) absent from their RBCs.

Predominantly IgM

Titer: at birth, quantity of agglutinins are almost
zero. An infant begins to produce agglutins 2-8
months after birth. Maximum titer is usually
reached at 8-10 years of age and gradually
declines throughout the remaining years of life.
(Guyton, 2016)
C.
A and B Antigens – Agglutinogens

present on the surfaces of RBCs

Two antigens (type A and type B) are present on
the surfaces of RBCs (Guyton, 2016)

Often cause blood cell agglutination
Procedure
1. RBCs are first separated from the plasma and diluted
with saline solution
2. One portion is then mixed with anti-A agglutinin and
another portion with anti-B agglutinin
3. After several minutes, mixtures are observed under a
microscope.
4. Results:
Positive Result: With agglutination; RBCs have become
clumped= Ab-Ag reaction has resulted
Negative Result: without agglutination; homogenous mixture
(macroscopically)
Figure 6. Positive
demonstrations.

Figure 5. ABO Blood System Antigens and Antibodies.
Table 2. ABO antigens and antibodies.
BLOOD TYPE
A
B
AB
O
Note:



Agglutinogen
Agglutinin
(Antigen)
(Antibody)
present in Red
present in
Cell
Plasma
A
Anti – B
B
Anti – A
AB
none
UNIVERSAL RECIPIENT
none
Anti - A, Anti-B
UNIVERSAL DONOR
and
negative
(L)
Agglutination
Direct/Forward Blood Typing
o known anti-A and anti-B typing antiserums for
testing unknown RBCs
o Patient RBCs mixed with commercial antisera A
and B
Indirect/Reverse Blood Typing
o Patient serum is mixed with blood that is known
to be either type A or B and observed for
agglutination reaction
Table 3. Reactions in DIRECT/FORWARD blood typing
Blood Type
Anti – A Sera
Anti – B Sera
A
+
+
-
+
+
-
B
AB
O
In the RBC surface: Antigen(s) is/are present which
determines the individual’s blood type
In plasma/serum: Antiboby is present which is
directed against the antigen present in the RBC
surface.


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(R)
MD-1C 2019
Errors in blood transfusion may result in:
1. Agglutination
2. Hemolysis - destruction of RBC membrane by
phagocytes and antibodies
3. Renal shutdown
High-standard precautions exist to prevent errors in
blood transfusion since even marginal errors may prove to
be fatal for the patient receiving the blood.
Page 5 of 7
PHYSIOLOGY – A
Blood Physiology pt. 1
Dr. Joseph U. Olivar (JUO)
Lec 10 - 20 Aug 2015
Formation of Anti-Rh Agglutinins
Donor
Rh (+)
1.
2.
3.
Recipient
Rh (-)
Recipient
(+) anti-Rh in 2-4 months
Donor’s blood containing Rh factor is injected into a
person whose blood does not contain the Rh factor.
Anti-Rh agglutinins develops slowly on recipient’s blood,
reaching maximum concentration of agglutinins about 2-4
months later.
Rh-negative individual eventually becomes strongly
“sensitized” to Rh factor
Erythroblastosis Fetalis

Hemolytic disease of the Newborn (HDN)

Disease of the fetus and newborn child characterized by
agglutination and phagocytosis of the fetus’s RBCs
Baby’s blood
Rh (+)
Mother’s blood
Rh (-)
Anti-Rh
IgG’s
ATTACK

Figure 7. Results in direct or forward blood typing


VII. The Rh System
Primary cause of hemolytic disease of the newborn,
also known as Erythroblastosis fetalis and significant
cause of hemolytic transfusion reactions (Harmening,
2005
Rh Antigens
o Six (6) common types of Rh antigens called Rh
factor
C, D, E, c, d, e
o

A person with C antigen does not have c antigen
(same with D-d and E-e antigens)
o Each person has one of each of the three pairs of
antigens
o D antigen – more antigenic than the other Rh
antigens
o Rh positive: individual with D antigen
o Rh negative: without D antigen
Rh Antibodies

IgG in nature, can cross the placenta

Produced following exposure of the individual’s
immune system to foreign RBCs, through either
transfusion or or pregnancy.

Highly immunogenic
D > c > E >C > e
Note: Immunogenicity of common Rh antigens; D is the most
potent
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MD-1C 2019
This occurs when
o Mother: Rh negative
o Father: Rh positive
o Child: Rh positive
1. Baby’s blood (which is Rh positive) mixes with the
mother’s blood (Rh negative)
2. Mother will be sensitized, producing anti-Rh
antibodies
3. Anti-Rh Abs (which are IgG in nature) will diffuse
through the placenta into the fetus and cause HDN
Clinical picture of HDN/ Erythroblastosis fetalis

Anemic at birth

Liver and spleen become greatly enlarged

Presence of nucleated blastic forms of RBCs in
peripheral
blood
smear
(thus
the
name
erythroblastosis felatis)

Kernicterus – permanent mental impairment because
of precipitation of bilirubin in the neuronal cells
Management of Rh incompatibility
1. Exchange Transfusion

Rh (+) antibodies present in blood are removed during
birth, then replaced with Rh (-) blood to stop
interaction of antibodies with Rh (+) cells

Baby is allowed to produce its own Rh (+) antibodies
2.
Administration of Rho-gam ( Rh immunoglobulin)

Anti-D antibody that is administered to the expectant
mother starting at 28 to 30 weeks of gestation.

Also administered in Rh negative women who deliver
Rh positive babies to prevent sensitization of the
mother to D antigen.
Page 6 of 7
PHYSIOLOGY – A
Blood Physiology pt. 1
Dr. Joseph U. Olivar (JUO)
Table 4. Summary of the difference between ABO system and Rh
System
ABO
Mostly IgM
Antibodies are naturally
occuring
Rh
IgG
Person must first be
massively exposed to an Rh
antigen to cause a significant
transfusion reaction to
develop
Plasma agglutinins
responsible for causing
transfusion reactions
develop spontaneously
Spontaneous agglutinins
almost never occur
Table 5. Differences between ABO and Rh HDN
ABO HDN
Mother: Type O
Father: Type A/B/AB
Child: Type A or B
First pregnancy is affected
Destruction of fetal RBCs
leading to severe anemia is
rare
Bilirubin at birth is in normal
range
Rh HDN
Mother: Rh negative
Father: Rh positive
Child: Rh positive
First born infant is
unaffected because the
mother has not yet been
immunized; succeding
children are affected (if rhogam is not administered
during the first pregnancy)
Anemia is common
Bilirubin at birth is elevated
** In case the mother is Rh
positive and baby is Rh
negative, the baby and the
mother are unaffected
because no reaction will
occur. The baby cannot
produce antibody during this
stage.
Blood Compatibility

Present in Red Cell: antigen

Present in Serum: antibody
Major Crossmatch

PSDR: Patient’s Serum + Donor’s Red Cells
Minor Crossmatch

PRDS: Patient’s Red Cells + Donor’s Serum
VIII. Transfusion Sample Cases
Case 1: Type B patient x Type A donor

Present in patient RBC: B antigen

Present in patient serum: Anti-A

Present in donor RBC: A antigen

Present in donor serum: Anti-B
Galolo, Matias, Viacrusis, Zaragoza
MD-1C 2019

Lec 10 - 20 Aug 2015
Major Crossmatch:
PSDR: Anti-A Ab in serum of patient + A Ag in red cell
of Donor
Result: (+) Agglutination = incompatible
Minor Crossmatch:
PRDS: B Ag in red cell of patient + Anti-B Ab in serum
of donor
Result: (+) Agglutination = incompatible
In case 1, the blood types are incompatible. Do not
proceed with the transfusion.
Case 2: Type B patient x Type O donor

Present in patient RBC: B antigen

Present in patient serum: Anti-A

Present in donor RBC: none

Present in donor serum: Anti-A and Anti-B
Major Crossmatch:
PSDR: Anti-A Ab in serum of patient + No Ag in red
cell of Donor
Result: (-) Agglutination = compatible
Minor Crossmatch:
PRDS: B Ag in red cell of patient + Anti-A and Anti-B
Abs in serum of donor
Result: (+) Agglutination = incompatible
 In Case 2, you may proceed with transfusion. Patient may
suffer slight itchiness as reaction to small amounts of
antibodies from donor cell, which will easily be diluted in
patient’s serum. Type O is the universal donor.
Case 3: Type AB patient x Type A donor

Present in patient RBC: A and B antigens

Present in patient serum: none

Present in donor RBC: A antigen

Present in donor serum: Anti-B
Major Crossmatch:
PSDR: No Abs in serum of patient + A Ag in red cell
of Donor
Result: (-) Agglutination = compatible
Minor Crossmatch:
PRDS: A and B Ags in red cell of patient + Anti-B Ab
in serum of donor
Result: (+) Agglutination = incompatible
 In Case 3, you may proceed with transfusion. you may
proceed with transfusion. Patient may suffer slight
itchiness as reaction to small amounts of antibodies from
donor cell, which will easily be diluted in patient’s serum.
Type AB is the universal recipient.
REFERENCES
Old transes
Hall, J. E., & Guyton, A. C. (2011).
Blood cells, Immunity and Blood coagulation. Guyton and Hall
textbook of medical physiology.,
PPT by Dr. Olivar
Harmening, Modern Blood Bank and Transfusion practice.
Laboratory Manual and Lecture guide in Physiology (20122013).
Page 7 of 7
BLOOD (PLATELETS)
Dr. Olivar
PLATELETS (THROMBOCYTES)
-just like RBC, the main sources of platelets are the Pluripotent
Hematopoietic Stem Cell (PHSC) in the bone marrow.
-The precursor of platelets is called MEGAKARYOCYTES.
-very big cells which fragments to minute platelets.
PLATELETS
-DESCRIPTION: small, non-nucleated, colorless bodies
-main function: to achieve hemostasis
-Size: 1-4 um.
-Normal Values: 150,000 – 300,000
↓ = Thrombocytopenia (more important)
-decreased platelets = abnormal bleeding
-ex: Dengue
↑ = Thrombocytosis
FUNCTIONS: Hemostasis
1. Releases thromboxane A2  LOCAL VASOCONSTRICTION
2. Formation of PLATELET PLUG
3. Participates in BLOOD COAGULATION
4. Clot Retraction (by secreting “Thrombosthenin")
HEMOSTASIS –prevention of blood loss
3 Mechanisms:

LOCAL VASOCONSTRICITON
-a reflex response from local myogenic contraction of the
blood vessel
-1st line in hemostasis
-to prevent blood loss
*PLEASE REMEMBER*
Substances released by PLATELETS aiding in local vasoconstriction:
a. Thromboxane A2
b. Serotonin
* the 2 substances that helps the blood vessels to constrict in the 1 st
line of hemostasis
c. Factor 13: Fibrin Stabilizing Factor (FSF)

PLATELET PLUG FORMATION
Damaged vascular surface (exposed collagen from
endothelium)
↓
Platelets are attracted to the area
↓
Platelets swell, grow pseudopods, sticky, forms thromboxane
A2
↓
PLATELET PLUG FORMATION
-important in controlling/closing numerous minute fractures
in many small blood vessels that may occur many times daily
-They don’t have enough platelets that can perform the
function of platelet plug formation.

BLOOD COAGULATION
-3rd mechanism for hemostasis
-GOAL: to form a CLOT
Mechanism of Coagulation
3 Essential Steps:
1. The formation of PROTHROMBIN-CONVERTING ENZYME
or prothrombin activator
-readily converts prothrombin to thrombin
-(*RATE-LIMITING STEP*; PROTHROMBIN ACTIVATOR is
the RATE LIMITING ENZYME)
-once formed, Step 2,3 will automatically occur  fibrin
(clot)
-with the help of CALCIUM and PLATELET PHOSPHOLIPIDS
 Step2
2. The conversion of PROTHROMBIN to THROMBIN by this
agent.
-thrombin readily converts fibrinogen to fibrin
3. The conversion of FIBRINOGEN to FIBRIN clots thru the
action of THROMBIN.
PROTHROMBIN ACTIVATOR is generated
↓
Prothrombin is readily converted to thrombin under the help
of calcium and platelet phospholipid
↓
Thrombin once generated, will convert fibrinogen to fibrin
* the first fibrin generated from this reaction is just a fibrin
monomer (not a stable clot)
↓
The fibrin monomer must polymerize as fibrin polymer
through FIBRIN STABILIZING FACTOR (Factor XIII)
-released by platelet
-activated by thrombin
↓
Once polymerized, it forms CLOT (composed of fibrin
polymers running in all directions trapping within RBC’s,
PLATELETS and PLASMA)
↓
STOP BLEEDING
-IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP):
decreased platelet counts
-Manifestations: multiple lesions/hemorrhages
-Petechiae (smaller)
-Purpura (bigger)
1
BLOOD (PLATELETS)
Dr. Olivar
CLOTTING FACTORS IN THE BLOOD AND THEIR SYNONYMS
CLOTTING
SYNONYMS
FACTOR
Factor I
Fibrinogen
Factor II
Prothrombin
Factor III
Tissue Factor, Thromboplastin
Factor IV
Calcium
Proaccelerin, Labile Factor, Ac-globulin
Factor V
(Ac-G)
Serum prothrombin conversion
Factor VII
accelerator (SPCA), Proconvertin, Stable
Factor
Antihemophilic factor A, Antihemophilic
Factor VIII
factor (AHF); antihemophilic globulin
(AHG)
Antihemophilic factor B, Plasma
Factor IX
thromboplastin component (PTC),
Christmas factor
Factor X
Stuart-Power Factor
Antihemophilic factor C, Plasma
Factor XI
thromboplastin antecedent (PTA)
Factor XII
Hageman Factor, Contact Factor
Factor XIII
Fibrin Stabilizing Factor (FSF)
Prekallikrein
Fletcher Factor
Fitzgerald Factor, HMWK (high-molecularHMMK
weight kininogen)
platelet
*MEMORIZE!
*NO FACTOR VI
-these coagulation factors are plasma proteins; they are
synthesized mostly in the liver.
-they exist in blood vessel (plasma) in INACTIVE FORM.
-whenever the vessel is damaged, and one of the factors is
stimulated, they are converted to ACTIVE ENZYMES 
eventually forms the clot by converting fibrinogen to fibrin

EVENTUAL GROWTH OF FIBROUS TISSUE INTO THE BLOOD
CLOT TO CLOSE THE HOLE IN THE VESSEL PERMANENTLY
INITIATION OF THE CLOTTING PROCESS

Trauma to the vascular wall and adjacent tissues
(EXTRINSIC)

Contact of the blood with damaged endothelial cells/
collagen (INTRINSIC)

Trauma to the blood (INTRINSIC)
* EXTRINSIC and INTRINSIC pathways generate the PROTHROMBIN
ACTIVATOR.
EXTRINSIC PATHWAY
Stimulated by trauma to the vascular wall and adjacent tissues
↓
Starts with the release of Factor 3 (Tissue Factor/ Thromboplastin)
combines with Factor7
↓
F3 + F7 = activates Factor 10 to ACTIVATED FACTOR 10A
↓
Activated F10A converts Prothrombin to Thrombin
↓
Thrombin converts Fibrinogen to Fibrin
↓
Hence, the PROTHROMBIN ACTIVATOR is ACTIVATED FACTOR 10A
↓
FACTOR 5 accelerates the action of activated Factor 10A in converting
Prothrombin to Thrombin
* The action of F5 is possible if it is stimulated by THROMBIN
- significance:
the extrinsic pathway to begin with is very slow until the first
thrombin is generated
↓
once generated, it activates F5
↓
action of prothrombin activator is enhanced (factor 10)


Extrinsic pathway only makes two factors: Factor3 and
Factor7 to generate the prothrombin activator.
Extrinsic factor is short because tissue trauma is the one
stimulating this.
2
BLOOD (PLATELETS)
Dr. Olivar
INTRINSIC PATHWAY
*When blood is placed in these test tubes, the blood will
not clot because Ca++ is removed. Without Ca++, both
extrinsic and intrinsic pathways will not occur.
 NO CLOT FORMATION.
*Purpose of ANTI-COAGULANTS.
REVIEW/OVERVIEW:
PLATELETS.
FUNCTIONS: Hemostasis
1. LOCAL VASOCONSTRICTION
2. Formation of PLATELET PLUG
3. Participates in BLOOD COAGULATION
4. Clot Retraction (by secreting “Thrombosthenin")

It is stimulated by contact of the blood with damaged endothelial
cells/ collagen; trauma to the blood
↓
Starts with Factor12
↓
Activates Factor11
↓
Activates Factor9
↓
Activated F9 + Activated F8 = converts F10 to Activated Factor10A
↓
Again, Activated Factor10A is the Prothrombin Activator
HEMOPHILIA

Lacks FACTOR8.

Without F8, nothing can combine with F9  cannot convert F10
to Activated F10A.

Makes them prone to bleeding.
BOTH IN EXTRINSIC AND INTRINSIC PATHWAY, CALCIUM AND
PLATELETS ARE INVOLVED IN THE REACTION.

Even if the coagulation factors are complete, WITHOUT CALCIUM
AND PLATELETS, the coagulation pathways will NOT OCCUR or
will be impaired bleeding

It is rare to decrease the Calcium level in the blood. However, we
can remove the Calcium from the blood by placing it in a tube
with anticoagulant.

BLUE TOP: contains CITRATE - de-ionizes Calcium

GRAY TOP: contains OXALATE – precipitates Calcium
CLOT RETRACTION
-4th function of platelets.
-Serum
When blood is placed in a tube that does not contain an anticoagulant, soon it will clot. After sometime, the clot will retract and it
will extrude the serum.
↓
The blood clot that retracted, all coagulation factors are included.
Serum has no coagulation factor.




Clot retraction is a function of platelets because platelets
secrete a substance called THROMBOSTHENIN.
Platelets also have actin and myosin causing the platelets to
contract.
When the clot retracts, the serum is extruded and all the
coagulation factors are in that clot.
The SERUM CANNOT CLOT because the clotting factors are
all trapped in the clot.
COMPARED WITH PLASMA
If plasma is placed in a tube with anti-coagulant and placed in a
centrifuge, plasma will separate with RBC’s.
↓
Plasma contains coagulation factors, plasma can CLOT.
* SERUM cannot clot; produced by putting in a plain tube
* PLASMA can clot; produced if the blood is anticoagulated
3
BLOOD (PLATELETS)
Dr. Olivar
“As the clot retracts, the edges of the broken blood vessel are pulled
together, thus contributing still further to hemostasis.”
When clot is formed – no bleeding; but vessel is still damaged
↓
Clot needs to retract so the edges will be pulled together to reepithelialize = purpose of Clot Retraction = function of Platelets
↓
Purpose of clot in a damaged vessel: PREVENT BLOOD LOSS
Purpose of clot in a repaired vessel: NONE
↓
CLOT SHOULD BE LYSED

LYSIS OF BLOOD CLOT
INTRAVASCULAR ANTICOAGULANTS:
1. Endothelial Surface Factors

Because the endothelium of blood vessels is smooth due to
the layer of glycocalyx, there is no clotting because the
clotting factors are repelled by the glycocalyx.
Thrombin in the circulation
↓
Function of Thrombomodulin:
binds to any Thrombin that is circulating  inactivates thrombin
Thrombomodulin + Thrombin = Protein C (another anticoagulant)  deactivates Factor5, Factor8
* When blood vessels are smooth, it will not clot because it will repel
the coagulation factors
Plasminogen (INACTIVE in plasma)
↓
Once the vessel has repaired itself, t-PA is released by the damaged
endothelial cells converting plasminogen to PLASMIN
↓
Plasmin will dissolve the clot
*When the smoothness of the endothelium is damaged, the
glycocalyx and thrombomodulin factors are negated, thus clot occurs
* Once collagen is exposed, it stimulates Intrinsic Pathway beginning
with Factor12  forms thrombus
2.
Anti-thrombin action of fibrin and anti-thrombin III

FIBRIN itself deactivates the THROMBIN formed.

Anti-thrombin III, together with Heparin = causes the blood
not to clot.
FUNCTIONS OF PLASMIN:

Digest fibrin fibers

Digest fibrinogen, Factor 5, 8, 12 and prothrombin
3.
Heparin
*PLASMIN dissolves the clot
*t-PA only accelerates the conversion of plasminogen to plasmin
1.
PURPOSE OF PLASMIN:

to dissolve the fibrin fibers including coagulation factors

to remove clots from the vessels
Tissue Plasminogen Activator: ex. Streptokinase, Urokinase
o CASE: Heart attack
- cause: clot develops in major coronary supply of the heart
 blocks the blood flow
- if given with Streptokinase  immediately converts
plasminogen to plasmin  plasmin will dissolve the clot 
re-establish blood flow
COAGULATION DISORDERS:
COAGULATION DEFICIENCY- bleeding
a. Bleeding caused by Vitamin K deficiency
VITAMIN K: continuously synthesized by the normal flora in
the intestine.

Factors 9, 10, 7, 2 = dependent on VitK for them to be
produced

Protein C
“to remove the clots from the vessels that eventually would
become occluded where there is no way to clean them.”


Clotting does not occur normally because of the presence of
intravascular anti-coagulants.
In normal conditions (blood vessels are not damaged, anticoagulants pre-dominate more than pro-coagulants.
Liver produces plasma proteins or the coagulation factors. But for
Factors 9,10,7,2 to be activated, LIVER CARBOXYLASE enzyme uses
VitaminK.
ONCE the factors ACTIVATED, VITAMIN K is oxidized and rendered
NON-FUNCTIONAL.
4
BLOOD (PLATELETS)
Dr. Olivar
Vitamin K Epoxide Reductase Complex1 (VCOR c1) reduces back VitK
to its functional form.


ATHEROSCLEROTIC PLAQUE
-accumulation of cholesterol crystals beneath the intimal layer of
the blood vessel.
VitK is a fat-soluble vitamin

For it to be absorbed, it has to be absorbed with
fat

To absorb fat, bile is needed from the liver

NO bile  NO fat absorption  NO vitK
absorption
-Manifestations: Hypertension – because the blood vessel
diameter is decreased.
-Danger:
atherosclerosis can rupture
↓
breaks into the lumen of the blood vessel
↓
collagen is exposes
↓
stimulates Intrinsic Pathway (F12)
↓
formation of clot
↓
blocks blood flow
↓
infracted tissue
CAUSES OF VITAMIN K DEFICIENCY:

Liver diseases
- cannot synthesize plasma proteins
- cannot secrete bile  cannot absorb fat  cannot
absorb vitK


Seen among newborns
- GIT is still sterile
- 1st: dry the baby; 2nd: inject vitK
- to prevent intracerebral hemorrhage among newborns
b.
Hemophilia
- lacks Factor8 (85%); Factor9 (15%)
- Male ONLY; sex-linked disease
- Disease resides in the X-chromosome
- FEMALE are never affected because they have two
(XX); the other X can compensate; CARRIERS ONLY
- MALE offspring are affected because they only have
one (XY); once affected, patient manifest hemophilia
- TREATMENT: give RECOMBINANT FACTOR8 (very
expensive)
c.
2.
Blockage in the production of bile
- If gall bladder is removed, there will be NO bleeding
problems because LIVER is the one producing BILE
- Problems in bleeding will only arise if common hepatic
duct is cut  bile cannot flow to the intestine  no fat
absorption  no vitK absorption  bleeding problems.
Thrombocytopenia
COAGULATION EXCESS- abnormal clotting
a. Thrombus: an abnormal clot that develops in a blood vessel
-When clots are carried away by the blood flow  embolus
b.
Emboli: freely flowing clots
-blocks blood flow; tissue is devoid of blood flow 
infarcted
c.
Infarct: tissue devoid of blood supply
Blood Vessel Layers:
- Tunica Intima: location of atherosclerotic plaque- SUB-INTIMAL layer
- Tunica Media
- Tunica Adventitia

EMBOLISM
- exemplified by a clot developing on the deep veins of the leg
- accumulation of thrombus can be carried away by the blood 
embolus
- travels up to the main vessels  inferior vena cava  lungs 
PULMONARY EMBOLISM
- usual origin of pulmonary embolism: DEEP VEINS of the legs
- it will lodge on the PULMONARY CAPILLARIES because the
vessels are VERY SMALL
- after OR, early ambulation is necessary because tasis of blood
can cause formation of clots
* Any clot originating from the deep vein of the legs, is it possible to
see the clot on the left side of the heart?
- in normal conditions: No, because clot will just be stuck in the
pulmonary artery
- in Tetralogy of Fallot: Yes, there is reversal of flow; R ventricular
pressure is greater than the L ventricle
- in Atrial Fibrillation: spontaneously a clot can be developed in the
mitral valve
Activated Factor10A that can be stimulated by intrinsic and extrinsic
pathway
↓
Both pathways can activate the prothrombin activator
↓
Cleaves factor2 to thrombin
↓
Cleaves factor1 to fibrin
↓
st
1 result is a fibrin monomer; must polymerize to become a stable
clot which is brought about by factor13
↓
Fibrin polymers trap within are RBC, platelets, plasma
↓
The clot formed in the mitral valve can be thrown again as an
embolus
↓
CEREBRAL VESSELS
most common cause of stroke
5
BLOOD (PLATELETS)
Dr. Olivar
* Deep vein  Pulmunory embolism
* Left side of the heart  Stroke

2.
DISSEMINATED INTRAVASCULAR COAGULATION
- a clotting mechanism which becomes activated in widespread
areas of the circulation
- CAUSES:
a. Sepsis
- cause: bacterial toxins
- when there is overwhelming infection, the toxins
generated by the bacteria can stimulate the clotting
mechanism  clotting widespread in the circulation
- TREATMENT: massive antibiotics
b. Abruptio placenta
- premature detachment of placenta
- placenta is a tissue; a good source of “Tissue Factor” or
Factor3 which can stimulates Extrinsic Pathway 
D.I.C.
- Pathophysiology:
widespread stimulation of the coagulation pathway which will
produce clots in the circulation
↓
body will sense it and produce massive PLASMIN (fibrinolysin) to lyse
the clot
↓
but since the placenta is still present, it will generate another
widespread clotting
↓
plasmin will lyse again (VISCIOUS CYCLE of clot-lysis)
↓
until coagulation factors are already consumed
↓
results to bleeding = D.I.C. aka “CONSUMPTIVE COAGULOPATHY”
-TREATMENT:
- remove the PLACENTA
- supportive transfusions: (coagulation factors in the form of:)
fresh frozen plasma, cryoprecipitate
- anti-coagulants must NOT be given in DIC because giving of
anti-coagulants will accelerate death due to bleeding
ANTI-COAGULANTS FOR CLINICAL USE
1. HEPARIN
- produced naturally by basophils
- MODE OF ACTION: potentiates the action of ANTITHROMBIN III
- in itself is not a good anti-coagulant; if combined with
naturally-occurring ANTI-THROMBIN III (Heparin-Antithrombin Complex)  blocks FACTORS 12, 11, 9, 10, 2
- ANTIDOTE: PROTAMINE SULFATE
COUMADIN/ WARFARIN
-MODE OF ACTION: block the action of Vitamin K
Blocks the action of VCOR c1 enzyme
↓
Vitamin K will not be reduced back to its functional
form
↓
NO VitK = NO coagulation factors will be produced
BLOOD COAGULATION TESTS: to assess the coagulation competency
of an individual.
1. BLEEDING TIME
- fingertip is pricked
- time bleeding lasts (when the bleeding will stop)
- Normal Value: 1-6 minutes
- Operator-dependent; this method was abandoned; no
longer used
* TEST for QUALITY of PLATELETS: if platelets are of good
quality, they will perform platelet plug formation  bleeding will
stop
* TEST for QUANTITY of PLATELETS: Platelet Count (CBC)
2.
CLOTTING TIME
- putting blood in a non-anticoagulated test tube (plain
tube)
- time needed for blood to clot is assessed
- Normal Value: 6-10 minutes
*TEST FOR CLOTTING FACTORS
3.
PROTHROMBIN TIME (PT)
- TEST for QUANTITY of PROTHROMBIN in the blood
(EXTRINSIC PATHWAY)
- Normal Value: 12 seconds
[PET]
4.
PARTIAL THROMBOPLASTIN TIME (PTT)
- TESTS the INTRINSIC PATHWAY of coagulation
[PITT]
6
PHYSIOLOGY – A
Blood Physio pt. 2



Dr. Joseph U. Olivar (JUO)
I. Platelets (Thrombocytes)
Platelets (also called thrombocytes) are minute discs 1 to
4 micrometers in diameter.
They are formed in the bone marrow from
megakaryocytes,
The normal concentration of platelets in the blood is
between 150,000 and 300,000 per microliter.
Characteristics
Platelets have many functional characteristics of whole cells:

Non- nucleated, small, colorless bodies

Minute discs, 1-4 micrometer in diameter

Originates from the bone marrow
o Exists in the form of megakaryoctes and will
fragment to form platelets before being released
to blood circulation

Normal value: 150,000- 300,000

Thrombocytopenia: < 150,000
o at risk for bleeding due to lack of clotting factors
which are platelets
o Dengue Hemorrhagic Fever

Thrombocytosis: > 300,000
Functions

Actin and Myosin molecules, which are contractile proteins
and thrombosthenin, that can cause the platelets to
contract

Residuals of both the endoplasmic reticulum and the Golgi
apparatus that synthesize various enzymes storage of
large quantities of calcium ions.

Mitochondria and enzyme systems that are capable of
forming adenosine triphosphate (ATP) and adenosine
diphosphate (ADP)

Enzyme systems that synthesize prostaglandins, an
important protein called fibrin-stabilizing factor.
o A growth factor that causes vascular endothelial
cells, vascular smooth muscle cells,
o Fibroblast: helps repair damaged vascular walls.

Hemostasis – blood loss prevention
o The arrest of bleeding. Three processes acts to
stem the flow of blood: vasoconstriction, platelet
aggregation and blood coagulation




II. Platelet Aggregation and Clotting
Damage to the endothelium of a blood vessel causes
platelets to adhere to the site of injury. The adherent
platelets release adenosine diphosphate and thromboxane
A2, which cause additional platelets to adhere.
Platelets are prevented from aggregating along the length
of a normal vessel by the anti-aggregation action of
prostacyclin.
Also release serotonin which enhances vasoconstriction
and thromboplastin which hastens blood coagulation.
When the platelet count is low, as in thrombolytopenic
purpura, tiny hemorrhages (petechiae) or large
Mejia, Racho, Sanico, Villaflores
MD-1C 2019
Lec 11 - 25 Aug 2015
hemorrhages (ecchymoses) may appear in the skin and
mucous membranes.
Vasoconstriction

Immediately after a blood vessel has been cut, the trauma
to the vessel wall causes the smooth muscle in the wall to
contract; this instantaneously reduces the flow of blood
from the ruptured vessel.

The contraction results from
1. Local myogenic spasm
2. Local autacoid factors from the traumatized
tissues and blood platelets,
3. Nervous reflexes; initiated by pain nerve impulses
or other sensory impulses that originate from the
traumatized vessel or nearby tissues.

Responsible for much of the vasoconstriction by releasing
a vasoconstrictor substance, thromboxane A2.

The more severely a vessel is traumatized, the greater the
degree of vascular spasm.

Platelets come in contact to the vascular wall, the platelets
immediately change and they begin to swell; their
contractile proteins contract forcefully and cause the
release of granules that contain multiple active factors;
become sticky so that they adhere to collagen in the
tissues and to a protein called von Willebrand factor

ADP and thromboxane – activates nearby platelets, and
adds to the stickiness of these additional platelets

During blood coagulation, fibrin threads form. These attach
tightly to the platelets, thus constructing an unyielding
plug.
The Cell Membrane

Its surface is a coat of glycoproteins that repulses
adherence to normal endothelium and yet causes
adherence to injured areas of the vessel wall, especially to
injured endothelial cells and even more so to any exposed
collagen from deep within the vessel wall.
What is a clot?

mesh of fibrin polymers that trap RBC (red blood cells) and
platelets to prevent loss of blood
Steps in Blood Clotting
1. Local vasoconstriction/vascular spasm
o First line of defense
o Physical injury to a blood vessel elicits a
contractile response of the vascular smooth
muscle and thus narrowing of the vessel.
o Platelet secretion: thromboxane a2 and
serotonin
2.
Platelet plug formation
o Second line of defense
o The platelet membrane contains large amounts of
phospholipids that activate multiple stages in the
blood-clotting process
Page 1 of 4
PHYSIOLOGY – A
Blood Physio pt. 2
o
o
3.
Dr. Joseph U. Olivar (JUO)
When endothelium of vessel is damaged,
collagen is exposed, therefore attracting platelets
to form a plug.
Petechiae (small) and purpura (multiple
hemorrhages found on the skin)
Lec 11 - 25 Aug 2015
reactions. Therefore, in the absence of calcium ions, blood
clotting does not occur.
Blood Coagulation
o Third line of defense
o Bleeding stops; closure of injured vessel occurs
o Begins to develop in 15 to 20 seconds if the
trauma to the vascular wall has been severe, and
in 1 to 2 minutes if the trauma has been minor.
2+
Anticoagulants – remove Ca from blood which causes no
clotting of blood
o Citrate (deionize Calcium)
o Oxalate (precipitate Calcium)
Note: in transfusion, give patient CALCIUM to prevent
bleeding.
Intrinsic Mechanism for Initiating Clotting
1. Blood trauma causes activation of Factor XII and
release of platelet phospholipids.
o Trauma to the blood or exposure to vascular wall
collagen alters two important clotting factors in
the blood: Factor XII and the platelets.
2.
Activation of Factor XI
o The activated Factor XII acts enzymatically on
Factor XI to activate this as well, which is the
second step in intrinsic pathway. This reaction
also requires HMW (High molecular weight)
kininogen and is accelerated by prekallikrein.
3.
Activation of Factor IX
o The activated Factor XI then acts enzymatically
on Factor IX to activate this factor also.
4.
Activation of Factor X – role of Factor VIII
o The activated Factor IX, acting in concert with
activated Factor VIII and with the platelet
phospholipids and factor 3 from traumatized
platelets, activates Factor X.
5.
Action of activated Factor X to form prothrombin
activator – role of Factor V
o Activated Factor X combines with Factor V and
platelet or tissue phospholipids to form the
complex called prothrombin activator. The
prothrombin activator in turn initiates within
seconds the cleavage of prothrombin to form
thrombin, thereby setting into motion the final
clotting process.
Role of Calcium Ions in the Intrinsic and Extrinsic pathway

Except for the first 2 steps in the Intrinsic pathway, calcium
ions are required for promotion or acceleration of all the
Mejia, Racho, Sanico, Villaflores
MD-1C 2019
Figure 1. Blood clotting.

The key step in blood clotting is the conversion of
fibrinogen to fibrin by thrombin. The clot formed by this
reaction consists of a dense network of fibrin strands in
which blood cells and plasma are trapped.
Clot Lysis

Blood clots may be liquefied by a proteolytic enzyme
called plasmin.

Normal blood contains plasminogen, an inactive precursor
of plasmin.

Activators of the conversion of plasminogen to plasmin are
found in tissues, plasma and urine (urokinase).
Rate-Limiting Steps

Formation of prothrombin activator/ prothrombin
converting enzyme

Prothrombin converted to thrombin (via Prothrombin
activator which is an enzyme)

Thrombin converts fibrinogen to fibrin (forms unstable clot)

Fibrin monomer – will polymerize via factor XIII or Fibrin
Stabilizing Factor
Table 1. Clotting Factors In the Blood And Their Synonyms
Factor
I
II
III
IV
V
VII
VIII
Synonyms
Fibrinogen
Prothrombin
Tissue Factor/ Thromboplastin
Calcium
Labile factor; Proaccelerin
Stable factor; Proconvertin
Antihemophilic factor
Page 2 of 4
PHYSIOLOGY – A
Blood Physio pt. 2
IX
X
XI
HMW
Kininogen
Platelets
Dr. Joseph U. Olivar (JUO)


Antihemophilic B factor; Christmas
factor
Stuart factor
Plasma
Thromboplastin
Antecedent
Fitzgerald Factor
III. Coagulation Pathways
Production of prothrombin factors

The 2 coagulation pathways converge on the activation of
factor X, which catalyzes the cleavage of prothrombin to
thrombin.
Intrinsic Pathway

Is initiated by exposure of the blood to a damage
endothelium or a negatively charged surface.

When the endothelium of blood vessels is damage, blood
comes into contact with collagen. Outside the body,
clotting can occur when blood comes into contact with
negatively charged surfaces such as glass.

After a clot is formed, the actin and myosin of the platelets
trapped in the fibrin mesh interact in a manner similar to
that in muscle. The resultant contraction pulls the fibrin
strands towards the platelets, and thereby extrudes the
serum (plasma without the fibrinogen) and shrinks the clot.
This process is called clot retraction.

Several cofactors are required for blood coagulation; the
most important is calcium. If the calcium ions in the blood
are removed or bound, coagulation will not occur.
1.
2.
3.
4.
5.
6.
7.
8.
Figure 2. Coagulation cascade demonstrating intrinsic, extrinsic,
and common pathways.
9.
The Extrinsic Pathway

Extrinsic pathway only makes two factors: Factor 3 and
Factor 7 to generate the prothrombin activator.

Extrinsic factor is short because tissue trauma is the
one that stimulates its occurrence
o Initiated by tissue damage and the release of
tissue thromboplastin

Stimulated by trauma to the vascular wall and adjacent
tissues

Starts with the release of Factor 3 (Tissue Factor/
Thromboplastin) + Factor 7

F3 + F7 = activates Factor 10 to activated factor 10A

Activated F10A converts Prothrombin to Thrombin

Thrombin converts Fibrinogen to Fibrin

Note: Prothrombin Activator = Activated Factor 10A

Factor 5 accelerates the action of activated Factor 10A in
converting Prothrombin to Thrombin
o The action of F5 is possible if it is stimulated by
thrombin
Significance

The extrinsic pathway to begin with is very slow until
the first thrombin is generated


Mejia, Racho, Sanico, Villaflores
MD-1C 2019
Lec 11 - 25 Aug 2015
Once generated, it activates F5
Action of prothrombin activator is enhanced (factor
10)


Blood trauma or contact with collagen: activates Factor XII
Factor XII → XIIa
Factor XI → XIa
Factor IX → IXa
Factor VIII → VIIIa
Factor VII → VIIa
Factor VII with Factor III will convert Factor X → Xa
Xa (Prothrombin Coverting Factor)
o Splits prothrombin → thrombin
o Thrombin (Factor II → IIa)
Thrombin converts Fibrinogen → Fibrin
IV. Clot Retraction and Lysis
Thrombosthenin from platelets causes clot retraction
Serum: cannot clot ( due to coagulating factors trapped in
hematocrit layer)
Plasma: can clot (coagulating factors present)
Final event in clot repair → Lysis of clot
o How?

Plasminogen → Plasmin via TPA or
Tissue Plasminogen Factor
Anticoagulation Mechanisms in Cells

Glycocalyx – repels coagulation factors

Thrombomodulin – prevents coagulation
o Activates Protein C: deactivates FACTOR V and
VIII

Fibrin – natural occurring anticoagulant and has antithrombin functions

Anti-thrombin 3 – combines with heparin resulting to a
potent anticoagulant
Page 3 of 4
PHYSIOLOGY – A
Blood Physio pt. 2
A.
B.
Dr. Joseph U. Olivar (JUO)
Lec 11 - 25 Aug 2015
IV. Clinical Correlations
Coagulation deficiencies

Greater risk of bleeding

Vitamin K: synthesized by the intestinal flora; a fat
soluble vitamin

Vitamin K-dependent Factors: II, VII, IX, X
o (synthesized in the liver through the enzyme
liver carboxylase, Vitamin K will be oxidized
and becomes useless)
1. Vitamin K epoxide reductase complex
o Reactivates Vitamin K to its functional
form
2. Interventricular Hemorrhage
o No intestinal flora to produce Vitamin K;
seen in newborns
3. Hemophilia
o No Factor VIII and IX
4. Thrombocytopenia
o Lack of platelets causing bleeding
disorder
Anticoagulants in Use

Heparin
o potentiates the action of anti- thrombin 3 to block
factors XII, XI, IX, X, II
o Antidote: Protamine Sulfate

Coumadin/Warfarin
o
inhibits Vitamin K epoxide reductase → no
production of factors II, VII, IX, X
o imitates VCOR1
o Antidote: Vitamin K
Coagulation excess

Formation of unnecessary clots
1. Thrombus
o Abnormal clot formation
2. Embolus
o Traveling thrombus
o Can cause infarction
o Can dislodge in the smallest capillaries
in the lungs producing pulmonary
embolism
o Usually formed in the lower extremities
since stasis is very common in this area
o Can cause stroke when thrombus
dislodges in the mitral valve (left side of
the heart) which can dislodge and go to
the cerebral vessels
3. Atherosclerosis
o Rupture in the tunica intima of the blood
vessels causing activation of the intrinsic
pathway
o Can cause heart failure since it can
impede blood circulation
o Factor XIII – stabilizes clot

(Once clot has stabilized,
giving medications such as
streptokinase
is
rendered
useless)
4. Disseminated Intravascular Coagulation
o Results from widespread sepsis
5. Abruptio Placenta
o Results from sepsis during pregnancy;
detachment of placenta from the uterus
o Treatment: removal of the cause

antibiotics or remove placenta
3.
Mejia, Racho, Sanico, Villaflores
MD-1C 2019
Note: Blood coagulation can be prevented in vitro by the
addition of citrate or oxalate, which removes the calcium ions
from solution.
1.
2.
V. Clinical Procedures and Tests
Bleeding Time
o Test for platelet quality
o Normal value: 1-6 minutes
Platelet count
o
Test for platelet quantity
Clotting Time
o Test for clotting factors
o Normal value: 6-10 minutes
a. Prothrombin Time (PeT)
o
test for extrinsic pathway
b. Partial Thromboplastin Time (PiTT)
o
test for intrinsic pathway
References
Blood Physio PPT
Adarve, Normel C. (RMT, ASCP), Guide Notes & Laboratory
Workbook on Hematology, 2011.
Hall, John E. Guyton and Hall Textbook of Medical Physiology.
Twelfth. Philadelphia: Saunders Elsevier, 2011.
Page 4 of 4
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
WHITE BLOOD CELLS (WBC) / LUEKOCYTES

Unlike RBC’s and platelets, WBC’s are NUCLEATED.

Based on presence of granules: GRANULOCYTES and
AGRANULOCYTES

GRANULOCYTES:
 Neutrophils: engulf bacteria and cellular debris
(phagocytosis)
 Basophils: weak phagocytes; HYPERSENSITIVITY; release
histamine; secretes naturally-occurring anticoagulant,
HEPARIN
 Eosinophils: weak phagocytes; PARASITIC INFECTIONS;
allergic response

AGRANULOCYTES:
 Lymphocytes: B, T-lymphocytes (IMMUNOLOGY)
 Monocytes: engulf cellular debris (phagocytosis); antigen
processing

Normal Values: WBC- 5-10 x 109/L

Leukocytosis: abnormal ↑ in the no. of WBC’s; (+)
infection

Leukopenia: WBC count less than normal

In an overwhelming SEPSIS, WBC’s are called to action
and all are consumed
=↓WBC count
DENGUE: characteristic WBC is leukopenia


Also arise from the Pluripotent Hematopoietic Stem Cell (PHSC)
in the bone marrow.
LOCATION
GRANULOCYTES
MONOCYTES
LYMPHOCYTES
Originate in the bone
marrow;
Found in the circulation
Originate in the bone
marrow;
Placed in lymphoid tissues
(lymph nodes, tonsils,
spleen, thymus, appendix,
peyer’s patches)
3.
“Third, the immune system of the body develops antibodies against
infectious agents such as bacteria. The antibodies then adhere to the
bacterial membranes and thereby make the bacteria especially
susceptible to phagocytosis. To do this, the antibody molecule also
combines with the C3 product of the complement cascade. The C3
molecules, in turn, attach to receptors on the phagocyte membrane,
thus initiating phagocytosis. This selection and phagocytosis process
is called OPSONIZATION.”
How does phagocytosis occur? [video]
PHAGOCYTES:
1. NEUTROPHILS
- phagocytic
- active in the blood
- constantly formed in the bone marrow where they
develop and mature
- mature neutrophils circulate in the blood for 3-12 hours;
then, they move to other tissues where they will survive for
only 2-3 days
- acts as surveillance cells searching for infections
- contains lysosomes that degrades bacteria
- after digesting the bacteria, neutrophil shrinks in size
- a single neutrophil can usually phagocytize 3 to 20 bacteria
before the neutrophil itself becomes inactivated and dies
- SECOND LINE against invading microorganisms because it
degenerates after killing the bacteria
- ACUTE INFECTIONS
2.
FUNCTIONS OF THE LEUKOCYTES: Combat Infection

Destroy the invading agents by phagocytosis

Form antibodies and sensitized lymphocytes
PHAGOCYTOSIS (Cellular Ingestion)
- Phagocytes must be selective of the material that is phagocytized;
otherwise, normal cells and structures of the body might be ingested
- Normal tissues are not ingested because:
1. Most normal tissues have smooth surfaces
- which resist phagocytosis
- but if the surface is rough, the likelihood of phagocytosis is
increased
2.
Most natural substances of the body has protective protein
coats
- repels phagocytes
- conversely, most dead tissues and foreign particles are
rough and have no protective coats, which make them
subject to phagocytosis.
Foreign Ag + antibodies + C3
- when a foreign antigen enters the body, we mount an
immune system by producing an antibody = stimulates the
COMPLEMENT SYSTEM
- complement system brings the Antigen-Antibody complex
near the phagocyte
- phagocyte destroys the combination
- the process where the complement brings the antigenantibody complex near a phagocyte is called
OPSONIZATION.
MACROPHAGE
- phagocytic
- inactive monocytes in the blood
- monocytes must first arrive in the tissue and transform to
become MACROPHAGES before it can perform phagocytosis
- active macrophages in tissues
- they do not die in the tissues; they survive after doing
their function
- FIRST LINE OF DEFENSE
- ACUTE/CHRONIC INFECTIONS
MONOCYTE MACROPHAGE CELL SYSTEM
(RETICULOENDOTHELIAL SYSTEM)

strategically placed in PORTALS OF ENTRIES of
microorganisms

Tissue macrophage in the SKIN and SUBCUTANEOUS
TISSUES (Histiocytes)

Macrophages in the LYMPH NODES

Alveolar Macrophages in the LUNGS

Macrophages (Kupffer cells) in the LIVER sinusoids

Macrophages of the SPLEEN and BONE MARROW

Both NEUTROPHILS and MACROPHAGES can kill bacteria by
releasing BACTERICIDAL AGENTS:
1
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
BACTERICIDAL
AGENTS
Superoxide O2Hydrogen Peroxide H2O2
Hydroxyl ions OHH2O2 + Cl- -> (myeloperoxidase) ->
hypochlorite
“When tissue injury occurs, whether caused by bacteria, trauma,
chemicals, heat, or any other phenomenon, multiple substances are
released by the injured tissues and cause dramatic secondary changes
in the surrounding uninjured tissues. This entire complex of tissue
changes is called INFLAMMATION.”
INFLAMMATION is characterized by:
1. Vasodilatation of the local blood vessels with consequent excess
local blood flow.
2. Increased permeability of the capillaries.
3. Clotting of fluid in the interstitial spaces.
-because the plasma is being pushed into the interstitial space
-Plasma contains coagulation factors; thus, it can form a clot
4. Migration of large number of neutrophils and monocytes into
the tissue.
5. Swelling of the tissue.
5 Cardinal Signs of INFLAMMATION:
 the area inflamed will appear RED (RUBOR)
 due to vasodilatation, there is release of HEAT (KALOR)
 release of painful substances, causing PAIN (DOLOR)
 increased permeability of the capillaries  EDEMA
(TUMOR)
 LOSS OF FUNCTION
What is the purpose of the inflammatory process?

One of the first results of inflammation is to "wall off" the area
of injury from the remaining tissues. The tissue spaces and the
lymphatics in the inflamed area are blocked by fibrinogen clots
so that after a while, fluid barely flows through the spaces.

This walling-off process delays the spread of bacteria or toxic
products.

When neutrophils and macrophages engulf large numbers of
bacteria and necrotic tissue, essentially all the neutrophils and
many, if not most, of the macrophages eventually die. After
several days, a cavity is often excavated in the inflamed tissues.
It contains varying portions of necrotic tissue, dead neutrophils,
dead macrophages, and tissue fluid. This mixture is commonly
known as PUS.
“The intensity of the inflammatory process is usually proportional to
the degree of tissue injury.”
RESPONSE DURING INFLAMMATION:

Tissue MACROPHAGE is the FIRST LINE of defense against
infection.
because within minutes, the macrophages present in the
Reticulo-endothelial system (RES) will be activated.

NEUTROPHIL invasion of the inflamed area is a SECOND LINE of
defense
because within the first hour after the inflammatory
process, INFLAMMATORY CYTOKINES (Tumor Necrosis
Factor and Interleukin-1 - chemoattractants) will be
secreted
MARGINATION: process where the WBC’s attach to the walls of the
endothelium.
DIAPEDESIS: WBC’s squeeze through the pores of the capillaries.
CHEMOTAXIS: inflamed tissues release chemicals that attract
neutrophils and macrophages.
↓
FINAL EVENT: PHAGOCYTOSIS
-

TNF and IL-1 will attract the neutrophils to go to the
inflamed area
TNF and IL-1 also increase the expression of adhesion
molecules in the endothelium called SELECTIN and
IntraCellular Adhesion Molecule (ICAM)
Selectin and ICAM binds to NEUTROPHIL causing the
neutrophil to MARGINATE
followed by Diapedesis, then Chemotaxis
The second macrophage invasion into the inflamed tissue is the
THIRD LINE of defense.

BONE MARROW – increases its production of monocyte

Monocytes  go to the CIRCULATION  then to the
tissue as TISSUE MACROPHAGES
2
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar

Increased production of granulocytes and monocytes by the
bone marrow is the FOURTH LINE of defense.

Within 3-4 days, greatly increased production of
neutrophils and monocytes by the bone marrow.

Activated Macrophage secrete cytokines: TNF, IL-1, GCSF, M-CSF
(Granulocyte; Monocyte Colony Stimulating Factor)

Cytokines stimulate the bone marrow  ↑production of
WBC
- Therapeutic Radiation procedures: radiotherapy for cancer
(radiation is too much, enough to suppress the bone marrow 
(leukopenia)
-
Drugs: chlorampenicol (antibiotic), thiouracil (given to
hyperthyroid), chemotherapeutic agents
LEUKEMIA: uncontrolled production of WBC
cancerous mutation of a myelogenous and lymphogenous
cell (AML, ALL)
Effects of Leukemia in the body:
- metastatic growth of leukemic cells in abnormal areas of the body
- WBC’s should only be in the BONE MARROW or in the BLOOD
- Metastasis: WBC’s are found infiltrating the BONE
- infections, severe anemia, bleeding
- although WBC’s are excessively increased, they are IMMATURE
- because of the over proliferation of the WBC’s in the bone
marrow, RBC’s and platelets are displaced  patient suffers
from severe anemia and bleeding
- metabolic starvation
- cancer cells utilizing all the energy and nutrients of the body
3.
CASE:
4.
EOSINOPHILS
- weak phagocytes
- important role in ALLERGIC REACTIONS
- role in PARASITIC INFECTIONS (WORMS)
↑Eosinophil count = Parasitic infection
↑Neutrophil = Bacterial infection
BASOPHILS/ MAST CELLS
- releases HEPARIN: prevents blood coagulation
- releases HISTAMINE: involved in ALLERGIC REACTIONS
PLEASE REMEMBER!
Basophil and Mast Cells are associated closely with an
immunoglobulin (IgE)
Basophil + IgE (with antigen) = histamine
(Histamine mediates allergic reactions)

When the specific antigen for the specific IgE antibody
subsequently reacts with the antibody, the resulting attachment
of antigen to antibody causes the mast cell or basophil to
rupture and release large quantities of histamine, bradykinin,
serotonin, heparin, slow-reacting substance of anaphylaxis, and
a number of lysosomal enzymes.

These cause local vascular and tissue reactions that cause many,
if not most, of the allergic manifestations.
CLINICAL CORRELATION:
LEUKOPENIA: ↓WBC count
CAUSES:
- massive infection
- irradiation
PLEASE REMEMBER!
- Diagnostic Radiation (x-ray, CT-scan, MRI) is NOT enough to
suppress the bone marrow and cause leukopenia
3
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
IMMUNOLOGY
I. INNATE IMMUNITY
“Early defense against infections”
The INVADERS:
- Bacteria
- Viruses
- Parasites (such as fungi, protista, worms)
IMMUNITY
ability of the human body to resist almost all types of
organisms or toxins that tend to damage the tissues or
organs
ANTIGEN (Ag): antibody generation
any molecule that can bind to the components of the
specific immune response
Components of Innate Immunity:
i. Epithelial barriers
- provides physical barrier to infection
- killing of microbes by locally produced antibiotics
- killing of microbes and infected cells by intraepithelial
lymphocytes
ii. Phagocytes
- Neutrophils
- Monocytes/Macrophages
iii.
ANTIBODY (Ab)
family of defensive proteins the body makes when
stimulated by an antigen
CYTOKINES
- substances, mostly proteins, secreted by cells affecting the
behavior of nearby cells
- ex: interleukins (IL); interferons (INF)
- can be produced either by:
 INNATE IMMUNITY
o Macrophages, Natural Killer (NK) cells
o Both secrete cytokines
 ACQUIRED IMMUNITY
o T lymphocytes
INNATE IMMUNITY
 Phagocytosis by WBC’s and
macrophages
 Skin
 Acid secretion of stomach
 Presence in the blood of certain
compouns that attach to foreign
substances and destroy them
 Lysozymes
 Complement system
 NK cells
*already present, ready to protect
you even on first encounter
ACQUIRED IMMUNITY
(Adaptive Immunity)
 Immunity developed due to
previous exposure to
invading agents such as
bacteria, viruses, toxins,
foreign tissues
*lymphocytes are not ready
protect you on first encounter
*you have to be sick first; but
once you have developed the
protection, the immunity is
extremely powerful that you
might not even experience the
second disease (chickenpox)
or you might not even
experience the disease at all
(vaccination)
Dendritic Cells
- cells present in the skin; considered as bridge between
innate and adaptive immunity
- MECHANISM:
organism traversed the skin
↓
dendritic cells (cannot destroy the bacterium) will carry the organism
↓
presents the organism to the lymphocyte in the lymphoid tissue
(thus, bridging innate and adaptive immunity)
iv. Natural Killer Cells
are a class of lymphocytes that recognize infected cells,
respond by:
o
killing these cells or
o by secreting the macrophage activating cytokine
interferon gamma (IFN-ϒ)
When a macrophage ingested a microbe, macrophage cannot
degrade the organism
↓
Macrophage will secrete cytokine interleukin-12 (IL-12)
↓
Attracts natural killer (NK) cell; it will sense macrophage needs help;
secretes IFN-ϒ
↓
IFN-ϒ activates the macrophage
(ACTIVATED MACROPHAGE: secretes TNF, IL-1  attracts neutrophils
from the blood)
↓
Kills the phagocytized microbe
(*Cytokines: interleukin-12; interferon gamma)
4
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
v. The Complement System
- series of about 20 proteins, existing in a proenzyme form
(INACTIVE)
- once activated by the microorganism or antigen-antibody
complex, it can eliminate the invading microorganism
COMPLEMENT SYSTEM
 Once the microbe has escaped humoral immunity and has entered
the cell, cell-mediated immunity will now take over
o Two most predominant cells:

Cytotoxic T-cell
- directly kill the infected cell

Helper T-cell
- does not have the capability to degrade the cell
- however, once activated, it can release cytokines
which can:
o activate macrophage  cause inflammation
o proliferation of B lymphocytes and cytotoxic
T-cell and perform their actions
 Lymphocytes are also coming from the stem cell
 Once produced by the bone marrow, they are stored in the
lymphoid tissues
 But before birth, stored in the lymphoid tissues and processed first
in two organs:
- THYMUS  T-lymphocytes
- FETAL BONE MARROW  B-lymphocytes
 TWO PURPOSES OF PRE-PROCESSING OF THE LYMPHOCYTES IN
THE THYMUS, FETAL LIVER AND BONE MARROW:
1. To achieve SPECIFICITY
 1 antigen will react with only 1 lymphocyte or antibody
 Two Ways to activate:
o MICROORGANISM activates C3
-INNATE IMMUNITY
o
 Lymphocytes in the thymus and bone marrow are
presented with thousands of antigens  producing
thousands of lymphocytes
 1 antigen : 1 lymphocyte
ANTIGEN-ANTIBODY COMPLEX activates C1
-ACQUIRED/ADAPTIVE IMMUNITY
2.
Cytokines present in Innate Immunity
Interleukin 12 (IL-12)
Interferon gamma (IFN-ϒ)
Interleukin 1 (IL-1)
Tumor Necrosis Factor (TNF)
To achieve TOLERANCE
 The lymphocytes and antibodies must not react with
own cells
 Lymphocytes in the thymus and bone marrow are
presented with own cells
expected reaction: lymphocytes must not react
Once the lymphocytes react with own cells, it will be
destroyed
II. ACQUIRED IMMUNITY
a property of lymphocytes (T, B lymphocytes)
TWO BASIC TYPES OF ACQUIRED IMMUNITY
1. CELL-MEDIATED IMMUNITY (T lymphocytes)
= Activated lymphocytes
 Process of tolerance is only 90% perfect
- explains the occurrence of AUTOIMMUNE
DISEASES
2. HUMORAL IMMUNITY (B lymphocytes)
= Antibodies
MICROBE
RESPONDING
LYMPHOCYTES
EFFECTOR
MECHANISM
FUNCTIONS
HUMORAL
IMMUNITY
Extracellular
microbes
B lymphocytes
Secretes
antibody
 Block
infections
 Eliminate
extracellular
microbes
CELL-MEDIATED IMMUNITY
Phagocytosed
microbes in
macrophage
Helper T
lymphocyte
Intracellular
microbes (ex.
viruses)
replicating within
infected cell
Cytotoxic T
lymphocyte
Activate
macrophages to kill
phagocytosed
microbes
Kill infected cells
and eliminate
reservoirs of
infection
5
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar

TWO BASIC TYPES OF ACQUIRED IMMUNITY
CELL-MEDIATED IMMUNITY
HUMORAL IMMUNITY
(T lymphocytes)
(B lymphocytes)
↓
↓
Activated Lymphocytes
Antibodies
(directly kills the
Helper T-cells (CD4)
microbes; activation of
- LYMPHOKINES/CYTOKINES
complement system)
- stimulation of growth and
proliferation of cytotoxic T-cells
and suppressor T-cells
*upon recognition of
- stimulation of B-cell growth and
antigen,
differentiation to form plasma
B-lymphocytes
cells and antibodies
proliferate then
- activation of macrophage
differentiate to become:
system
- stimulatory effect on the helper
 Plasma cells
T-cells
(secretes antibodies)

Cytotoxic T-cells (CD8)
- directly attacks the cell


Suppressor T-cells
- subtype of helper T-cells
- regulate/suppressive function on
both cytotoxic (CD8) and helper
T-cells (CD4)

Memory T-cells
- cause more rapid response on
subsequent exposure to the
same antigen
*In both immunities, MEMORY CELLS are produced
Memory B-cells
i. CELL MEDIATED IMMUNITY: involves T-lymphocytes
CD8 (Cytotoxic T-cell)
- directly kills the infected cell
 Cytotoxic T-cells (CD8) and Helper T-cells (CD4) do not have the
capability to recognize the antigen directly
 A cell must be presented first by an ANTIGEN PRESENTING CELL
 ANTIGEN PRESENTING CELLS: Dendritic cells, Macrophages, Blymphocytes
o once the antigen presenting cell presents the antigen to
either CD4 or CD8, both T-cells will proliferate, undergoing
clonal expansion and the effector mechanism will proceed
o CD8 – directly kills the organism
o CD4 – produces cytokines that can stimulate B-lymphocyte,
macrophage, cytotoxic T-cell
 Every time that B & T-lymphocyte undergo clonal expansion,
memory cells are produced
 Once recognized by the T-cell, it will destroy both the antigen and
antigen-presenting cell
CD4 (Helper T-cell)
- cannot kill the cell
- releases Lymphokines/Cytokines = B lypmhocytes proliferate to
produce antibody = antibody will kill the cell
- Function of Lymphokines/Cytokines:
o can activate the macrophage system, thus activating the
inflammatory reaction
o can stimulate the B-lymphocyte to differentiate into plasma
cells and produce antibodies
o can stimulate the growth and proliferation of both
Cytotoxic T and Suppresor T cells
o has stimulatory effect on the Helper T-cells themselves
 The CYTOKINES released by HELPER T-CELLS modulate the whole
immune response. Without them, the whole immune system will
be paralyzed.
CASE: HIV/AIDS
- attacks CD4 (Helper T-cells)
- full blown AIDS patient usually dies from overwhelming infection
because their immune system is paralyzed due to the absence of
cytokines coming from the helper T-cells
[(Immu1)video- 16:23-17:50]
6
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
CYTOKINES OF ACQUIRED IMMUNITY: produced by T lymphocytes
- Interferon gamma (IFN-ϒ): produced by NK cells; also produced by
CD4, CD8 T-cells
- Interleukin-2 (IL-2)
- Interleukin-4 (IL-4)
- Interleukin-5 (IL-5)
ii. HUMORAL IMMUNITY: involves B-lymphocytes
 Unlike T lymphocytes, B lymphocytes can distinguish a microbe
or an antigen
 If B lymphocytes react with the microbe or an antigen, it is only
activated
 It needs cytokines released by Helper T-cells (CD4) before they
can proliferate as plasma cells  produce antibody, memory Bcells
-activates the complement system
- cytolytic (can destroy the cell)
- crosses the placenta (anti-RH IgG)
CASE: Hepatitis
- jaundiced, (+)HBS antigen
- IgM, IgG titers to determine whether it is acute or chronic

If ACUTE, the patient will get well even if without
medication; self-limiting

If CHRONIC, patient can suffer with liver cancer or
cirrhosis
IgA: second most abundant
- chief immunoglobulin in EXOCRINE secretions (breast milk)
IgE: mediates certain allergic reactions
- attached to basophils and mast cells
IgD: very small amount
- attaches to surface of B-lymphocyte
- helps in antigen recognition by B-cells
MECHANISM OF ACTION OF ANTIBODIES:
1. Direct attack on the invaders through
 Agglutination
 Precipitation
 Neutralization
 Lysis
* If not enough, the complement system is activated
2. Activation of the complement system
Configuration of an antibody

COMPLEMENT SYSTEM
VARIABLE PORTION
- the portion that attaches specifically to a particular type of
antigen
- it varies according to the antigen to which the antibody will
react
EXAMPLE: IgM antibody for chicken pox; IgM antibody for
measles
- the variable portion for chicken pox, is different from the
variable portion for measles
- but they are both IgM

CONSTANT PORTION
- it is used in its attachment to the complement system
- diffusivity of antibody to tissues
- adherence of antibody to tissues
- attachment to the complement (most important function)
CLASSES OF ANTIBODIES:
o
IgM: first to appear in ACUTE INFECTION/ 1 antigen stimulus
- activates the complement system
- cytolytic (can destroy the cell)
- does NOT cross the placenta
o
IgG: first to appear in CHRONIC INFECTION/2 antigen stimulus
-most abundant (75%)
 Antigen-antibody complex stimulates C1 =products are produced
resulting to elimination of the infection via:
- Lysis of cells
- Chemotaxis of WBC’s
- Activation of inflammation
- Opsonization
- Ag-Ab complex causes the complement -> complement
brings the complex to the phagocyte -> phagocytosis
Question: What part of the antibody stimulates the Complement
System?
Answer: “Constant”
7
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
MEMORY B-CELLS
 FIRST EXPOSURE (blue): mounting of immune response is delayed
and level is low
 SECOND EXPOSURE (red): since memory cells are already
developed, response is rapid, level is high, long-lasting;
- at second exposure, patient might not even manifest the
disease because at the onset, he is already protected
- PRINCIPLE being used in VACCINES




ACQUIRED IMMUNITY
ACTIVE IMMUNITY
PASSIVE IMMUNITY
Produced by individuals in
 Antibodies derived from
response to natural or
another either by natural
artificial stimulation
transfer or by injection
Generates own antibodies
 Given pre-formed antibodies
Chickenpox infection
 Newborn
MMR vaccination
 Immunoglobulins
ADVANTAGE: immunity is lifelong once produced
DISADVANTAGE: it takes time
before you are protected; you
get the disease first before
producing the antibodies


On first exposure, produces a response.
On second exposure, response is greater
INFECTIONS
CELL-MEDIATED
HUMORAL IMMUNITY
IMMUNITY
(B lymphocytes)
(T lymphocytes)
 Transplant rejection
 Antibodies against bacteria
 Destruction of cancer
and viruses
cells
 Fungi, viruses,
Ex. Measles, Mumps, Chicken
parasites, bacteria (ex.
pox
TB –most common)
ADVANTAGE: immediately
protected
DISADVANTAGE: the pre-formed
antibody is short-lived
 We do not get diseases from the vaccine because the virus is
INACTIVATED.
AUTOIMMUNE DISEASES
- because the process of immune tolerance is not perfect (90%)
- some individuals generate autoimmune antibodies
CASE: Myasthenia Gravis
- Acetylcholine receptors are destroyed
- Cannot generate an end-plate potential =weakness
Allergy/Hypersensitivity
ACUTE: due to IgE
CHRONIC: due to cytotoxic T-cells (CD8)
-Urticaria
-Allergic Rhinitis
-Bronchial Asthma
8
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
WHITE BLOOD CELLS (WBC) / LUEKOCYTES

Unlike RBC’s and platelets, WBC’s are NUCLEATED.

Based on presence of granules: GRANULOCYTES and
AGRANULOCYTES

GRANULOCYTES:
 Neutrophils: engulf bacteria and cellular debris
(phagocytosis)
 Basophils: weak phagocytes; HYPERSENSITIVITY; release
histamine; secretes naturally-occurring anticoagulant,
HEPARIN
 Eosinophils: weak phagocytes; PARASITIC INFECTIONS;
allergic response

AGRANULOCYTES:
 Lymphocytes: B, T-lymphocytes (IMMUNOLOGY)
 Monocytes: engulf cellular debris (phagocytosis); antigen
processing

Normal Values: WBC- 5-10 x 109/L

Leukocytosis: abnormal ↑ in the no. of WBC’s; (+)
infection

Leukopenia: WBC count less than normal

In an overwhelming SEPSIS, WBC’s are called to action
and all are consumed
=↓WBC count
DENGUE: characteristic WBC is leukopenia


Also arise from the Pluripotent Hematopoietic Stem Cell (PHSC)
in the bone marrow.
LOCATION
GRANULOCYTES
MONOCYTES
LYMPHOCYTES
Originate in the bone
marrow;
Found in the circulation
Originate in the bone
marrow;
Placed in lymphoid tissues
(lymph nodes, tonsils,
spleen, thymus, appendix,
peyer’s patches)
3.
“Third, the immune system of the body develops antibodies against
infectious agents such as bacteria. The antibodies then adhere to the
bacterial membranes and thereby make the bacteria especially
susceptible to phagocytosis. To do this, the antibody molecule also
combines with the C3 product of the complement cascade. The C3
molecules, in turn, attach to receptors on the phagocyte membrane,
thus initiating phagocytosis. This selection and phagocytosis process
is called OPSONIZATION.”
How does phagocytosis occur? [video]
PHAGOCYTES:
1. NEUTROPHILS
- phagocytic
- active in the blood
- constantly formed in the bone marrow where they
develop and mature
- mature neutrophils circulate in the blood for 3-12 hours;
then, they move to other tissues where they will survive for
only 2-3 days
- acts as surveillance cells searching for infections
- contains lysosomes that degrades bacteria
- after digesting the bacteria, neutrophil shrinks in size
- a single neutrophil can usually phagocytize 3 to 20 bacteria
before the neutrophil itself becomes inactivated and dies
- SECOND LINE against invading microorganisms because it
degenerates after killing the bacteria
- ACUTE INFECTIONS
2.
FUNCTIONS OF THE LEUKOCYTES: Combat Infection

Destroy the invading agents by phagocytosis

Form antibodies and sensitized lymphocytes
PHAGOCYTOSIS (Cellular Ingestion)
- Phagocytes must be selective of the material that is phagocytized;
otherwise, normal cells and structures of the body might be ingested
- Normal tissues are not ingested because:
1. Most normal tissues have smooth surfaces
- which resist phagocytosis
- but if the surface is rough, the likelihood of phagocytosis is
increased
2.
Most natural substances of the body has protective protein
coats
- repels phagocytes
- conversely, most dead tissues and foreign particles are
rough and have no protective coats, which make them
subject to phagocytosis.
Foreign Ag + antibodies + C3
- when a foreign antigen enters the body, we mount an
immune system by producing an antibody = stimulates the
COMPLEMENT SYSTEM
- complement system brings the Antigen-Antibody complex
near the phagocyte
- phagocyte destroys the combination
- the process where the complement brings the antigenantibody complex near a phagocyte is called
OPSONIZATION.
MACROPHAGE
- phagocytic
- inactive monocytes in the blood
- monocytes must first arrive in the tissue and transform to
become MACROPHAGES before it can perform phagocytosis
- active macrophages in tissues
- they do not die in the tissues; they survive after doing
their function
- FIRST LINE OF DEFENSE
- ACUTE/CHRONIC INFECTIONS
MONOCYTE MACROPHAGE CELL SYSTEM
(RETICULOENDOTHELIAL SYSTEM)

strategically placed in PORTALS OF ENTRIES of
microorganisms

Tissue macrophage in the SKIN and SUBCUTANEOUS
TISSUES (Histiocytes)

Macrophages in the LYMPH NODES

Alveolar Macrophages in the LUNGS

Macrophages (Kupffer cells) in the LIVER sinusoids

Macrophages of the SPLEEN and BONE MARROW

Both NEUTROPHILS and MACROPHAGES can kill bacteria by
releasing BACTERICIDAL AGENTS:
1
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
BACTERICIDAL
AGENTS
Superoxide O2Hydrogen Peroxide H2O2
Hydroxyl ions OHH2O2 + Cl- -> (myeloperoxidase) ->
hypochlorite
“When tissue injury occurs, whether caused by bacteria, trauma,
chemicals, heat, or any other phenomenon, multiple substances are
released by the injured tissues and cause dramatic secondary changes
in the surrounding uninjured tissues. This entire complex of tissue
changes is called INFLAMMATION.”
INFLAMMATION is characterized by:
1. Vasodilatation of the local blood vessels with consequent excess
local blood flow.
2. Increased permeability of the capillaries.
3. Clotting of fluid in the interstitial spaces.
-because the plasma is being pushed into the interstitial space
-Plasma contains coagulation factors; thus, it can form a clot
4. Migration of large number of neutrophils and monocytes into
the tissue.
5. Swelling of the tissue.
5 Cardinal Signs of INFLAMMATION:
 the area inflamed will appear RED (RUBOR)
 due to vasodilatation, there is release of HEAT (KALOR)
 release of painful substances, causing PAIN (DOLOR)
 increased permeability of the capillaries  EDEMA
(TUMOR)
 LOSS OF FUNCTION
What is the purpose of the inflammatory process?

One of the first results of inflammation is to "wall off" the area
of injury from the remaining tissues. The tissue spaces and the
lymphatics in the inflamed area are blocked by fibrinogen clots
so that after a while, fluid barely flows through the spaces.

This walling-off process delays the spread of bacteria or toxic
products.

When neutrophils and macrophages engulf large numbers of
bacteria and necrotic tissue, essentially all the neutrophils and
many, if not most, of the macrophages eventually die. After
several days, a cavity is often excavated in the inflamed tissues.
It contains varying portions of necrotic tissue, dead neutrophils,
dead macrophages, and tissue fluid. This mixture is commonly
known as PUS.
“The intensity of the inflammatory process is usually proportional to
the degree of tissue injury.”
RESPONSE DURING INFLAMMATION:

Tissue MACROPHAGE is the FIRST LINE of defense against
infection.
because within minutes, the macrophages present in the
Reticulo-endothelial system (RES) will be activated.

NEUTROPHIL invasion of the inflamed area is a SECOND LINE of
defense
because within the first hour after the inflammatory
process, INFLAMMATORY CYTOKINES (Tumor Necrosis
Factor and Interleukin-1 - chemoattractants) will be
secreted
MARGINATION: process where the WBC’s attach to the walls of the
endothelium.
DIAPEDESIS: WBC’s squeeze through the pores of the capillaries.
CHEMOTAXIS: inflamed tissues release chemicals that attract
neutrophils and macrophages.
↓
FINAL EVENT: PHAGOCYTOSIS
-

TNF and IL-1 will attract the neutrophils to go to the
inflamed area
TNF and IL-1 also increase the expression of adhesion
molecules in the endothelium called SELECTIN and
IntraCellular Adhesion Molecule (ICAM)
Selectin and ICAM binds to NEUTROPHIL causing the
neutrophil to MARGINATE
followed by Diapedesis, then Chemotaxis
The second macrophage invasion into the inflamed tissue is the
THIRD LINE of defense.

BONE MARROW – increases its production of monocyte

Monocytes  go to the CIRCULATION  then to the
tissue as TISSUE MACROPHAGES
2
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar

Increased production of granulocytes and monocytes by the
bone marrow is the FOURTH LINE of defense.

Within 3-4 days, greatly increased production of
neutrophils and monocytes by the bone marrow.

Activated Macrophage secrete cytokines: TNF, IL-1, GCSF, M-CSF
(Granulocyte; Monocyte Colony Stimulating Factor)

Cytokines stimulate the bone marrow  ↑production of
WBC
- Therapeutic Radiation procedures: radiotherapy for cancer
(radiation is too much, enough to suppress the bone marrow 
(leukopenia)
-
Drugs: chlorampenicol (antibiotic), thiouracil (given to
hyperthyroid), chemotherapeutic agents
LEUKEMIA: uncontrolled production of WBC
cancerous mutation of a myelogenous and lymphogenous
cell (AML, ALL)
Effects of Leukemia in the body:
- metastatic growth of leukemic cells in abnormal areas of the body
- WBC’s should only be in the BONE MARROW or in the BLOOD
- Metastasis: WBC’s are found infiltrating the BONE
- infections, severe anemia, bleeding
- although WBC’s are excessively increased, they are IMMATURE
- because of the over proliferation of the WBC’s in the bone
marrow, RBC’s and platelets are displaced  patient suffers
from severe anemia and bleeding
- metabolic starvation
- cancer cells utilizing all the energy and nutrients of the body
3.
CASE:
4.
EOSINOPHILS
- weak phagocytes
- important role in ALLERGIC REACTIONS
- role in PARASITIC INFECTIONS (WORMS)
↑Eosinophil count = Parasitic infection
↑Neutrophil = Bacterial infection
BASOPHILS/ MAST CELLS
- releases HEPARIN: prevents blood coagulation
- releases HISTAMINE: involved in ALLERGIC REACTIONS
PLEASE REMEMBER!
Basophil and Mast Cells are associated closely with an
immunoglobulin (IgE)
Basophil + IgE (with antigen) = histamine
(Histamine mediates allergic reactions)

When the specific antigen for the specific IgE antibody
subsequently reacts with the antibody, the resulting attachment
of antigen to antibody causes the mast cell or basophil to
rupture and release large quantities of histamine, bradykinin,
serotonin, heparin, slow-reacting substance of anaphylaxis, and
a number of lysosomal enzymes.

These cause local vascular and tissue reactions that cause many,
if not most, of the allergic manifestations.
CLINICAL CORRELATION:
LEUKOPENIA: ↓WBC count
CAUSES:
- massive infection
- irradiation
PLEASE REMEMBER!
- Diagnostic Radiation (x-ray, CT-scan, MRI) is NOT enough to
suppress the bone marrow and cause leukopenia
3
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
IMMUNOLOGY
I. INNATE IMMUNITY
“Early defense against infections”
The INVADERS:
- Bacteria
- Viruses
- Parasites (such as fungi, protista, worms)
IMMUNITY
ability of the human body to resist almost all types of
organisms or toxins that tend to damage the tissues or
organs
ANTIGEN (Ag): antibody generation
any molecule that can bind to the components of the
specific immune response
Components of Innate Immunity:
i. Epithelial barriers
- provides physical barrier to infection
- killing of microbes by locally produced antibiotics
- killing of microbes and infected cells by intraepithelial
lymphocytes
ii. Phagocytes
- Neutrophils
- Monocytes/Macrophages
iii.
ANTIBODY (Ab)
family of defensive proteins the body makes when
stimulated by an antigen
CYTOKINES
- substances, mostly proteins, secreted by cells affecting the
behavior of nearby cells
- ex: interleukins (IL); interferons (INF)
- can be produced either by:
 INNATE IMMUNITY
o Macrophages, Natural Killer (NK) cells
o Both secrete cytokines
 ACQUIRED IMMUNITY
o T lymphocytes
INNATE IMMUNITY
 Phagocytosis by WBC’s and
macrophages
 Skin
 Acid secretion of stomach
 Presence in the blood of certain
compouns that attach to foreign
substances and destroy them
 Lysozymes
 Complement system
 NK cells
*already present, ready to protect
you even on first encounter
ACQUIRED IMMUNITY
(Adaptive Immunity)
 Immunity developed due to
previous exposure to
invading agents such as
bacteria, viruses, toxins,
foreign tissues
*lymphocytes are not ready
protect you on first encounter
*you have to be sick first; but
once you have developed the
protection, the immunity is
extremely powerful that you
might not even experience the
second disease (chickenpox)
or you might not even
experience the disease at all
(vaccination)
Dendritic Cells
- cells present in the skin; considered as bridge between
innate and adaptive immunity
- MECHANISM:
organism traversed the skin
↓
dendritic cells (cannot destroy the bacterium) will carry the organism
↓
presents the organism to the lymphocyte in the lymphoid tissue
(thus, bridging innate and adaptive immunity)
iv. Natural Killer Cells
are a class of lymphocytes that recognize infected cells,
respond by:
o
killing these cells or
o by secreting the macrophage activating cytokine
interferon gamma (IFN-ϒ)
When a macrophage ingested a microbe, macrophage cannot
degrade the organism
↓
Macrophage will secrete cytokine interleukin-12 (IL-12)
↓
Attracts natural killer (NK) cell; it will sense macrophage needs help;
secretes IFN-ϒ
↓
IFN-ϒ activates the macrophage
(ACTIVATED MACROPHAGE: secretes TNF, IL-1  attracts neutrophils
from the blood)
↓
Kills the phagocytized microbe
(*Cytokines: interleukin-12; interferon gamma)
4
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
v. The Complement System
- series of about 20 proteins, existing in a proenzyme form
(INACTIVE)
- once activated by the microorganism or antigen-antibody
complex, it can eliminate the invading microorganism
COMPLEMENT SYSTEM
 Once the microbe has escaped humoral immunity and has entered
the cell, cell-mediated immunity will now take over
o Two most predominant cells:

Cytotoxic T-cell
- directly kill the infected cell

Helper T-cell
- does not have the capability to degrade the cell
- however, once activated, it can release cytokines
which can:
o activate macrophage  cause inflammation
o proliferation of B lymphocytes and cytotoxic
T-cell and perform their actions
 Lymphocytes are also coming from the stem cell
 Once produced by the bone marrow, they are stored in the
lymphoid tissues
 But before birth, stored in the lymphoid tissues and processed first
in two organs:
- THYMUS  T-lymphocytes
- FETAL BONE MARROW  B-lymphocytes
 TWO PURPOSES OF PRE-PROCESSING OF THE LYMPHOCYTES IN
THE THYMUS, FETAL LIVER AND BONE MARROW:
1. To achieve SPECIFICITY
 1 antigen will react with only 1 lymphocyte or antibody
 Two Ways to activate:
o MICROORGANISM activates C3
-INNATE IMMUNITY
o
 Lymphocytes in the thymus and bone marrow are
presented with thousands of antigens  producing
thousands of lymphocytes
 1 antigen : 1 lymphocyte
ANTIGEN-ANTIBODY COMPLEX activates C1
-ACQUIRED/ADAPTIVE IMMUNITY
2.
Cytokines present in Innate Immunity
Interleukin 12 (IL-12)
Interferon gamma (IFN-ϒ)
Interleukin 1 (IL-1)
Tumor Necrosis Factor (TNF)
To achieve TOLERANCE
 The lymphocytes and antibodies must not react with
own cells
 Lymphocytes in the thymus and bone marrow are
presented with own cells
expected reaction: lymphocytes must not react
Once the lymphocytes react with own cells, it will be
destroyed
II. ACQUIRED IMMUNITY
a property of lymphocytes (T, B lymphocytes)
TWO BASIC TYPES OF ACQUIRED IMMUNITY
1. CELL-MEDIATED IMMUNITY (T lymphocytes)
= Activated lymphocytes
 Process of tolerance is only 90% perfect
- explains the occurrence of AUTOIMMUNE
DISEASES
2. HUMORAL IMMUNITY (B lymphocytes)
= Antibodies
MICROBE
RESPONDING
LYMPHOCYTES
EFFECTOR
MECHANISM
FUNCTIONS
HUMORAL
IMMUNITY
Extracellular
microbes
B lymphocytes
Secretes
antibody
 Block
infections
 Eliminate
extracellular
microbes
CELL-MEDIATED IMMUNITY
Phagocytosed
microbes in
macrophage
Helper T
lymphocyte
Intracellular
microbes (ex.
viruses)
replicating within
infected cell
Cytotoxic T
lymphocyte
Activate
macrophages to kill
phagocytosed
microbes
Kill infected cells
and eliminate
reservoirs of
infection
5
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar

TWO BASIC TYPES OF ACQUIRED IMMUNITY
CELL-MEDIATED IMMUNITY
HUMORAL IMMUNITY
(T lymphocytes)
(B lymphocytes)
↓
↓
Activated Lymphocytes
Antibodies
(directly kills the
Helper T-cells (CD4)
microbes; activation of
- LYMPHOKINES/CYTOKINES
complement system)
- stimulation of growth and
proliferation of cytotoxic T-cells
and suppressor T-cells
*upon recognition of
- stimulation of B-cell growth and
antigen,
differentiation to form plasma
B-lymphocytes
cells and antibodies
proliferate then
- activation of macrophage
differentiate to become:
system
- stimulatory effect on the helper
 Plasma cells
T-cells
(secretes antibodies)

Cytotoxic T-cells (CD8)
- directly attacks the cell


Suppressor T-cells
- subtype of helper T-cells
- regulate/suppressive function on
both cytotoxic (CD8) and helper
T-cells (CD4)

Memory T-cells
- cause more rapid response on
subsequent exposure to the
same antigen
*In both immunities, MEMORY CELLS are produced
Memory B-cells
i. CELL MEDIATED IMMUNITY: involves T-lymphocytes
CD8 (Cytotoxic T-cell)
- directly kills the infected cell
 Cytotoxic T-cells (CD8) and Helper T-cells (CD4) do not have the
capability to recognize the antigen directly
 A cell must be presented first by an ANTIGEN PRESENTING CELL
 ANTIGEN PRESENTING CELLS: Dendritic cells, Macrophages, Blymphocytes
o once the antigen presenting cell presents the antigen to
either CD4 or CD8, both T-cells will proliferate, undergoing
clonal expansion and the effector mechanism will proceed
o CD8 – directly kills the organism
o CD4 – produces cytokines that can stimulate B-lymphocyte,
macrophage, cytotoxic T-cell
 Every time that B & T-lymphocyte undergo clonal expansion,
memory cells are produced
 Once recognized by the T-cell, it will destroy both the antigen and
antigen-presenting cell
CD4 (Helper T-cell)
- cannot kill the cell
- releases Lymphokines/Cytokines = B lypmhocytes proliferate to
produce antibody = antibody will kill the cell
- Function of Lymphokines/Cytokines:
o can activate the macrophage system, thus activating the
inflammatory reaction
o can stimulate the B-lymphocyte to differentiate into plasma
cells and produce antibodies
o can stimulate the growth and proliferation of both
Cytotoxic T and Suppresor T cells
o has stimulatory effect on the Helper T-cells themselves
 The CYTOKINES released by HELPER T-CELLS modulate the whole
immune response. Without them, the whole immune system will
be paralyzed.
CASE: HIV/AIDS
- attacks CD4 (Helper T-cells)
- full blown AIDS patient usually dies from overwhelming infection
because their immune system is paralyzed due to the absence of
cytokines coming from the helper T-cells
[(Immu1)video- 16:23-17:50]
6
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
CYTOKINES OF ACQUIRED IMMUNITY: produced by T lymphocytes
- Interferon gamma (IFN-ϒ): produced by NK cells; also produced by
CD4, CD8 T-cells
- Interleukin-2 (IL-2)
- Interleukin-4 (IL-4)
- Interleukin-5 (IL-5)
ii. HUMORAL IMMUNITY: involves B-lymphocytes
 Unlike T lymphocytes, B lymphocytes can distinguish a microbe
or an antigen
 If B lymphocytes react with the microbe or an antigen, it is only
activated
 It needs cytokines released by Helper T-cells (CD4) before they
can proliferate as plasma cells  produce antibody, memory Bcells
-activates the complement system
- cytolytic (can destroy the cell)
- crosses the placenta (anti-RH IgG)
CASE: Hepatitis
- jaundiced, (+)HBS antigen
- IgM, IgG titers to determine whether it is acute or chronic

If ACUTE, the patient will get well even if without
medication; self-limiting

If CHRONIC, patient can suffer with liver cancer or
cirrhosis
IgA: second most abundant
- chief immunoglobulin in EXOCRINE secretions (breast milk)
IgE: mediates certain allergic reactions
- attached to basophils and mast cells
IgD: very small amount
- attaches to surface of B-lymphocyte
- helps in antigen recognition by B-cells
MECHANISM OF ACTION OF ANTIBODIES:
1. Direct attack on the invaders through
 Agglutination
 Precipitation
 Neutralization
 Lysis
* If not enough, the complement system is activated
2. Activation of the complement system
Configuration of an antibody

COMPLEMENT SYSTEM
VARIABLE PORTION
- the portion that attaches specifically to a particular type of
antigen
- it varies according to the antigen to which the antibody will
react
EXAMPLE: IgM antibody for chicken pox; IgM antibody for
measles
- the variable portion for chicken pox, is different from the
variable portion for measles
- but they are both IgM

CONSTANT PORTION
- it is used in its attachment to the complement system
- diffusivity of antibody to tissues
- adherence of antibody to tissues
- attachment to the complement (most important function)
CLASSES OF ANTIBODIES:
o
IgM: first to appear in ACUTE INFECTION/ 1 antigen stimulus
- activates the complement system
- cytolytic (can destroy the cell)
- does NOT cross the placenta
o
IgG: first to appear in CHRONIC INFECTION/2 antigen stimulus
-most abundant (75%)
 Antigen-antibody complex stimulates C1 =products are produced
resulting to elimination of the infection via:
- Lysis of cells
- Chemotaxis of WBC’s
- Activation of inflammation
- Opsonization
- Ag-Ab complex causes the complement -> complement
brings the complex to the phagocyte -> phagocytosis
Question: What part of the antibody stimulates the Complement
System?
Answer: “Constant”
7
BLOOD (WBC & IMMUNOLOGY)
Dr. Olivar
MEMORY B-CELLS
 FIRST EXPOSURE (blue): mounting of immune response is delayed
and level is low
 SECOND EXPOSURE (red): since memory cells are already
developed, response is rapid, level is high, long-lasting;
- at second exposure, patient might not even manifest the
disease because at the onset, he is already protected
- PRINCIPLE being used in VACCINES




ACQUIRED IMMUNITY
ACTIVE IMMUNITY
PASSIVE IMMUNITY
Produced by individuals in
 Antibodies derived from
response to natural or
another either by natural
artificial stimulation
transfer or by injection
Generates own antibodies
 Given pre-formed antibodies
Chickenpox infection
 Newborn
MMR vaccination
 Immunoglobulins
ADVANTAGE: immunity is lifelong once produced
DISADVANTAGE: it takes time
before you are protected; you
get the disease first before
producing the antibodies


On first exposure, produces a response.
On second exposure, response is greater
INFECTIONS
CELL-MEDIATED
HUMORAL IMMUNITY
IMMUNITY
(B lymphocytes)
(T lymphocytes)
 Transplant rejection
 Antibodies against bacteria
 Destruction of cancer
and viruses
cells
 Fungi, viruses,
Ex. Measles, Mumps, Chicken
parasites, bacteria (ex.
pox
TB –most common)
ADVANTAGE: immediately
protected
DISADVANTAGE: the pre-formed
antibody is short-lived
 We do not get diseases from the vaccine because the virus is
INACTIVATED.
AUTOIMMUNE DISEASES
- because the process of immune tolerance is not perfect (90%)
- some individuals generate autoimmune antibodies
CASE: Myasthenia Gravis
- Acetylcholine receptors are destroyed
- Cannot generate an end-plate potential =weakness
Allergy/Hypersensitivity
ACUTE: due to IgE
CHRONIC: due to cytotoxic T-cells (CD8)
-Urticaria
-Allergic Rhinitis
-Bronchial Asthma
8
PHYSIOLOGY – A
Blood Physio pt. 3






Dr. Vienna Blessie N. Baloloy (VBNB)
I. Intro to the Immune System Components
Our bodies have a special system for combating the
different infectious and toxic agents. This system is
composed of blood leukocytes (WBC) & tissue cells
derived from WBC. They work together in two ways to
prevent disease:
o Destroying invading bacteria or viruses by
phagocytosis
o Forming antibodies and sensitized lymphocytes
which may destroy or inactivate the invader
Function of Leukocytes
o Destroy invading agents via phagocytosis
o Formation of antibodies and sensitizing
lymphocytes – parts of our bodies are always
exposed to bacteria or invading agents
Types of invaders:
o Bacteria
o Viruses
o Parasties such as fungi, protista & worms
II. White Blood Cells (WBCs)
Also known as leukocytes
Cells which protect our bodies from invading agents
Located in blood
Type


Description
Polymorphonuclear
Neutrophils
Polymorphonuclear
Eosinophils
Polymorphonuclear
Basophils
Monocytes
Lymphocytes
Plasma Cells
Normal
Percentage
62.0%
Granulocytes and are
called “Polys”
(multiple nuclei)
2.3%
0.4%
5.3%
30.0%
Table 3. Location of WBCs
Granulocytes &
Monocytes
Lymphocytes
Lymph Nodes
(commonly found here);
Location
Bone marrow and the Tonsils; Thymus;
Circulations
Appedix; Peyer’s
patches (packets in the
GIT)


Table 1. Main Classes of WBC
Granulocytes
Agranulocytes
resposible in
procduces
engulfing
antibodies;
bacteria and
Neutrophils
Lymphocytes
regulates
cellular debris;
the immune
most numerous
resoponse
in the blood
capable of
hypersensitivity
Plasma
Basophils
reaction and
Cells
release of
histamine
phagocytic
involved in
cells;
parasitic
antigenic
Eosinophils
Monocytes
infection;
cells
Allergic
(antigen
response
processing)
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Table 2. Six Types of WBCs and their Percentage




Leukocytes protect us from infection by
o Phagocytosis
o Formation of antibodies & sensitizing the
lymphocytes
Lymphocytes in general
o Mostly stored in various lymphoid tissues, except
for a small number that are temporarily being
transported in the blood.
Granulocytes and monocytes
o protect body against invading organisms mainly
by ingesting them (Phagocytosis)
o Formed only in the bone marrow
o They are stored within the marrow until they are
needed in the circulatory system
Lymphocytes and plasma cells
o Formed mainly in various lymphogenous tissues
(lymph glands, spleen, thymus, tonsils, Peyer’s
patches [at gut wall], etc.)
III. Genesis of WBCs
Myelocytic Lineage
o Begins with Myeloblast (1)
Lymphocytic Lineage
o Begins with Lymphoblast
Normal WBC Count:5-10 x 109/L; A normal adult human
being has ~7000 WBC per microliter of blood
o Leukocytosis – abnormal increase in the
number of WBC’s
o Leukopenia – WBC count less than normal
Blood cells all came from the bone marrow which contains
the pluripotent hematopoietic stem cells which will
eventually differentiate into different types of cells such as
your granulocytes, monocytes and lymphocytes.
Figure 1. Promyelocyte and its descendant cells.
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MD-1C 2019
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PHYSIOLOGY – A
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Dr. Vienna Blessie N. Baloloy (VBNB)
III. Life Span of the WBC
Granulocytes
o 4-8 hrs circulating the blood
o 4 to 5 days in tissues where they are needed
o Can be shortened secondary to serious tissue
infections because granulocytesproceed evem
more rapidly to the infected area, perform their
function, and in the process, are themselves
destroyed
Monocytes
o 10 to 20 hrs in blood before going to tissues
o They swell and become larger in size, once they
are in the tissue and becomes the tissue
macrophagesthat can live for months unless
destroyed during phagocytic response
IV. Neutrophil and Macrophage Defense
Both attack and destroy invading bacteria, viruses, and
other injurious agents.
Neutrophils are mature cells that can attack and destroy
bacteria even in the circulationg blood, while tissue
macrophages begin life as blood monocyes (immature
cells) wth little ability to fight infectious agents at that time
Margination – Lining up to the capillary walls
Diapedesis – the way of passing through blood capillaries
even it is smaller than the neutrophils and monocytes
Amoeboid motion – movement of both neutrophil and
macrophages through the tissues
Chemotaxis – chemical attraction of both neutrophil and
macrophages to move to the source (inflamed tissue
areas). It depends on concentration gradient of the
chemotactic substance.
o Caused by:

Bacterial or viral toxins

Degenerative products of the inflamed
tissues themselves

Several reaction products of the
complement complex activated in
inflamed tissues

Several reaction products caused by
plasma clotting in inflamed area
Lec 12 - 27 Aug 2015
Phagocytosis

Is a specific process

Most important function of neutrophils and macrophages

Selective of the material that is phagocytised

The body’s cells is protected from intracellular digestion
because:
o Most normal tissues have a smooth surface
which resists phagocytosis
o Most natural substance of the body has a
protective protein coat which repels the cells
involved in phagocytosis
o Ehancement of phagocytosis by the Forgein
Antigen
+
Antibodies
+
Complements
(Opsonization)

Antibodies adheres to the infectious
agents membrane that makes it
susceptible to phagocytosis
Table 4. Phagocytosis by neutrophils vs phagocytosis by
macrophages
Phagocytosis by
neutrophils
Enter tissues as mature
cells already
Immediately begin
phagocytosis
Phagosomes (freefloating phagocytic
vesicle) but not capable
of engulfing larger
particles
1neutrophil : 3 to 20
bacteria before it
becomes inactivated and
die
Phagocytosis by macrophages
Enter tissues as immature
monocytes
Stronger than neutrophil once
activated by immune system
Has the ability to engulf bigger/
larger particles (such as whole
RBCs, malarial parasites)
1 macrophage : up to 100 or more
bacteria, they can extrude residual
products and often survive and
function for many more months
Figure 3. Phagocytes.
Neutrophils

Considered as a phagocytic cell; it can ingest up to 3-5
bacterial molecule, which is its maximum capacity;
eventually they will die

Active in the blood

It is the body’s 2nd line of defense against invading
microorganisms

Commonly seen during actude infection

Hypersegmented/ Lobulated nucleus
Figure 2. Defense mechanism of tissue or vessel injury.
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MD-1C 2019
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PHYSIOLOGY – A
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Dr. Vienna Blessie N. Baloloy (VBNB)

Your macrophages is known as the monocytes once they
are in the blood, however once these monocytes migrate
into the infected tissue they eventually enlarged and
become macrophages
Macrophages

First line of defense during infection

Usually active also in the blood, but once in the tissue it
can engulf more bacteria as compared to the neutrophils
o Up to 100 bacterial cells before cell death

Can ingest larger cellular debris/particles
Reticuloendothelial System

Also known as the Monocyte-Macrophage Cell System

A collective term for the combination of the special
endothelial cells found in the thymus together with the
other fixed tissue macrophages and the mobile
macrophages

Numerous parts of the body contain macrophages, this
explains why when we are exposed to bacteria we do not
immediately get sick
o Langerhans cells in the skin and subcutaneous
tissue
o Sinus histiocytes in the lymph nodes
o Alveolar Macrophages/ Dust cells in the lungs
o Von Kuppfer cells in the liver sinusoids
o Monocytes in the Bone Marrow

Once the neutrophils and macrophages ingest invading
agents their intracellular enzymes kill the bacteria. When
lysosomal enzymes fail, bactricidal agents such as
superoxides kills most bacteria. These include hydrogen
peroxide, hydroxyl ions, and myeloperoxidase.
V. Inflammation

Series or complex of tissue changes that occur in the
instance of injury caused by bacteria, trauma, chemicals,
heat or any other phenomenon.

Trauma can lead to local vasodilation, which increases
blood flow and capillary permeability, allowing some fluid
in the blood to diffuse into the tissues

Vasodilation would lead to an increase in blood flow thus
a higher number of neutrophils and monocytes
o There will then be the presence of margination,
and because of increase capillary permeability
there would be enough space for the monocytes
and neutrophils to pass through the membrane
(diapedesis). Once outside these cells migrated
towards the site of infection (chemotaxis).

Usually these responses to trauma are localized because
of fibrinogens

Some fluid contents of the blood such as the plasma also
leak out. The plasma contains antibodies, proteins, and
clotting factors such as fibrinogens. Once these
fibrinogens become activated, the tissue injury is isolated
(“walled off”) and the spread of the bacteria and toxic
products is delayed.

Products that cause inflammation:
o Histamine
Mari, Merene
MD-1C 2019
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Lec 12 - 27 Aug 2015
o Bradykinin
o Serotonin
o Prostaglandins
o Reaction products of complement system
o Reaction products of blood clotting system
o Lymphokines (released by sensitized T cells)
Pus – contains dead tissue cells, dead phagocytic cells
The intensity of the inflammatory process is proportional to
tissue injury
In summary, inflammation is characterized by:
1. Vasodilatation of the local blood vessels with
consequent increase local blood flow
2. Increase permeability of the capillaries
3. Clotting of fluid in the interstitial spaces
4. Migration of large number of neutrophils and
monocytes into the tissue
5. Swelling of the tissue cells
Cells involved in Inflammation
1. Tissue Macrophage

first line of defense against infection

Within minutes after inflammation begins, these
macrophages are activated to control the
invading agent; after an hour or so the
neutrophils would then migrate to the site of
infection via the release of inflammatory
cytokines.

Number are not great, but they are lifesaving

Effects
o Rapid enlargement of each cell
o Break loose from their attachments and
become mobile
2. Neutrophils

Act within first hour or so

Large in number, invading the inflamed area
(caused by the inflammatory cytokines)

Reactions:
o Increase in the expression of selectin and
intracellular adhesion molecules found in
the capillary walls or in the endothelial
walls; these molecules have a high
capacity in binding with the interleukin-8
receptors found in the neutrophils.
o Once there is numerous selectin &
intracellular adhesion molecules they will
induce margination.
o Loosening of the attachment of each
endothelial cell, allowing passage of the
neutrophils (diapedesis)
o Invasion of infected tissue via chemotaxis
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PHYSIOLOGY – A
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Dr. Vienna Blessie N. Baloloy (VBNB)
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VI. Clinical Correlations

Figure 4. Migration of Neutrophils
3.
4.
5.
6.
Second Macrophage Invasion

Third line of defense

buildup of macrophages in the inflamed tissue
area is much slower than that of neutrophils
Increased Granulocyte and Monocyte Production

Fourth line of defense

Only noticeable after the 3rd of 4th day from the
time of inflammation; here there is a marked
increase in the number of leukocytes
and
monocytes (takes 3 to 4 days to mature and
leave the bone marrow)

Activated macrophage releases a cytokinase
called TNF (tumor necrotic factor) and
interleukin-1 together with other colony
stimulating factors, the bone marrow will be
stimulated to produce more leukocytes and
monocytes.
Eosinophils

Release hydrolytic enzymes from their granules
(which are modified lysosomes)

Release highly reactive forms of oxygen that are
lethal to parasites

Release highly larvicidal polypeptide “major
basic protein”

But doubtful that they are significant in protecting
against the usual types of infection

Trichinosis – parasitic diseases that causes
eosinophilia. Results from invasion of the body’s
muscles by the Trichinella parasite (“pork worm”)
after eating undercooked infested pork
Basophils or Mast Cells

Similar to monocytes
o Basophil in blood, mast cells in tissue

They release heparin, histamine, bradykinin,
and serotonin
o Heparin – are responsible for the anticoagulant factor; they prevent the
coagulation of the blood
o Histamine – incharge of the allergic
reaction
Mari, Merene
MD-1C 2019
Leukopenia
o WBC count less than normal
o Bone marrow produces very few WBC
o Leaves the body unprotected against many
bacteria
o Occurs due to frequent exposure to irradiation
(gamma or x-rays)
o Exposure to drugs such as : chlorampehnicol
(antibiotic) or usahe of thiouracil (for
hyperthyroidism)

Leukemia
o increased production of WBC
o uncontrolled production of WBC secondary to the
cancerous mutation of a myelogenous or
lymphogenous cells
o Types
a) Lymphocytic Leukemia
 Caused by cancerous production of
lymphoid cells
 Beginning the spread from a lymph
node or other lymphocytic tissue
and spreading to other areas of the
body
b) Myelogenous Leukemia
 Caused by cancerous production of
young myelogenous cells in the
bone marrow and then spreads
throughout the body so hat WBC
are
produced
in
many
extramedullary tissues (especially
lymph nodes, spleen and liver)
 The cancerous process occasionally
produces partially differentiated
cells, resulting in what might be
called
o Neutrophilic leukemia
o Eosinophilic leukemia
o Basophilic leukemia
o Monocytic leukemia
Note: The more undifferentiated the cell the more acute is the
leukemia, often leading to death within a few months if
untreated.
Consequences and Effects of Leukemia

Severe bone pain

Prone to infection due to the fact that the released cells
are undifferentiated or immature thus nonfunctional (this
determines how acute the leukemia is)

Severe anemia

Metastatic growth of leukemic cells in abnormal areas of
the body

Displacement of bone marrow and lymphoid cells by the
non-functional leukemic cells

Development of infection, severe anemia

Bleeding tendency caused by thrombocytopenia
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PHYSIOLOGY – A
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Dr. Vienna Blessie N. Baloloy (VBNB)
IMPORTANT EFFECT: excessive use of metabolic
substrates by the growing cancerous cells that reproduce
new cells so rapidly = metabolic starvation (thinness)
Energy of patient is then greatly depleted,
Excessive utilization of amino acid by the leukemic cells
causes rapid deterioration of normal protein tissues of the
body
VII. Immunology
Immunity – it is the ability of the human body to resist
almost all types of organisms or toxins that tend to
damage the tissue or organs
Antigen (Ag) – antibody-generating cells
o Any molecule that can bind to the components of
the specific immune response
Antibody (Ab) – formed by two heavy chains and two light
chains
o A family of defensive proteins the body makes
when stimulated by an antigen
Cytokines – are substances, mostly composed of
proteins, secreted by cells affecting the behavior of nearby
cells
o Examples: Tumor Necrotic Factor (TNF) &
Interleukins
(IL)
secreted
by
activated
macrophages, which induce the bone marrow to
produce more leukocytes and monocytes;
Interferons (INF)
Lec 12 - 27 Aug 2015
o
o
o
Acts as a physical barrier to infection
Also produce locally produce antibiotics
which kills the microbes
Contain intraepithelial lymphocytes which
kills microbes and infected cells
Figure 6. Epithelial barriers.
2.
Acquired or Adaptive Immunity

Results from exposure to antigenic material (bacteria,
toxins, etc)

Engages the action of T lymphocytes

After exposure normally our bodies will develop
antibodies or activate T lymphocytes into effector T
cells

Often requiring weeks or months to develop immunity

Caused by a special immune system that forms
antibodies and/or activated lymphocytes that attack
and destroy the specific invading organism or toxin.

Immunization – treatment process to protect human
beings against disease and toxins
Figure 5. Parts of an antibody molecule.
Types of Immunity
1. Innate Immunity

Inborn immunity

Utilizes macrophages and natural killer cells

In charge during early stages of defense against
infection

Phagocytosis by WBC’s and macrophages

Skin

Acid secretion of stomach

Presence in the blood of certain compounds that
attach to foreign substances and destroys them
o Lysozymes
o Complement System
o Natural Killer Cells

Includes epithelial barriers
Mari, Merene
MD-1C 2019
Figure 7. Innate vs. acquired immunity
VIII. Acquired Immunity
Humoral Acquired Immunity

B-cell immunity (because B lymphocytes produce the
antibodies)

Development of circulating antibodies, which are globulin
molecules in the blood plasma that are capable of
attacking the invading agent.

Once the invading cells are presented to the B
lymphocytes they then would further differentiate into
Page 5 of 13
PHYSIOLOGY – A
Blood Physio pt. 3
Dr. Vienna Blessie N. Baloloy (VBNB)
plasma cells and would the produce or secrete antibodies
which can block the infection and eliminate those invading
agents
Cell-Mediated Acquired Immunity

T-cell immunity (because activated lymphocytes are T
Lymphocytes)

Once the T lymphocytes are exposed to the different
macrophages or invading cells, these naive lyphocytes
would be activated or become effector agents
o Helper T cells – activated macrophages which
kills phagocytosed microbes; the all so activates
reproduction of same cells
o Cytotoxic T cells – kill directly the infected cells
and elimates the source of your infection

Achieved through the formation of large numbers of
activated T lymphocytes that are specifically crafted in the
lymph nodes to destroy the foreign agent

Lec 12 - 27 Aug 2015
Both react highly specifically against specific antigens
o Role of Lymphocyte Clones
o Exposure to antigen will become activated T and
B lymphocytes which in turn react highly
specifically against the particular types of
antigens that initiated their development
o Clone of lymphocyte – general term used to all
different lymphocytes that are capable of forming
one specific antibody or T cells that are activated
by a specific antigen.
o Each clone of lymphocyte is responsive to only a
single type of antigen (or to several similar
antigens that are almost exactly the same
stereochemical characteristics)
Figure 9. Lymphocyte differentiation
Figure 8. Basic Types of Acwuired Immunity
Lymphocytes

Located mostly extensively in the lymph nodes, but they
are also found in special lymphoid tissues such as spleen,
submucosal areas of GIT, thymus, bone marrow.
o Lymphoid tissue of GIT – immediately exposed to
antigens invading from the gut
o Lymphoid tissue of the throat and pharynx
(tonsils and adenoids) – are located to intercept
antigens that enter upper respiratory tranct
o Lymphoid tissue in the lymph nodes – exposed to
antigens that invade the peripheral tissues of the
body
o Lymphoid tissue of spleen, thymus, bone marrow
– plays the specific role of intercepting antigenic
agents that have succeeded in reaching the
circulating blood

Both are derived originally in embryo from pluripotent
hematopoietic stem cells that form common lymphoid
progenitor cells as their most important offspring as they
differentiate.
Mari, Merene
MD-1C 2019
T Lymphocytes

Responsible for forming the activated lymphocytes that
provide “cell-mediated” immunity

Formation
o Originate from bone marrow
o Lymphoid progenitor cells first migrate to
Thymus gland
o Preprocessed in Thymus gland
o Designate the role of the Thymus (cell mediated
immunity)

The thymus makes certain that any T lymphocytes leaving
the thymus will not react against proteins or other antigens
that are present in the body’s own tissues
HOW? thymus selects which T lymphocytes will be
released by first mixing them with virtually all the specific
“self-antigens” from the body’s own tissues. If a T
lymphocyte reacts, it is destroyed and phagocytised (90%
of the cells) instead of being released to the blood.

Have surface receptor proteins (aka T-cell markers)
o Acts like antibodies of B lymphocytes which are
also highly specific for one specified activating
antigen.

Role of the T Cells in activation of the B Lymphocytes
o Most antigens activate both T and B
lymphocytes
o Some of the T cells formed are called:

Helper T Cells

Secretes specific substance : lymphokines

Activate the specific B lymphocytes
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PHYSIOLOGY – A
Blood Physio pt. 3
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Dr. Vienna Blessie N. Baloloy (VBNB)
Special Attributes of the T-Lymphocyte System - Activated
T Cells and Cell-Mediated Immunity
o Release of activated T cells from lymphoid tissue
and formation of memory cells

Instead of releasing antibodies, whole
activated T cells formed and released into
the lymph.

T Lymphocyte memory cells are formed in
same way as B memory cells in the antibody
system
Lec 12 - 27 Aug 2015
Nice to know: Three Major types on antigen presenting cells
1. Macrophages
2. B Lymphocytes
3. Dendritic cells (most potent of the 3), only action
is to present antigens to T cells
Antigen Presenting cells (epithelium)
Antigens
Lymphoid Tissues
T Lymphocytes

Figure 10. Activation of T Cells

Antigen-Presenting Cells, MHC Proteins, and Antigen
Receptors on the T Lymphocytes
o Antigenic specific
o Acquired immune responses usually require
assistance from T cells to begin the process.
o T cells play a major role in actually helping to
eliminate invading pathogens
o T lymphocytes only respond to antigens when they
are bound to specific molecule MHC proteins on the
surface of antigen-presenting cells.

Dendritic Cells – called as antigen presenting cells
because these cells in the spleen will engulf the invading
cells which then migrate and mature, ultimately presenting
the antigen in the lymphoid tissue which then would
activate the T cells.
Natural Killer Cells – a class of lymphocytes that
recognize infected cells, and respond by killing these cells
and by secreting the macrophage activating cytokine IFN-ˠ
o Can kill infected cells
o Produce or relaese IFN - ˠ which enhances other
phagocytic cell function
Figure 12. Dendritic cells.
Figure 11. Pivot Role of Helper T cells. Major Histocompatibility
Complex (MHC)
Mari, Merene
MD-1C 2019
Several Types of T cells and their functions

Regulatory T cells
o Helper T cells

Most numerous 3/4th of all the 3 types
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PHYSIOLOGY – A
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Dr. Vienna Blessie N. Baloloy (VBNB)
Lec 12 - 27 Aug 2015

o
o
Serve as major regulatory of virtually all immune
functions

Lymphokines

Stimulation of growth and proliferation of

Cytotoxic T cells and suppressor T cells

Stimulation of B cell growth and
differentiation to form plasma cells and
antibodies

Activation of the macrophage system

Stimulatory effect on the Helper T cells

Interleukin-2 (strong stimulator effect in
causing growth and proliferation of both
cytotoxic and suppressor T cells)

Interleukin-3

Interleukin-4, 5 and 6 (potent effects on the B
cells that they have been called B-cell
stimulating factors or B-cell growth factors)

Granulocyte-monocyte
colony-stimulating
factor

Interferon ɣ
Suppressor T cells

Capable of suppressing the functions of both
cytotoxic and helper T cells

Has an important role in limiting the ability of the
immune system to attack a person’s own body
tissues – immune tolerance
Cytotoxic T cells

Direct-attack cell that is capable of killing
microorganisms

At times, kill even some of the body’s own cells

After killing the attacked cell, they pull away from
it and kill more cells

Perforins = literally produces punch round holes
in the membrane of the attacked cell

Immune regulator
Figure 14. Direct destruction by cytotoxic T cells.

o
T Cells CD4 is a direct attack cell; once this cell is
attacked to the antigen presenting cell these T
cells will secrete a protein call perforin. These
proteins perforate the walls of the antigen, which
would induce cell lysis.
Memory T cells

Causes more rapid response on subsequent
exposure to the same antigen
Figure 15. Cytokines or Acquired Immunity
Figure 13. Helper and Cytotoixic T cells.
Trivia: In HIV we check the levels of CD4 & CD8.When we
monitor HIV we focus on the levels of CD4, since the body
can no longer produce antibodies and CD4 acts to boost
the ability of other phagocytic cells and its own selfreproduction. Once the levels of CD4 drops, the HIV
patient becomes more susceptible to infection, thus they
develop autoimmune diseases.
Mari, Merene
MD-1C 2019
B Lymphocytes

Responsible for forming antibodies that provide “humoral”
immunity

Formation
o Lymphoid progenitor cells first migrate and
preprocessed at liver during mid-fetal life then in the
Bone marrow in late fetal life and after birth

Actively secrete antibodies that are the reactive agents.

Reactive agents – large protein molecules capable of
combining with and destroying the antigenic substance

Have greater diversity than T lymphocytes
Trivia: It was first discovered in birds, which have a special
preprocessing organ called the bursa of Fabricius. =
reason that they are called “B” Lymphocytes to designate
the role of the bursa.

Plasma cells form the antibodies through an antigen that
activate only the lymphocytes that have cell surface
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PHYSIOLOGY – A
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Dr. Vienna Blessie N. Baloloy (VBNB)
receptors that are complementary and recognize a specific
antigen.
o HOW: B lymphocytes specific for the antigen
immediately enlarge and take on the appearance of
lymphoblasts. Some of these lymphoblasts further
differentiate to form plasmablasts which are
precursors of plasma cells.

Mature plasma cell – produces gamma globulin
antibodies which are then secreted into the lymph
and carried to the circulating blood


Lec 12 - 27 Aug 2015
Role of Macrophages in the activation process of B
Lymphocytes
o Most invading organisms are first phagocytised and
partially digested by the macrophages, and the
antigenic products are liberated into the macrophage
cytosol
o These macrophages then pass the antigens by cellto-cell contact directly to the lymphocytes, thus
leading to activation of the specified lymphocytic
clones.
o Secretes activating substance interleukin-1, that
promotes still further growth and reproduction of the
specific lymphocytes
Nature of the Antibodies
o They are gamma globulins called immunoglobulin (Ig)
o Constitute about 20% of plasma proteins
o Composed of combination of light and heavy
polypeptide chains.

Most are two light and two heavy chains

Variable portion – the portion that attached
specifically to a particular type of antigen

constant portion
o Diffusivity of Ab to tissues
o Adherence of Ab to tissues
o Attachment to the complement (activating)
o Each heavy chain is paralleled by a light chain at one
of its ends, forming a heavy-light pair
Figure 16. Formation of specific antibodies from specific antigen.
Difference Between Primary Response and Secondary
Response

Other lymphoblasts formed by activation of a clone of B
lymphocytes do not become plasmablasts. They become
new B Lymphocytes similar to those of the original clone
but are greatly enhanced.
o These are called memory cells which remain dormant
until activated once again by a new set but same
antigen.

Secondary response is then more rapid and more potent
antibody response as compared to the primary response.
Figure 18. The Nature of an Antibody

Specificity of Antibodies
o Secondary to unique structural organization of amino
acids in variable portions of both the light and heavy
chains

HOW: amino acid organization has a different
steric shape for each antigen specificity, so whe
an antigen comes in contact with it, multiple
prosthetic groups of the antigen fit as a mirror
image with those of the antibody, thus allowing
rapid and tight bonding between the antibody and
the antigen.

Hydrophobic bonding

Hydrogen bonding

Ionic attraction

Van der waals forces
Figure 17. Primary vs. Secondary response.
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MD-1C 2019
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PHYSIOLOGY – A
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Where Ka = affinity constant or measure of high tightly the
antibody binds with the antigen
Table 5. Classes of Antibodies
Ab
IgM
IgG
IgA
IgD
IgE

Properties
Large share of antibodies formed during the primary
response are of this type; pentamer have 10 binding
sites that make them exceedingly effective in
protecting body even there are not many IgM;
(recent/acute infection)
st
1 to appear in 1° antigen stimulus/ acute
activates the complement system
cytolytic
does not cross the placenta
Bivalent antibody and constitute about 75% of
antibodies of normal person (most abundant; previous
infection)
smaller
st
1 to appear in 2° antigen stimulus / chronic
activates the complement system
cytolytic
crosses the placenta
For mucosal immunity
nd
- 2 most abundant
- chief Ig in exocrine secretions (saliva; semen; vaginal
fluid; colostrum in breast milk)
1% only, usually coexpressed with another cell surface
antibody (IgM); binds to basophils and mast cells
(antimicrobial factors to respiratory immunity)
- helps in Ag recognition by B-cells
Constitutes only a small percentage of the antibodies
but is especially involved in allergy
- high propensity to attach to mast cells, which are
responsible for the body’s hypersensitivity reactions
Mechanism of Action of Antibodies
o By direct attack on the invader
o Activation of the “complement system” that has
multiple means of destroying the invader
Table 6. Direct Action of Antibodies on Invading Agents
Agglutination Multiple large particles with antigen on their
surfaces are bound together into a clump
Precipitation
Molecular complex of soluble antigen and
antibody becomes large that it is rendered
insoluble and precipitates
Neutralization The antibodies cover the toxic sites of the
antigenic agent
Lysis
Some antibodies occasionally capable of
directly attacking membranes of cellular
agents that cause rupture of the agent
Mari, Merene
MD-1C 2019
Figure 19. Attachment of specific antigens and specific antibodies
Complement System for Antibody Action

is a made up of 20 proteins

usually seen in our plasma

Once there is antigen-antibody complex reaction this
system would be activated (classical pathway):
o C3B: will increase optimation or the phagocytic cells
o C3a, C4a, C5a: will activate the mast cells and
neutrophils

Important because these cells when they
rupture would release histamine which can
cause vasodilatation increaseing WBC
migration
o C5b C7, C8, C9: causes rupture or lysis of cells
Figure 20. Classic Pathway of Complement

Classic Pathway
o Initiated by an antigen-antibody reaction
o Activation of the proenzyme C1
o Formation of Enzyme C1
o From a small beginning, an extremely large
“amplified” reaction occurs. Multiple end products are
formed and several of these cause important effects
that help to prevent damage to the body’s tissues
caused by the invading organism or toxin.
o Important Effects:

Opsonization and phagocytosis

C3b strongly activates phagocytosis by both
neutrophils and macrophages, causing these
Page 10 of 13
PHYSIOLOGY – A
Blood Physio pt. 3







Dr. Vienna Blessie N. Baloloy (VBNB)
cells to engulf the bacteria to which the
antigen-antibody complexes are attached.
(opsonization)
Lysis

One of the most important of all the products
of the complement cascade is the lytic
complex, whis is combination of multiple
complement
factors
and
designated
C5b6789.

Has direct effect of rupturing the cell
membranes of bacteria or other invading
organisms
Agglutination

Complement products also change the
surfaces of invading organisms, causing
them to adhere to one another promoting
agglutination
Neutralization of viruses

Complement
enzymes
and
other
complement products attack the structures of
some viruses that render them nonvirulent
Chemotaxis

C5a initiates chemotaxis of neutrophils and
macrophages
Activation of mast cells and basophils

C3a, C4a, C5a activate mast cells and
basophils

Release of histamine, heparin, etc into the
local fluid

Causes increase local blood flow, increase
leakage of fluid and plasma protein into
tissue, inactivatation or immobilization of the
antigenic agent.
Inflammatory Effects

The already increased blood flow to increase
still further

Capillary leakage of proteins are increased

Interstitial fluid proteins coagulate in tissue
spaces, thus preventing movement of
invading organism through the tissues
Figure 21. Phases of Adaptive Immune Responses
Table 7. Basic Types of Acquired Immunity and their
responses
Cell Mediated Immunity
Humoral Immunity
(T Lymphocytes)
(B Lymphocytes)
Activated Lymphocytes
Antibodies
 Fungi, Viruses, Parasites,
 Antibodies
against
Bacteria e.g. TB
bacteria and viruses e.g.
 Destruction of Cancer
measles; mumps and;
Cells
chicken pox
 Transplant Rejection
Table 8. Acquired Immunity.
Active Immunity
 Produced by individuals in
response to natural or
artificial stimulation
 Chickenpox infection
 MMR vaccination


Memory B Cells
o Initial/primary antigen exposure there is a delayed
reaction, weaker in potency and shorter duration
o Once the memory B cells are formed; upon exposure
to the antigen there is an immediate, antibodyantibody reaction, higher potency and longer duration
o Explains the principle of immunization

Mari, Merene
MD-1C 2019
Lec 12 - 27 Aug 2015
Passive Immunity
 Antibodies are derived
from another either by
natural transfer (maternal)
or by injection
 Newborn
 Immunoglobin
IX. Allergy and Hypersensitivity
An important undesirable side effect of immunity is
development, under some conditions, of allergy or other
types of immune hypersensitivity
Allergy caused by Activated T Cells
o Delayed – Reaction Allergy
o Caused by activated T cells and not by antibodies
o Example: poison ivy

Toxin in itself does not cause much harm to the
tissues, however on repeated exposure to the
toxin within a day or so, the activated T cells
diffuse from the circulating blood in large
numbers into the skin to respond to the poison ivy
toxin
Allergies in the “Allergic” Person Who Has Excess IgE
Antibodies
o Atopic allergies – caused by nonordinary response of
immune system
o Genetically passed from parents to child
Page 11 of 13
PHYSIOLOGY – A
Blood Physio pt. 3
o
o
o
o
o
o
Dr. Vienna Blessie N. Baloloy (VBNB)
Presensce of large quantities of IgE in the blood

Reagins / sensitizing antibodies that distinguishes
them from the more common IgG antibodies

IgE reagins is a strong propensity to attach to
mast cells and basophils
Allergen – antigen reacts specifically to IgE reagin
antibody
Anaphylaxis

Widespread
allergic
reaction
occurring
throughout the vascular system and closely
associated tissues.

Hstamine is released into the circulation and
causes body-wide vasodilation, as well as
increased permeability of the capillaries with
resultant marked loss of plasma from the
circulation.

Slow-reacting substance of anaphylaxis if
released can cause spasm of smooth muscle of
the bronchioles, eliciting an asthma like attack,
sometimes causing death by suffocation
Urticaria

Results from antigen entering specific skin areas
and causing localized anaphylactoid reactions.

Histamine released locally causes:

Vasodilation induces red flare

Increased local permeability of the capillaries
leading to local circumscribed areas of
swelling of skin called hives
Hay Fever

Allergen-reagin reaction occurs in the nose

Histamine released in response to the reaction
causes local intranasal vascular dilation, with
resultant incread capillary pressure and
increased capillary permeability
Asthma

Often occurs in the “allergic” type of person

The allergen-reagin reaction occurs in the
bronchioles of the lungs

Sloe-reacting substance of anaphylaxis – causes
spasm of the bronchial smooth muscle

Person then has difficulty breathing until the
reactive products of the allergic reaction have
been removed.
Lec 12 - 27 Aug 2015
X. References
Blood Physio Part 3 ppt
Hall, John E. Guyton and Hall Textbook of Medical Physiology.
Twelfth. Philadelphia: Saunders Elsevier, 2011.
APPENDIX
Figure 22. Acquired Immunity
Mari, Merene
MD-1C 2019
Page 12 of 13
PHYSIOLOGY – A
Blood Physio pt. 3
Dr. Vienna Blessie N. Baloloy (VBNB)
Lec 12 - 27 Aug 2015
Figure 23. Immune response.
Figure 24 Woohoo sa wakas! Cytokines of Innate Immunity.
Mari, Merene
MD-1C 2019
Page 13 of 13
CARDIOVASCULAR PHYSIOLOGY (Gloria Marie M. Valerio, MD)
Outline:
1.
2.
3.
4.
5.
6.
7.
8.
Functional Anatomy of the Heart
Properties of the Myocardial Cells
Electrical Events
Cardiodynamics
Characterics, Properties, Functions of the Different Types of
Blood Vessels
Hemodynamics
Microcirculation
Mechanisms that Regulate Cardiovascular Function
Functional Anatomy of the Heart
The normal position of the heart inside the thoracic cavity is
slightly tilted to the left, pointing downwards.
When the heart contracts, it has a wringing action, meaning to
say, when the heart contracts, it rotates slightly to the right and that will
now expose the cardiac apex, so that when you place the diaphragm of
the stethoscope over the chest wall particularly on the fifth intercostal
space, left mid-clavicular line, that is where you will heartbeat the loudest
called apex beat or point of maximum impulse.
Fifth intercostal space: Start palpating below the clavicle and
first rib – the second intercostal space, and move three spaces down. The
midclavicular line: left of the left clavicle, take note of the mid-point then
move five spaces below. In males, it is easily located because it is exactly
below the left nipple. In females, the location may be variable so you need
to palpate.
the different organs of the body. This is made possible by the pumping
action of the heart, so when the heart contracts, it will pump blood to the
arteries. The arteries in turn will distribute blood at a high pressure to
the different organs of the body. And from the different organs of the
body, blood then will be collected by the veins and returned to the heart.
So the arteries are distributing blood vessels while the veins are
collecting blood vessels. The capillaries will allow the exchange of fluid
and solutes between intravascular and interstitial fluid compartments.
The human heart is divided into two pumps: right and left and
they are connected in series. The left heart pumps blood to the systemic
or peripheral circulation by way of the aorta. The right heart pumps
blood to the pulmonary circulation by way of the pulmonary artery.
Systemic or peripheral circulation includes blood flow to all
organ systems of the body except for the lungs. When the cells of the
systemic or peripheral circulation are metabolizing, they consume oxygen
and produce carbon dioxide that will now be collected by the veins and
will have a low oxygen tension and a high carbon dioxide tension called
unoxygenated/deoxygenated/venous blood. This blood will be
emptied by way of vena cava to the right side of the heart. When the right
heart contracts, this same blood will be ejected to the pulmonary
circulation by way of pulmonary artery. Unlike the other arteries of the
body, the pulmonary artery carries deoxygenated or venous blood. This
same blood will then reach the pulmonary capillaries and this is where
exchange of gases will take place between the alveoli in the lungs and
blood in pulmonary capillary across respiratory membrane. The blood
from the pulmonary capillaries will come from the right side of the heart
– low oxygen tension, high carbon dioxide tension. The opposite is true
with regards to air in alveoli - increase oxygen tension, low carbon
dioxide tension. Movement or transport of these gases across the
respiratory membrane is a passive process. It occurs by simple diffusion
brought about by pressure gradient. So the transport of movement of
oxygen will take place from alveoli to pulmonary capillary, the carbon
dioxide goes in opposite direction. So the blood that will enter the
Alveoli
Increase pO2
Decrease pCO2
Decrease pO2
Increase pCO2
Pulmonary capillary
pulmonary vein is already oxygenated. Unlike the other veins in the body,
the pulmonary vein carries oxygenated or arterial blood which will then
be emptied on the left side of the heart which means the left heart pumps
blood to the systemic circulation and receives blood from the pulmonary
circulation while the right heart pumps blood to the pulmonary
circulation and receives blood from the systemic circulation.
The circulatory system is a closed system – whatever amount
of blood will be pumped by the blood per minute will be equal to the
volume of blood that will return to the heart per minute.
Structures of the Human Heart
PHOTO: Schematic diagram of the parallel and series arrangement of the vessels
composing the circulatory system. The capillary beds are represented by thin lines
connecting the arteries (on the right) with the veins (on the left). The crescent-shaped
thickenings proximal to the capillary beds represent the arterioles (resistance vessels).
The cardiovascular system consists of the heart at the center
and the different blood vessels which are arranged in parallel and in
series with each other. The red are the arteries, the blue are the veins,
and the capillaries are the smallest vessels in the body.
The major function of the cardiovascular system is to transport
nutrients including oxygen to the different organs of the body and to
remove the waste products of metabolism including carbon dioxide from
1
Shannen Kaye B. Apolinario, RMT
The heart is divided into two pumps: the right and the left. The
two pumps in turn are made up of two chambers: atrium and ventricle.
The right heart is made up of the right atrium and right ventricle while
the left heart is made up of the left atrium and left ventricle.
The two atria are separated by a band of connective tissue
forming the interatrial septum. The two ventricles are also separated by
a band of connective tissue forming the interventricular septum. The
two atria are separated from the two ventricles by a mass of connective
tissue. The four chambers of the heart are separated by connective
tissues.
Other important structures in the heart are the valves and
there are two sets of cardiac valves. Between the atria and ventricles are
the atrioventricular valves - tricuspid valve on the right side and
mitral valve on the left side. The tricuspid valve is between the right
atrium and right ventricle while the mitral valve is between the left
atrium and left ventricle. The other sets of cardiac valves are between the
ventricles and the arteries – the pulmonary valve between the right
ventricle and pulmonary artery; the aortic valve between the left
ventricle and aorta. Functions of the valves: first, when they open, they
allow blood to flow from one chamber of the heart to another – when the
atrioventricular valves are open, blood flow from the atria to the
ventricles and when the semilunar valves are open, blood ejects from the
ventricles to the arteries. When they close, they will prevent regurgitation
or backflow of blood. However, there are no cardiac valves between the
atria and veins so when there is atrial contraction, small amount of blood
backflows to the veins. There is only small amount of backflow because
when the atria contracts, there is increase in pressure and the tendency is
to push blood downwards to the ventricles and at the same time, when it
contracts, the orifice of the veins becomes smaller.
Structure of Cardiac Valves
The wall of the atria and ventricles is made up of cardiac
muscle. The atrial wall/musculature is thinner compared to the
ventricular wall or musculature. The two atria functions as a primer
pumps for the ventricles and as conduits of blood from veins to ventricles.
It is therefore the ventricles with the thicker wall that are the major
pumps in the heart with the left ventricular wall thicker than the right
ventricular wall. The left ventricular wall is thicker because it pumps
blood to the systemic circulation with an average pressure of 70-130
mmHg. On the other hand, the right ventricle will pump blood to the
pulmonary circulation with an average pressure of only 4-25 mmHg. The
left ventricle will have to pump blood against a higher pressure resistance
in the systemic circulation compared to the right ventricle that will pump
blood against a lower pressure in the pulmonary circulation. Since the
opposing force is higher in the left ventricle, the tendency is to contract
more forcefully because of increased workload resulting to hypertrophy
of the muscle fibers. Although the left ventricular wall is thicker, contract
more forcefully, higher workload and higher opposing force than the
right, the output of the two ventricles is the same. Whatever amount will
be ejected by the left ventricle per minute is the same with the amount of
blood ejected by the right ventricle per minute.
Aside from the cardiac muscles, the atrial and ventricular wall
also contains a fair amount of elastic tissues that will enable the
different chambers of the heart to dilate when the volume of the blood
inside increases. Also present in the atrial and ventricular wall is a fair
amount of connective tissue and this connective tissue in turn will
prevent overstretching or distension of cardiac muscles when the cardiac
size increases.
PHOTO: Four cardiac valves as viewed from the base of the heart. Note how the leaflets
overlap in the closed valves.
2
Shannen Kaye B. Apolinario, RMT
PHOTO: Drawing of a heart split perpendicular to the interventricular septum to
illustrate the anatomic leaflets of the atrioventricular and aortic valves.
The three cardiac valves – tricuspid, pulmonary and aortic
contains three cusps. It is only the mitral valve that contains only two
cusps. For the atrioventricular valve, the cusps are attached by strong
ligaments called chordae tendinae to the papillary muscle and the
papillary muscle arises from the ventricular wall. Mitral valve has two
cusps attached by the chordae tendinae to the papillary muscle. The
semilunar valve – aortic valve has no chordae tendinae. Tricuspid valve
has chordae tendinae attached to the papillary muscle and arises from the
ventricular wall.
Each cusp has an orifice or opening covered by leaflets which
are made up of loose fibrous tissue. One end of the leaflets is attached to
the border of the orifice while the central part is freely movable. Since it
is thin and freely movable, it can open. However when they close, they
close completely because there is extensive overlapping of the leaflets
that cover the orifice of the cusp. Opening and closing of the cardiac valve
is a passive process brought about by pressure differences between the
two chambers of the heart. In the case of tricuspid valve for example, if
the right atrium is contracting, the right ventricle is in a relaxed state.
When the right atrium is contracting, the pressure increases and that will
push open the tricuspid valve so that blood will flow from the right
atrium and right ventricle. On the other hand, if it now the right ventricle
contracting and the right atrium is relaxed, the high pressure in the right
ventricle will close the tricuspid valve to prevent back flow of blood to the
right atrium. It is also a passive process due to the pressure gradient.
Same things happen with regards to the mitral valve as well as to the
semilunar valves. When the ventricle is contracting, the papillary muscle
also contracts but the contraction of the papillary muscle is not essential
in closing the atrioventricular valves. Remember that when the ventricle
is contracting due to the thick musculature, the pressure is high. So the
high pressure will tend to push the AV valves to bulge into the atria
however, when the papillary muscle contracts, it will pull the chordae
tendinae to prevent eversion or over-bulging of the AV valves during
ventricular contraction.
the leaflets. In insufficient or incompetent cardiac valve, the leaflets do
not close completely allowing back flow of the blood either from the
ventricles to the atria or from the arteries to the ventricles.
In normal mitral valve, when the left atrium is contracting, that
is the amount of blood that will be ejected to the left ventricle. In stenotic
mitral valve, even if the left atrium is contracting, there will be less
amount of blood that will be ejected to the left ventricle. There will be
now pooling of blood in the left atrium causing the left atrium to dilate. In
stenotic aortic valve, the leaflets hardened so that during contraction, the
amount of blood ejected in the aorta will be decreased. There will be
pooling of blood in the left ventricle causing the left ventricle to dilate.
An example of an insufficient or incompetent cardiac valve is a
prolapsed mitral valve. When the left ventricles contract, it does not
close even if there is blood ejected in the aorta, it will be lessened because
of the backflow of blood in the left atrium.
Presence of a stenotic or an incompetent cardiac valve will
produce abnormal heart sounds called a murmur.
PHOTO: Mitral and aortic valves (the left ventricular valves)
Heart Sounds
Aortic
Closing of the cardiac valves will produce the normal heart
sounds. The first heart sound is at the onset of ventricular contraction
with closing of AV valve. That closing of AV valve produces the first heart
sound. Compared to the second heart sound, closing of the AV valve is
said to be louder and longer in duration. The sound produced by the
closing of the tricuspid valve is heard best on the fifth intercostal space,
left of the sternum while the sound produced by closing of the mitral
valve is heard best on the fifth intercostal space at the cardiac apex - left
mid-clavicular line. The second heart sound occurs at the onset of
ventricular relaxation with closing of the semilunar valves. And because
of the pressure in the arterial system, when the semilunar valves close,
they close abruptly and that will make the duration of the heart sound
shorter. The sound produced by the closing of the pulmonary valve is
heard best on the second intercostal space left of the sternum while the
sound produced by the closing of the aortic valve is heard best on the
second intercostal space right of the sternum. The quality of the second
heart sound can be affected by respiratory phase – expiration and
inspiration. During expiration, you will hear only one second heart sound
– there is simultaneous closure of the aortic and pulmonary valves.
During inspiration, there is a physiological splitting of the second sound
with closing of the aortic valve occurring a little ahead of the pulmonary
valve and the sound produced by closing of aortic valve is louder than
that produced of the closing of the pulmonary valve except in patients
with pulmonary hypertension.
The pressure inside the thoracic cavity is negative or below
atmospheric pressure – causing a suction effect on structures that can be
dilated. (In positive or above atmospheric pressure, it will compress the
structures in the thoracic cavity.) The more negative the intra-thoracic
pressure is, the more the heart and lungs are dilated. When the heart is
dilated, it allows more blood to return especially to the right heart – more
blood will return from the systemic circulation. There will be an increase
volume of blood to the right heart causing a delay of the closing of the
pulmonary valve during inspiration.
In children with thin chest wall or patients suffering from left
ventricular failure, a third heart sound can be heard and that will coincide
with filling of blood in the ventricles. Rarely, there is a fourth heart sound
that can be heard and that will coincide with atrial contraction. In some
abnormal conditions, the third and fourth heart sounds may be
accentuated so that what you will hear in the stethoscope will be triplets
of sounds resembling the sound that is produced by galloping horses
called a gallop rhythm.
Certain abnormal conditions like an infection in the heart may
damage the cardiac valves and there are two types of lesions that may
occur in the cardiac valve: stenosis and incompetent cardiac valve. In
stenosis, the valve cannot open completely because of the hardening of
3
Valve
Mitral
Shannen Kaye B. Apolinario, RMT
Type of lesion
Stenosis
Incompetent
Stenosis
Incompetent
Timing of murmur
Diastole
Systole
Systole
Diastole
Diastole – ventricular relaxation
Systole – ventricular contraction
The Pericardium
Pericardial fluid
Parietal pericardium
Visceral pericardium
The heart is covered by a membrane which is made up of
connective tissue – the pericardial sac or pericardium. This connective
tissue that makes up the pericardium is less distensible. Presence of this
will also prevent overstretching of the cardiac muscle when the cardiac
size increases. The pericardium is made up of two membranes: visceral
and parietal pericardium. The visceral pericardium is the membrane
directly attached to the anterior surface of the myocardium. When the
visceral pericardium is reflected back, it forms the parietal pericardium.
The space in between the two membranes is filled with 30cc of
pericardial fluid. The importance of the pericardial fluid is to lubricate
the heart facilitating the movement of the heart when it contracts.
(2) Groups of Myocardial Cells
1.
Automatic Cells
An automatic cell is a cell that is capable of spontaneously
generating its own action potential independent of extrinsic nervous
stimulation. In the case of myocardial cells, it is independent of automatic
stimulation. Aside from generating its own action potential, the cells of
the heart are capable of transmitting or conduction action potentials
throughout the heart. Structures that make up the hearts’ conduction
system:

Synoatrial (SA) node = located at the junction of superior vena
cava and right atrium.

Atrioventricular (AV) node = located posteriorly on the right side
of interatrial septum. It is divided into three zones:
o
Atrionodal (AN) zone – most proximal zone, a transitional
zone between the right atrium and AV node
o
Nodal (N) zone - middle
o

1
Nodal His (NH) zone – most distal, connects with the bundle
of His
Purkinie system/ventricular conduction system = made up of
bundle of HIS and purkinje fibers
o
Bundle of HIS – located at the interventricular septum. The
bundle of HIS forms right and left bundle branches. The left
bundle branch will divide to form the posterior and anterior
fascicles. The left posterior and anterior fascicles as well as the
right bundle branch will then connect with the Purkinje fibers
that are present mostly at the apex of the heart.
2
0
-90 mv
4
3
Skeletal muscle action potential: 5-30 millisecond
Phase 4 – Resting Membrane Potential (-90mv) – membrane is highly
permeable to potassium because of the presence of many potassium leak
channels. Since there are many potassium leak channels on the
membrane of the skeletal muscle and there is a concentration gradient for
potassium, the tendency is for potassium to move out – decreasing the
amount of positively charged ions inside. Also present inside the cell are
negatively charged molecules including proteins which are large
molecules so they remain inside. The main extracellular cation is sodium,
there is a concentration gradient for sodium but the membrane is only
slightly permeable to sodium ions because of there are only few sodium
leak channels – most sodium will remain outside. The membrane is
permeable to chloride at rest, it allows the chloride ions to move in but
because of the presence of the negatively charged ions inside the cell,
chloride will eventually get out. To maintain the concentration of Na and
K inside the cell, you have the activity Na-K pump (3 Na out, 2 K in). These
things stabilize the RMP of the cell to -90mv.
PHOTO: The cardiac conduction system
All of these cells are automatic cells and can generate own
action potential. But in a normally functioning heart, all action potentials
are generated by the sinoatrial (SA) node and is referred as the primary
pacemaker of the heart while the other automatic cells are latent
pacemakers. They are called latent pacemakers because although they do
not normally generate action potential, in some abnormal conditions,
they can be stimulated to generate their own action potential.
The primary pacemaker of heart is the one that determines the
heart rate – number of heart beats per minute. The average heart beats
per minute is 75-80 beats per minute. The SA node is the primary
pacemaker of the heart because it is the fastest that can generate an
action potential. Overdrive suppression is the increase frequency of
discharge of an action potential from an automatic cell will diminish the
automaticity of other automatic cells. The SA node will fire at a high rate
of 75-80 beats per minute with each action potential that will depolarize
other automatic cells. With each depolarization, a certain amount of
sodium ions will enter the cell that will create a concentration gradient
for sodium that will activate the Na-K exchange pump. The Na-K pump
will extrude sodium ions. The more frequent the other automatic cells are
depolarized, the more sodium ions will enter the cell, the more Na-K
pump will be activated, the more sodium ions will be extruded from the
cell that would cause the cell to be hyperpolarized. If the other automatic
cells are hyperpolarized, they will become less excitable. When the
overdrive stops, the activity of Na-K pump will not stop immediately; it
will remain active, continuing to extrude sodium ions, the more the other
automatic cells will become hyperpolarized, the more they will become
less excitable, and the more their automaticity will be diminished. (44m)
Intracellular
Increase K+
Negatively charged proteins
Decrease Na+
Decrease Cl-
Extracellular
Decrease K+
Increase Na+
Increase Cl-
Resting Membrane Potentials:

Neurons = -70mv

Skeletal muscle = -90 mv

SA node = -60mv

Ventricular muscle = -90mv

Gastrointestinal smooth muscle = -60mv
The resting membrane potential is different in each cells because of
the potassium leak channels. The more potassium leak channels present
on the membrane, more K+ will move out of the cell, making the
membrane potential more negative and vice versa.
Phase O – depolarization – opening of fast voltage gated Na+ channels
Phase 1,2,3 – repolarization – re-establishing the RMP, brought about by
the closure of fast voltage gated Na channels and opening of slow voltage
gated K channels. Since these K channels are slow, they remain open for a
long time allowing K+ to continuously move out so that at some point, the
MP will go below the resting level = hyperpolarization. When the K+
gated are closed, the RMP will be restored
Automatic Fiber Action Potential
Non-automatic cells
Non-automatic cells cannot generate own AP and are specialized
mainly for contraction. The presence of non-automatic cells in the heart,
even if you cut the automatic innervation to the cardiac muscle, it can still
contract. Non-automatic cells are the cardiac muscle cells present in the
atrial wall and ventricular wall.
1
2.
0
4
Properties of Myocardial Cells
1st Property: Automaticity – generation of action potentials
4
Shannen Kaye B. Apolinario, RMT
2
3
4
-60 mv
250-300 milliseconds
hyperpolarization
Action potential of an automatic cell- SA node
Difference from the AP of skeletal muscle:

Duration is longer – 250-300 millisecond

RMP is less negative - -60 mv
Non-automatic Fiber Action Potential
(ventricular muscle)
Phase 4 – slow rise in membrane potential and is unstable. The slow rise
in membrane potential is called the pre-potential or slow diastolic
depolarization. There is more Na leak channels, membrane potential
increases.
Phase 0 – Depolarization. Somewhat inclined, depolarization occurs
slowly
Phase 1,2,3 –Repolarization. Inclined, occurs slowly, there is
hyperpolarization like in the skeletal muscle

The increase in sodium leakage and a decrease in the
membrane permeability to potassium will account for the
automaticity of the SA node.
Activation of slow (inclined)
voltage gated long lasting Ca++
channels allowing Ca influx with
some Na influx = MP will become
less negative
Voltage gated K channels will
open allowing K efflux. But
repolarization cannot occur
rapidly because of the long
lasting Ca channels are still open.
Ca influx and K efflux
Midway of repo: Ca
channels close, K
channels open
-40 mv
Na leakage,
Decrease K
-50 mv
Hyper: prolonged
opening of K
channels
-60 mv
250-300 milliseconds
Action potential of an automatic cell
(same thing happens in SA node, AV node, bundle of HIS)
With
parasympathetic
or
vagal
stimulation,
the
neurotransmitter released (NTA) released is acetylcholine (Ache). When
Ache binds with muscarinic 2 receptors in the SA node, it increases
permeability to K+, allowing more K+ efflux. Parasympathetic or vagal
stimulation will hyperpolarize the SA node. If it is hyperpolarized, it is
less excitable and the duration of the membrane pre-potential is longer or
delayed generation of action potential. In parasympathetic or cholinergic
stimulation, SA node is inhibited, heart rate decreases.
The opposite happens with sympathetic stimulation,
norepinephrine released by sympathetic nerves will bind with the B1
receptor in the SA node resulting to an increased permeability to Na and
Ca causing hypopolarization of the SA node, making it more excitable and
the heart rate increases.
PHOTO: Action potential of the SA node
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Shannen Kaye B. Apolinario, RMT
PHOTO: Action potential in the ventricle (250-300 milliseconds)
RMP - -90, straight line, it is stable
Phase 0 – depolarization, straight line. Occurs rapidly due to opening of
fast voltage-gated Na channels = Na influx then reaches the threshold
voltage of -60 mv resulting to depolarization. When the membrane
potential reaches -20 mv, it will open up slow, long lasting voltage gated
Ca channels = Ca influx. (The main factor responsible for depolarization is
Na influx)
Peak of the spike – Na channels closes, K channels open. Ca++ channels
are still open
Phase 1 – initial phase of repolarization – brought about mainly by slow
voltage gated K+ channels
Phase 2 – plateau – the amount of K+ that goes out is equal to the amount
of Ca++ that goes in. no electrical activity. At the end of the plateau, the
Ca++ channels will close leaving only the K+ channels open that will bring
about the final phase of repolarization
Phase 3 – final phase of repolarization
Phase 4 - -90 RMP is re-established. The increase membrane permeability
to potassium is responsible for the -90 mv RMP.
No hyperpolarization –Although the K+ channels can remain open for a
long time, because of the plateau, it is open for a long period of time thus
it does not reach hyperpolarization
Similarities and differences with the action potential of skeletal and
cardiac muscles:

Similarities: -90 mv RMP, fast-paced depolarization

Differences: repolarization, no hyperpolarization, duration
PHOTO: Action potential of the atrium
Similarities and differences between the ventricle and atrium:

Similarities: same, RMP, depolarization, phase 1

Differences:
o
phase 2 – plateau. In the atrium, the membrane is
more permeable to K+ than to Ca++. More K+
conductance than Ca++ conductance that will make
the duration of the plateau shorter and not
sustained as compared to that of the ventricle.
o
Repolarization phase is shorter in atrium than in the
ventricle
Periods of Refractoriness
ARP
RRP
The importance of prolonged duration of refractoriness is for
the ventricles to be filled with blood resulting to a more effective
pumping action, no fatigue, no tetanic contractions. One cannot elicit
successive action potentials or contractions without tetanic or sustained
contractions in the cardiac muscle = allow more time for ventricular
filling. The musculature of the ventricle is thick so when it contracts, it
compresses the coronary arteries. The coronary arteries supply blood
and oxygen to the cardiac muscle thus when it is compressed, there is
poor perfusion of cardiac muscle and less oxygen supply, this happens if
there is tetanic contractions but in the cardiac muscle, there are no
tetanic contractions. There is longer period of relaxation, when the
ventricles are relaxed, there will be better perfusion of the cardiac
muscle.
Duration
Action potential
ARP
RRP
In Absolute or Effective Refractory Period (ARP), no
amount of stimulus intensity will be able to re-excite the membrane of
that cell. It covers the whole of depolarization until 1/3 of the
repolarization phase. At phase 0, it is absolute refractory because all the
voltage gated sodium channels are open and it is not able to re-open the
already open sodium channels. In phases 1 and 2, the Na channels are
already close but it is still absolute refractory because Na channels are
voltage gated and they only open at a certain voltage or membrane
potential near the critical firing level of about -60mv more so if the
membrane potential is at its resting level. It is far from the CFL.
In Relative Refractory Period (RRP), its level is near the
critical firing level and resting level, the membrane becomes more
excitable so that a stronger than threshold stimulus can be able to open
up the voltage gated sodium channels and elicit a second action potential.
Heart rate of 75
beats per min
0.25 sec
0.20 sec
0.05 sec
Heart rate
200/min
0.55 sec
0.13 sec
0.02 sec
Skeletal muscle
0.005 sec
0.004 sec
0.001 sec
PHOTO: Changes in action potential amplitude and upstroke slope as action potentials
are initiated at different stages of the relative refractory period of the preceding
excitation
As the membrane potential reaches the relative refractory
period as well as the RMP, if there is stimulus later in the RRP, that will
open up more and more voltage gated Na channels so that its
depolarization increases its amplitude, same thing happens in the SA
node.
2nd Property: Rhythmicity
It is said that the SA node generates the action potentials at
regualr intervals. Even if the heart rate increases, if the impulses are still
generated at regular intervals, that is still called the sinus rhythm.
Photo: Normal sinus rhythm
PHOTO: Relationship between action potential and contraction in the ventricle
A contraction cannot be elicited unless the ventricle is almost
completely relaxed.
Photo: Normal ECG
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Shannen Kaye B. Apolinario, RMT
P wave – represents atrial depolarization
QRS complex – represents ventricular depolarization
When seeing a normal sinus rhythm, take note of the interval
between successive P waves – regular interval, take note of the interval
between successive QRS complex – regular interval.
Photo: Sinus tachycardia
The heart rate may increase with sympathetic stimulation,
during moderate to heavy exercise, and increase temperature during
fever. In these three conditions, the heart rate will increase but if the
impulses are generated at regular intervals, that is still sinus rhythm. But
since the rate will increase, it is now called sinus tachycardia.
With regards to the right and left atrium, transmission of
impulses can occur locally through gap junctions. When the impulse
reaches the AV node, there is a delay in the transmission of impulses so
the velocity of conduction decreases at the AV node and this is called the
AV nodal delay. Most of the delay will take place between the AN and N
zones of the AV node. There is a delay in the transmission of impulses in
the AV node because it has a small fiber diameter and few gap junctions –
spaces or channels between the membranes of the muscle fibers that will
allow ions to flow freely from one muscle fiber to the next. The smaller
fiber diameter and fewer gap junction causes increased resistance to
impulse conduction - the AV nodal delay. The importance of AV nodal
delay is for the ventricles to remain in a relaxed state for a longer period
of time allowing more time for the ventricular filling and to ensure that
the atria and ventricles will not contract simultaneously.
From the AV node, the impulse will then travel to the bundle of
His then to the left and right bundle branches then to the Purkinje fibers
then it would stop (from antero-basal  apex  end).
Transmission of impulse in heart:
antero-basal  apex  postero-basal
The part of the heart that will depolarize last is the posterobasal.
Conduction Speed in Cardiac Tissue
Photo: Sinus bradycardia
On the other hand, in cold temperatures or if there is vagal
over stimulation that inhibits the SA node, the rate of firing will decrease
but if the impulses are generated at regular intervals, that is still sinus
rhythm but this time, it is now called sinus bradycardia.
If there is no rhythm or if it is irregular, it is now called
arrhythmia.
SA node
Atrial muscle
AV node
Bundle of His
Purkinje fibers
Ventricular muscle
Conduction rate (m/sec)
0.05
1
0.05
1
4
1
Conduction speed is lowest in the AV node (not in the SA node
because it is generation). Fastest is in the Purkinje fibers because of the
large fiber diameter. In the atria and ventricles, conduction of impulses
may occur locally through gap junctions.
Reentry
3rd Property: Conductivity
Photo: Transmission of the cardiac impulse through the heart, showing the time of
appearance (in fractions of a second after initial appearance at the sinoatrial node) in
different parts of the heart.
All impulses from a normal functioning heart will come from
the SA node. From the SA node, the impulse will be transmitted to the AV
node and transmission of impulses from the SA node to the AV node is
facilitated by means of three internodal tracts: anterior internodal tract of
Bachmann, middle internodal tract of Wenckeback and posterior
internodal tract of Thorel. Take note that the tips of the fibers of the SA
node are directly connected to the right atrial muscle cells so there is
direct transmission of impulses from the SA node to the right atrium.
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Shannen Kaye B. Apolinario, RMT
Photo: The role of unidirectional block in re-entry. In A, an excitation wave traveling
down a single bundle (S) of fibers of continues down the left (L) and right (R)
branches. The depolarization wave enters the connecting branch (C) from both ends
and is extinguished at the zone of collision. In B, the wave is blocked in the L and R
branches. In C, a bidirectional block exists in branch R. in D, a unidirectional block
exists in branch R. the antegrade impulse is blocked, but the retrograde impulse is
conducted through and re-enters bundle S.
A – Normal direction. Coming from the SA node to the AV node to the
bundle of His. From the bundle of His, the impulse will be transmitted to
the left and right bundle branches. From the left and right bundle
branches to the apex of the heart but there is a connecting fiber between
the right and left bundle branches.
B – Both left and right bundle branches are blocked so there is no impulse
transmission to the apex of the heart as well as to the connecting fiber.
C – Only one bundle branch is blocked (right bundle branch). The impulse
that is supposed to go the right bundle branch is blocked but the left
bundle branch goes to its normal route – to the apex and to the
connecting fiber. The one that goes to the connecting fiber can now go to
the apex but can also go back to the area that is blocked; this is called reentry or circus movement.
D – Since the right bundle branch is blocked, the transmission of impulse
is blocked while that coming from the left will re-enter the area where the
impulse came from, it goes round and round that’s why it is called circus
movement. Reentry or circus movement is possible because the distance
travelled by this impulse is longer compared to other one which is
blocked so it becomes refractory. Since the distance is longer, when it
reaches the area that is blocked, it becomes out of refractory/out of
refractoriness so it can go back. Because of this phenomenon, this is the
path that is responsible for atrial or ventricular fibrillation/flatter. In
the synchronised contraction, the whole atria or the whole ventricle,
there is an area that will contract and there is an area that will relax.
Ectopic Tachycardias
Atrial contraction
Ventricular contraction
AV nodal delay
Most of the blocks takes place in the AV node so that it will
produce the 1st degree, 2nd degree and 3rd degree heart block, all of
these are abnormal conditions. The normal ratio between atrial and
ventricular depolarization is 1:1, so that during atrial and ventricular
contraction, if the atria will contract three times, the ventricles will also
contracts three times but atrial contraction happens first than ventricular
contraction causing an AV nodal delay.
1st degree heart block – Incomplete heart block. All impulses from the SA
node can still be transmitted to the ventricles. Based on the spacings in
the photo, there is atrioventricular depolarization happening. The ratio of
ventricular depolarization is still 1:1. So that when it contracts – three
contractions in the atria, there will also be three contractions in the
ventricles. The difference from the normal is that it has a longer duration
of the AV nodal delay.
2nd degree heart block – Not all impulses from the SA node will reach the
ventricles. What happens is P-P-QRS, P-P-QRS. This time, the ratio of the
atrial to ventricular depolarization is 2:1 or 3:1. Not all the impulses
reach the ventricles but since there are impulses that can reach the
ventricles, this is still an incomplete heart block.
3rd degree heart block – Complete heart block. No impulses from the SA
node will be able to reach the ventricles. What happens is P-P-P-P. The
atria will be contracting normally at a rate that is dictated by the SA node;
that is 75 beats per minute. Initially, the ventricle will not contract
because no impulses will reach the ventricles but there are pacemaker
cells in the ventricles – the bundle of His and Purkinje fibers. The two are
latent pacemakers and they are also automatic cells. For 20 seconds,
there will be no impulse coming from the SA node, the latent pacemaker
in the ventricle specifically the Purkinje fibers will be activated, it will
escape from the overdrive suppression and this is called the ventricular
escape. When activated, the Purkinje fibers will generate its own impulse
causing the ventricles to contract at a rate that is dictated by the Purkinje
fibers. If the contraction in the atria is 75 beats per minute, in the
ventricle, it is 30-40 beats per minute. The firing of Purkinje fibers is
slower than the SA node.
Another abnormal condition is the presence of a premature
contraction or an extrasystole wherein another contraction happens in
response from an impulse that will not come from the SA node. For
example, there is atrial contraction that is initiated by the impulse from
the SA node, other parts of the atria will be activated, and there will be an
ectopic fossi – impulse coming from other sources. So when it contracts, if
there is another impulse, there will be another contraction and this is
premature contraction or extrasystole.
PHOTO: Frequency summation and tetanization
In wave summation in the skeletal muscles, if three maximal
stimuli is applied successively, the magnitude of the 2nd contraction is
higher than the first because in the muscle, calcium ions have not yet
returned to the sarcoplasmic reticulum and when another stimuli is
applied, there will be more releasing of calcium ions that will increase the
force of contraction.
PHOTO: AV blocks. A, First-degree block; the PR interval is 0.28 second (normal: <0.20
sec). B, Second-degree block (2:1). C, Third-degree block; note the dissociation between
the P waves and the QRS complexes
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Shannen Kaye B. Apolinario, RMT
In cardiac muscle, the magnitude of the 2nd contraction is lower
than the first. Take note that extrasystole can only be elicited during the
mid or late diastole. It is not able to elicit an extrasystole during systole or
early diastole because of the long duration of the Absolute Refractory
Period. Another contraction can be produced only during the mid or late
diastole when the muscle is almost completely relaxed (Note: “almost”
but not yet relaxed).
Remember that one of the important factors that will
determine the force of cardiac muscle contraction is the volume of blood
that will stretch the muscle before contraction. The longer the relaxation
phase, the more blood will be filled in the ventricles, the greater the
stretch of the cardiac muscle will be and the greater the force of
contraction will be.

There is a decrease in the magnitude of the 2nd contraction
because the relaxation phase is not yet complete so the filling of the blood
is less resulting to less stretch of the muscle and less force of contraction.
Elastic tissue. Fair amount of elastic tissue that will enable the
chambers of the heart to dilate to accommodate a greater volume of
blood.

Connective tissue. Presence of connective tissue that will prevent
over distension or overstretching of a cardiac muscle when the
cardiac size increases.

More mitochondria and active capillaries. Compared to the skeletal
muscle, there are more mitochondria as well as active capillaries in
the cardiac muscle and that is important because the main source of
energy for cardiac muscle contraction is oxidative metabolism.

Sarcoplasmic reticulum. The sarcoplasmic reticulum in the cardiac
muscle is less well developed. Meaning to say, it can’t store large
quantities of calcium ions that will provide for full contraction so
there has to be another source of Ca++ for the cardiac muscle
contraction and that is the extracellular fluid (ECF). And because the
transverse tubular system in the cardiac muscle is more developed –
it has a bigger diameter; it can allow more Ca++ from the ECF to
enter the cardiac muscle cell.




4th Property: Contractility
Important characteristic of a cardiac muscle:

Involuntary. Activity of the heart is not controlled by the cerebral
cortex, it is controlled by the autonomic nervous system although
there are automatic cells present in the heart.

Smaller. Compared to skeletal muscle cell, the cardiac muscle cell is
smaller

Either binucleated or mononucleated

Striated. Just like the skeletal muscle cell, the cardiac muscle is
striated. Striated means that the muscle fibers are distinctly
separated from one another. What separates the individual muscle
fibers is the Z line that is why the area between two Z lines will form
a sarcomere. The difference between the skeletal and cardiac muscle
cell is that the membrane of the cardiac muscle branches out to
reconnect with the membrane of the next muscle fiber so that the
force generated with one muscle fiber can be transmitted to the
other muscle fibers as well.
Nebulin – forms the scaffold of the thin filament
α actinin – will connect the thin filament to the Z line
Titin – connects the thick filament to the Z line
Tropomodulin – regulates the length of the thin filament
PHOTO: “Syncytial,” interconnecting nature of cardiac muscle fibers.


Presence of the intercalated disk. The intercalated disk is present on
the Z line. Its function is to separate one muscle fiber from another
but at the same time, to connect one muscle fiber to another by
means of gap junctions. Present in the intercalated disk are channels
that will allow ions to flow freely from one muscle fiber to the next
so that when an action potential is generated anywhere in a bundle,
it can be transmitted rapidly causing the whole bundle to be
depolarized at the same time and to contract as a single unit and this
is called a syncytial type of arrangement of muscle fibers. The
cardiac muscle cell anatomically is striated but functionally or
physiologically, it is a syncytium. The syncytial arrangement of
muscle fibers is important because it will provide synchronized
contraction of the atria and ventricles that is important for the
pumping action of the heart. It will also provide synchronized
relaxation of the atria and ventricles that is important for filling of
blood in the different chambers of the heart.
Contractile proteins present:
 Thick filament - myosin
 Thin filament – actin, troponin, tropomyosin
 Meromyosin, C protein – forms the scaffold or suport of the
thick filament
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Shannen Kaye B. Apolinario, RMT
PHOTO: Cardiac muscle (panel A) has high resistance to stretch when compared with
skeletal muscle (panel B). When either cardiac or skeletal muscle is stretched, there is
an increase in resting tension (RT). If the muscle is then stimulated to contract
maximally, it generates more tension (termed total tension – TT). The difference
between total tension and resting tension at any given length is the force produced by
contraction (e.g. active tension – AT). The bell-shaped dependence of active tension on
muscle length is consistent with the sliding filament theory of cardiac and skeletal
muscle. It is, however, difficult to stretch cardiac muscle beyond its optimal sarcomere
length, as evidenced by the rapid rise in resting tension in the middle of the bell-shaped
AT curve.
Above is a graph that shows the importance of the presence of
elastic tissue in the cardiac muscle. The blue line represents the resting
tension – tension that develops in the muscle before contraction. The red
line represents active tension – tension that develops in the muscle
during contraction. Because of the many elastic tissue in the cardiac
muscle, even in the resting state or resting length, passive tension
increases in the muscle and it can dilate so that when the cardiac muscle
fiber contracts, the difference between active and passive tension is
smaller compared to skeletal muscle. The importance of that is the
different chambers of the heart can accommodate a large volume of blood
with little increase in pressure.
Excitation-Contraction Coupling
potassium ions pumped into the cell so that it will create a concentration
gradient for sodium – increased concentration outside, low concentration
on the inside. That will now activate the sodium-calcium exchange pump
that will pump three Na+ in, in exchange for one Ca++ that is pumped out
of the cell and that is the main means by which Ca++ is extruded from the
cardiac muscle cell.
In patients suffering from heart failure, the main problem is
poor force of contraction of the ventricle. This poor force of contraction
has to be made strong by giving cardiac glycosides (e.g. digitalis). The
main mechanism of action of cardiac glycosides is to inhibit the sodiumpotassium pump. If this pump is inhibited, Na+ will not be extruded so
that will not create a concentration gradient for Na+. If there is no
concentration gradient for Na+, nothing will activate the sodium-calcium
pump so Ca++ will remain inside the cell and that can be utilize to
increase the force of ventricular contraction.
Arrangement of Muscle Fibers
When the heart contracts, it rotates slightly to the right and
that will expose the cardiac apex. The heart can rotate when it contracts
because of the arrangement of muscle fibers. The arrangement of muscle
fibers is synospiral and bulbospiral.
Autonomic Innervation of the Heart
How does the Autonomic Nervous System (ANS) regulates the
cardiac activity?
Sympathetic:
T3
T4
T5
PHOTO: Excitation-contraction coupling in the heart requires Ca++ influx
through L-type Ca++ channels in the sarcolemma and T tubules.
Present on the membrane or sarcolemma is a calcium pump,
calcium-sodium exchange pump, sodium-potassium exchange pump and
the last two are antiporters. Invagination of the sarcolemma will form the
T-tubules. Present on the membrane of the T-tubules are voltage-gated
calcium channels. Inside the cell, there are myofilament and sarcoplasmic
reticulum (SR). On the membrane of the sarcoplasmic reticulum is
another calcium pump. Also on the membrane of SR are ryanodine
receptors and these receptors are calcium-gated calcium channels.
What happens is when a membrane is depolarized, this will
activate the voltage-gated calcium channels of the membrane of the T
tubule and that will allow Ca++ to enter from the extracellular fluid (ECF)
to the inside of the cardiac muscle cell. Some of this Ca++ will
immediately bind with troponin C forming the calcium-troponin C
complex that will initiate muscle contraction but some of the Ca++ will
bind with the ryanodine receptors on the membrane of SR activating the
calcium-gated calcium channels that will allow Ca++ to move out from the
SR to the cytoplasm to bind with troponin C. The difference of this from
the skeletal muscle is that the Ca++ from the SR will not move out unless
there is a trigger that will cause the Ca++ to move out. The trigger is also
Ca++ from the ECF that will bind with ryanodine receptors hence it is
called calcium-gated calcium channels. It needs Ca++ from ECF to trigger
movement of Ca++ from SR into the cytoplasm. That is why it has two
sources of Ca++ compared to skeletal muscle – the SR and ECF. If there
are already many Ca++, the force of contraction is stronger. With
repolarization, it is expected that the muscle will relax but for the muscle
relax; Ca++ has to be removed. Ca++ is removed by the activity of calcium
pump on the membrane of the SR that will actively transport Ca++ back
into the SR. Another means to remove Ca++ is through the activity of the
calcium pump on the sarcolemma that will actively transport Ca++ back
into the ECF. But the most important means by which calcium is extruded
from the cardiac muscle cell is through the activity of the sodium-calcium
antiporter. Initially, with repolarization, the sodium-potassium pump is
activated that will pump three sodium ions out in exchange for two
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Shannen Kaye B. Apolinario, RMT
Norepinephrine + β1 receptor
SA node
AV node
Purkinje system
Atrial muscle
Ventricular muscle
First, the sympathetic nerves that innervate the heart originate
from T3, T4, and T5 segments (T = thoracic). Pre-ganglionic fibers from
T3, T4 and T5 will synapse with the sympathetic ganglia and this is called
the sympathetic chain. Post-ganglionic fibers from the sympathetic
chain will bind with β1 receptors in the heart and the neurotransmitter
agent (NTA) released by these sympathetic nerves is norepinephrine
(NE). The effect of NE at the myocardial cells is to increase membrane
permeability to Ca++ and Na+ so that will make the myocardial cell more
excitable and therefore increased cardiac activity. Sympathetic nerves
innervate ALL structures in the heart either automatic and non-automatic
so that will include the sinoatrial (SA) node, atrioventricular (AV) node,
ventricular conduction system or the Purkinje system as well as the atrial
and ventricular muscle.
Parasympathetic:
CN 10
Acetylcholine + M2
SAN
AVN
Atrial muscle
On the other hand, parasympathetic innervation to the heart is
carried by the vagus nerve which originates from the medulla. So the
vagus nerve will bind with muscarinic 2 receptors in the heart and the
NTA released is acetylcholine (Ache). The effect of Ache on the
myocardial cells is to increase membrane permeability to K+ so that will
hyperpolarize the myocardial cells inhibiting them or decreasing cardiac
activity. The structures in the heart that receive parasympathetic or vagal
innervation are the SA node, AV node, only the proximal part of the
bundle of His, atrial muscle, and there is very little, if any, vagal
innervation to the ventricles.
Chronotropic regulation:
Sympathetic
Increased frequency of discharge of the SA node
Increased the heart rate
Parasympathetic
Decreased frequency of discharge by the SA node
Decreased the heart rate
In relation to this, let’s look at how the autonomics regulate
cardiac activity: First, regulation of heart rate is called chonotropic
regulation. The sympathetic nervous system will increase the activity of
the SA node so that this stimulation will increase the frequency of
discharge of action potentials from the SA node, increasing the heart rate.
On the other hand, parasympathetic or vagal stimulation will inhibit the
SA node, decreasing the heart rate.
Dromotropic regulation
Sympathetic
Increased velocity of conduction
Decreased duration of AV nodal delay
Parasympathetic
Decreased velocity of conduction
Increased duration AV nodal delay
Lead I represent electrical potential difference between
electrodes that are placed on the right arm and on the left arm. In lead I,
the electrode that is on the right arm is the negative electrode that of the
left arm is the positive electrode.
Lead II represents electrical potential difference between
electrodes that are placed on the right arm and on the left leg. The
electrode of the right arm is designated as the negative electrode that of
the left leg as the positive electrode.
Lead III represents electrical potential difference between
electrodes that are placed on the left arm and on the left leg. The
electrode of the left arm is designated as the negative electrode that of the
left leg as the positive electrode.
Regulation of the velocity of conduction of impulses in the
heart is called dromotropic regulation. Sympathetic stimulation will
increase the velocity of conduction of impulses in the heart so it will
decrease the duration of the AV nodal delay. In contrast, parasympathetic
stimulation decreases the velocity of conduction of impulses in the heart
prolonging the duration of the AV nodal delay.
*** In parasympathetic or VAGAL stimulation, buma-VAGAL ang heart
rate and velocity of conduction. 
Inotropic regulation
Sympathetic
Increased force of atrial and ventricular contraction
Parasympathetic
Decreased force of atrial contraction
Regulation of the force contraction of the myocardial cells or
inotropic regulation is by increasing membrane permeability to Ca++.
Sympathetic stimulation increases the force of contraction of both the
atria and ventricles. As for parasympathetic stimulation, it decreases the
force of atrial contraction and it has no direct effect on the force of
ventricular contraction. It has no direct effect but it has an indirect effect,
that is, parasympathetic stimulation will prolong the duration of the AV
nodal delay allowing more time for ventricular filling so the more the
ventricles are filled with blood, the more the ventricular wall is stretched,
and the greater will be the force of ventricular contraction.
Cardiac Cycle
Cardiac cycle is the sequence of events - electrical and
mechanical events taking place in the heart from the beginning of one
heart beat initiated by an impulse from the SA node to the beginning of
the next heart beat also initiated by an impulse from the SA node.
Electrical events – depolarization, repolarization of the atria and
depolarization and repolarization of the ventricle
Mechanical events – contraction or relaxation of the atria and ventricles
Electrical events
The electrical events will precede the mechanical events. All
the electrical events taking place in the heart can be recorded by the
electrocardiogram (ECG). To get an ECG tracing, electrodes are placed
on the four extremities of the subject as well as on different locations on
the chest wall. This electrodes act as sensors so that it will be able to pick
up electrical potentials produced by the myocardial cells so that what is
seen on the ECG tracing will represent electrical potentials and electrical
activities of the myocardial cell.
PHOTO: Einthoven triangle illustrating the electrocardiographic connections for
standard limb leads I, II, and III.
The electrode that is placed on the right arm is always negative
and on the left leg, it is always positive. In one lead, the electrode is
positive when it is located nearer on the apex of the heart. Lead II will
approximate the direction of impulse transmission in the heart. So that
when asked to measure the duration of the different ECG waves, the
amplitude of the different ECG waves, it is preferable to use lead II
because it approximates the direction of impulse transmission in the
heart – right arm is negative, left leg is positive (from base to apex).
Right arm
(negative)
By placing electrodes particularly on the four extremities,
bipolar limb leads are formed or standard limb leads. There are three
bipolar limb leads – Lead I, II and III. These leads will represent electrical
potential difference between two electrodes placed on two different
extremities. In order to have an electrical potential difference between
two electrodes, one electrode is arbitrarily designated as the negative
electrode and the other one is the positive electrode.
Left leg
(positive)
Lead II
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Shannen Kaye B. Apolinario, RMT
repolarization, it will appear as a downward or negative deflection
because the direction of repolarization in the atria follows the direction of
depolarization – repolarization is toward a positive electrode. This means
that in the atria, the first part to depolarize is also the first part to
repolarize and the last to depolarize is also the last part to repolarize.
P-R segment
(isoelectric)
S-T segment
(isoelectric)
When the impulse reaches the AV node, there will an AV nodal
delay ad that is represented by the straight line called a P-Q or P-R
segment. The P-R segment starts at the end of P up to the beginning of
the QRS complex. It is a straight or isoelectric line because of the delay on
the impulse transmission at the AV node.
From the beginning of P to the beginning of the QRS complex is
the P-R interval. The P-R interval will cover the P wave representing
atrial depolarization and the P-R segment that represents AV nodal delay.
PHOTO: Depolarization of interventricular septum from the left to right bundle branch
PHOTO: Important deflections and intervals of a typical scalar ECG.
Above is an example of an ECG tracing that shows electrical
events in the heart in one cardiac cycle. The P wave represents atrial
depolarization, QRS wave or complex represents ventricular
depolarization, and T wave represents ventricular repolarization.
ECG Rules:
Depolarization
(+) electrode = upward
Depolarization away from (+) electrode = downward
Repolarization
(+) electrode = downward
Repolarization away from (+) electrode = upward
Why is there an upward or positive deflection and a downward
or negative deflection? The rule in ECG is that if depolarization will move
towards a positive electrode, it is recorded as an upward or positive
deflection. On the other hand, if depolarization will move away from a
positive electrode, it is recorded as a downward or negative deflection. In
repolarization, if the electrode moves toward a positive electrode, it is
recorded as negative or downward deflection and if repolarization will
move away from a positive electrode, it is recorded as an upward or
positive deflection. Remember that in lead II, the positive electrode is on
the left leg.
P wave
P wave - atrial depolarization, it is a positive deflection.
Remember that the impulse is generated from the SA node transmitted to
the AV node so the direction of impulse transmission in the atria is it
moves towards a positive electrode. That is why the P wave is recorded
as an upward deflection.
There is no ECG wave that represents atrial repolarization
because atrial repolarization occurs simultaneously with ventricular
depolarization. If ever there is an ECG wave that will represent atrial
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Shannen Kaye B. Apolinario, RMT
QRS complex will represent ventricular depolarization. It is a
complex made up of three waves. In the QRS complex, there is an initial
negative or downward deflection that represents depolarization of the
interventricular septum which will occur from left bundle branch to right
bundle branch. The positive electrode is in the left leg [it is moving from
the left to right bundle branch] so it is moving away from a positive
electrode that is why the Q wave which represents the depolarization of
the interventricular septum and is recorded as a downward or negative
deflection.
R wave is a very high positive deflection that represents
depolarization of the cardiac apex that is definitely towards a positive
electrode.
Then there is a second downward deflection which is the S
wave. So which part of the heart will depolarize last? Usually it goes from
the anterobasal  apex  posterobasal so when the wave of
depolarization moves from the apex to posterobasal part, again it is
moving away from a positive electrode so the S wave which represents
depolarization of the posterobasal part of the ventricle is recorded as
negative or downward deflection.
T wave is only a part of ventricular repolarization because
ventricular repolarization starts at the end of QRS complex. So from the
end of S wave to the beginning of T wave, there is an isoelectric line or the
S-T segment. Recall the action potential generated in the ventricle, the
phase of repolarization that represents the S-T segment is the plateau or
phase II. There is a straight line because of the equal conductance of Ca+
and K+; there is no change in membrane potential.
The T wave will represent only the phase III of repolarization
or the final phase of repolarization and it is a positive or upward
deflection. In the ventricles, the repolarization does not follow the
direction of depolarization, unlike in the atria. Repolarization will occur
in the opposite direction: from posterobasal  apex  anterobasal. It is
moving away from a positive electrode because from the apex, it will go
up hence it is recorded as an upward or positive deflection. So in the
ventricles the first part of the ventricles that will depolarize is the last
part to repolarize and the last part to depolarize will be the first part to
repolarize. So when it is said ventricular repolarization, it is actually the
S-T interval, from the end of S to the end of T, not just the T wave.
Mechanical events
Following depolarization, the atrial and ventricular muscles
will contract and it is called the systole. During systolic phase of the
cardiac cycle, blood is ejected from the different chambers of the heart.
Following repolarization, the muscles will relax and it is called diastole.
During diastolic phase, there will be filling of blood in the different
chambers of the heart.
The average duration of one cardiac cycle is 0.8 second. The
duration of the systolic phase is 0.27 second and that of the diastolic
phase is longer which 0.53 of a second and this happens at the heart rate
of 75 beats per minute. When the heart rate increases, the duration of the
cardiac cycle will decrease so the duration of the systole and diastolic
phases is also decreased. But there is a greater decrease in the duration of
the diastolic phase and there is a constant duration in the systolic phase
when the heart rate increases.
Correlation of the Electrical and Mechanical Events in the Heart in
One Cardiac Cycle
SAN
atr. depo
(P wave)
AVN
VCS
atr. systole
delay
(P-R segment)
20% VF
inc. AP (a wave)
inc. VF
vent. depo
(QRS)
atr. repo
vent. systole
inc. VP
atr. diastole
dec. AP
VP > AP
close AV valves (1st heart sound)
isovolemic contractions: slight inc. AP (C wave)
VP > 80 mmHg
open SL valves
rapid ejection
reduced ejection; atrial filling
vent. repo
vent. diastole
dec. VP
(S-T interval)
AP > VP
protodiastole
close SL valves
(2nd heart sound)
isovolemic relaxation; inc. atr. filling;
inc. AP (V wave)
AP > VP
open AV valves
rapid inflow
diastasis – reduced inflow of blood to the ventricles
atr. – atrial
AV - antrioventricular
AVN – atrioventricular node
dec. - decrease
depo – depolarization
inc. - increase
repo – repolarization
SAN – sinoatrial node
SL - semilunar
vent. – ventricular/ventricle
VF- ventricular filling
VP – ventricular pressure
At the beginning of one cardiac cycle, before an impulse is
generated from the sinoatrial (SA) node, the atrium and ventricles are all
relaxed – atrial systole and ventricular diastole. The semilunar (SL)
valves are closed but the atrioventricular (AV) valves are open so that
will allow blood to flow from the atria to the ventricles. In fact, 80% of
ventricular filling (VF) takes place when all four chambers of the heart
are in a relaxed state. It is not needed for the atria to contract to have
ventricular filling because its contraction is weak – “primer pump”, so
whenever the AV valves are open, there is 80% of ventricular filling.
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Shannen Kaye B. Apolinario, RMT
An impulse will be generated from the SA node transmitted to
the AV node. Transmission of the impulse from the SA node to the AV
node is facilitated by the three internodal tracts: Bachman, Wenckeback
and Thorel. In the process, the atria will undergo depolarization recorded
in the ECG as the P wave. The response of the atrial muscle to
depolarization is to contract so there will be atrial systole. When the atria
contracts, although it is a weak pump, there is still blood ejected to the
ventricles and that will account for only 20% of ventricular filling. When
the atria are contracting, atrial pressure increases and remember that
there are no cardiac valves between the atria and veins so that any
increase in atrial pressure can be transmitted to the veins so that in the
recording of the jugular venous pressure curve will show increase atrial
pressure during atrial systole and this is called A wave. A wave is not an
ECG tracing, it is only a label to the increase atrial pressure during atrial
systole.
When the impulse reaches the AV node, there will be a delay
called the AV nodal delay, in the ECG that is recorded as the P-R segment.
The importance of the AV nodal delay is that it will provide more time for
ventricular filling.
From the AV node, the impulse will now be transmitted to the
ventricular conduction system (VCS) or Purkinje system and that will
cause ventricular depolarization in the ECG recorded as the QRS complex.
The response of the ventricular muscle to depolarization is to contract so
following ventricular depolarization will be ventricular systole. When the
ventricles contract, the ventricular pressure increases. Simultaneous with
ventricular depolarization is atrial repolarization and no ECG wave
represents atrial repolarization. The response of the atrial muscle to
repolarization is to relax so atrial diastole happens. Since the atria is
relaxed, there will be a decrease in the atrial pressure. When the
ventricular pressure exceeds atrial pressure, there will be a pressure
gradient and that will now close the AV valves therefore the first heart
sound will be heard. There will be a condition wherein the SL are still
closed and the AV valves are now closed, there is no change in ventricular
volume because all the cardiac valves are closed but since the ventricles
are contracting, there is increase in ventricular pressure and this is called
isovolumic or isovolumetric contraction phase of the cardiac cycle.
When the ventricles are contracting, ventricular pressure still
increases and this high pressure may push the AV valves to bulge into the
atria and that will cause a slight increase in atrial pressure which is now
called the C wave. But remember that the AV valves does not over-bulge
into the atria when the ventricular pressure is increased because when
the ventricles contract, the papillary muscles will contract pulling the
chordae tendinae which will prevent over-bulging of the AV valves into
the atria resulting to only a slight increase in the atrial pressure.
When ventricular pressure exceeds 80 mmHg, this will push
open the SL valves and following the opening of the SL valves is the
period of rapid ejection of blood from the ventricles to the arteries: aorta
and pulmonary arteries. But when it is ejecting more and more blood, the
volume of the blood in the ventricles as well as ventricular pressure will
start to decrease. So the period of rapid ejection will now be followed by a
period of reduce ejection of blood from the ventricles to the arteries and
at the same time, the blood that is contained in the aorta will drop off to
the arteries to the different organs of the body and the veins are also
collecting blood so that little by little, there will be atrial filling.
The ventricles will undergo repolarization so this is the S-T
interval in the ECG. The response of the ventricular muscle to
repolarization is to relax so there will be ventricular diastole therefore
ventricular pressure will start to decrease. Pressure in the aorta or in the
arterial system is always high so that when arterial or aortic pressure
now exceeds ventricular pressure, this will close the semilunar valves and
that will produce the second heart sound. But there is a short interval of
time between ventricular diastole and closure of SL valves which is called
protodiastole.
There will be a condition again wherein the SL valves are now
closed, the AV valves are still closed so there is no change in ventricular
volume but since the ventricles are in a relaxed state, ventricular
pressure decreases and this is called isovolumic relaxation. At the same
time as isovolumic relaxation, the atrial filling increases which will again
increase atrial pressure and is called the V wave.
When atrial pressure exceeds ventricular pressure, this will
now open the AV valves which will be followed by a period of rapid
inflow of blood to the ventricles and this event will account for the 80% of
ventricular filling. When there is more blood filled in the ventricle, it will
be slightly stabilized so that the period of rapid inflow will be followed by
a period of reduced inflow of blood to the ventricles called diastasis.
From that, there will be another impulse from the SA node beginning
another cycle. All of these events take place in the heart for 0.8 second.
Ventricular pressure is initially low. It will increase slightly
during atrial systole because of the additional volume of blood that will
be ejected by the atria to the ventricles. Ventricular pressure will actually
increase during isovolumic contraction and still high during the period of
ejection of blood. But as the volume of blood in the ventricles decreases,
ventricular pressure will also decrease. It will continue to decrease
during the period of isovolumic relaxation. It will remain low during the
periods of rapid inflow of blood to the ventricles and diastasis. Again,
slight increase with atrial systole because of the additional volume of
blood ejected from the atria to the ventricles.
Closing of the AV valves will mark the onset of isovolumic
contraction. Remember that in isovolumic contraction, all the cardiac
valves are closed so there will be no change in the volume of ventricles.
So that means at that point, the first heart sound will be heard.
Cardiac Cycle
Opening of the AV valves mark the end of isovolumic relaxation
so there will be period of ventricular filling.
What will happen at the end of isovolumic contraction? There
will be opening of the SL valves. While at the beginning of isovolumic
relaxation, the SL valves close so the second heart sound will be heard.
Atrial Pressure Curve
incisura
Phases:
as – atrial systole
ic – isovolumic contraction
ejection – rapid and reduced ejection phase
ir – isovolumic relaxation
R inflow – rapid inflow of blood to the venticles
diastasis
as – atrial systole
The period of ventricular systole covers from the beginning of
isovolumic contraction until the end of the ejection phase while the
ventricular diastole will start with isovolumic relaxation up to the end of
atrial systole.
Ventricular Pressure Curve
SL valves
open
SL valves close –
2nd heart sound
***Atrial pressure curve – yellow dotted line
Aortic pressure or arterial pressure is always high. It will
continually increase during the period of rapid ejection because of the
increased volume that will be ejected from the ventricle to the aorta. So if
the volume of blood in the aorta is greater, there will be greater force
exerted by that volume of blood on the aortic wall.
During the period of reduced ejection, the aortic pressure
decreases because there will be peripheral run-off blood, meaning to say,
blood that is contained in the aorta will now be distributed to the arteries,
to the arterioles, and to the different organs of the body so the volume of
blood in the aorta will decrease and that will now cause the aortic wall to
recoil. When the aortic wall recoils, there is a slight vibration of blood
inside so there will be slight increase again in aortic pressure which is
called a dichotic notch or incisura.
All throughout the period of ventricular diastole, the aortic
pressure is stable and is slightly low but it is still higher compared to the
ventricular pressure.
*** Ventricular pressure curve – green line
1st heart
sound
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AV valves
open
Shannen Kaye B. Apolinario, RMT
The pressure difference between the aorta and the ventricles
will cause the closing of the SL valves when aortic pressure exceeds
ventricular pressure.
Ventricular Volume Curve
The 3rd heart sound heard in abnormal conditions is due to
ventricular filling. There is an increase in ventricular filling coinciding
with the appearance of the 3rd heart sound.
At the start, there is additional increase in volume with atrial
systole – additional 20% of ventricular filling. During isovolumic
contraction, all cardiac valves are closed so there is no change in the
ventricular volume. During period of rapid ejection, blood is ejected from
the ventricles so the ventricular volume will decrease. In the period of
isovolumic relaxation, all cardiac valves are closed so there is no change
in ventricular volume. During the period of rapid inflow, there is a very
high increase in ventricular volume. It is somewhat stabilized in diastasis
and a slight increase again during atrial systole.
Atrial Pressure or Central Venous Pressure (CVP) Curve
a
c
c
v
PHOTO: Left atrial, aortic, and left ventricular pressure pulses correlated in time with
aortic flow, ventricular volume, heart sounds, venous pulse, and the electrocardiogram
for a complete cardiac cycle.
Ventricular Volume Pressure Curve (Ejection Loop)
A wave is increase in atrial pressure during atrial systole. C
wave is slightly increased in atrial pressure during isovolumic
contraction when the increased ventricular pressure pushes the AV
valves to bulge into the atria. The V wave is increase atrial pressure
during isovolumic relaxation where it is simultaneous with the increase
in atrial filling.
Heart Sounds
The 1st heart sound is due to closure of the AV valves. Closure
of the AV valves will mark the onset of the period of isovolumic
contraction so when seen at the ventricular volume curve, it is a straight
line – no change in ventricular volume.
The 2nd heart sound is due to the closure of the SL valves that
will now mark the onset of the period of isovolumic relaxation. Again,
there is no change in the ventricular volume.
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Shannen Kaye B. Apolinario, RMT
PHOTO: Relationship between left ventricular volume and intraventricular pressure
during diastole and systole. Also shown by the heavy red lines is the “volume-pressure
diagram,” demonstrating changes in intraventricular volume and pressure during the
normal cardiac cycle. EW, net external work.
Reduced ejection
Volume of blood
remain on
ventricles after
contraction
Rapid ejection
PHOTO: Pressure-volume loop
The vertical axis will represent changes in ventricular
pressure, the unit is mmHg. The horizontal axis represents changes in
ventricular volume and the unit is either cc or mL.
In relation to changes in ventricular volume and pressure, the
cardiac cycle is divided into four phases. The letters represent each point.
Point A - ventricular volume is 50 mL. This 50 mL is actually the volume
of blood remaining in the ventricles after contraction. At 50 mL, the
pressure is low – a little above 0 mmHg. At point A, the atrioventricular
valves open.
Phase I – from 50 mL, the volume of blood in the ventricles increased to
120 or 130 mL but there is little increase in pressure. Phase I is
ventricular filling.
Point B - the volume of blood is 130 mL. There is closing of the AV valves
so the first heart sound is heard.
Phase II – the volume of blood is 130 mL and the pressure continues to
increase. At phase II, there is period of isovolumic contraction.
Point C – opening of SL valves. When the SL valves open, the ventricular
pressure still increases but the volume is already decreasing. From C
prime, it is the period of rapid ejection.
Phase III – in the latter part of Phase III – the volume decreases and the
pressure decreases, this is now the reduced ejection.
Point D – closing of the SL valves so the second heart sound is heard.
Phase IV – the volume of blood is still 50 mL but the pressure is
decreasing and decreasing. This is isovolumic relaxation.
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Shannen Kaye B. Apolinario, RMT
“ I can do EVERYTHING through Him who gives me strength”
-Philippians 4:13
GOD BLESS YOU! 
Cardiodynamics
(Gloria Marie M. Valerio, MD)
Definition of Terms:
Cardiac Output (CO)
is the amount/quantity/volume of blood ejected by each
ventricle per minute
CO = SV x HR
Normal Value: 5 L/min
5, 000 mL/min
* Although the left ventricle will pump blood against a higher pressure of
resistance in the systemic circulation compared to the right ventricle,
although the workload of the left ventricle is greater than that of the right
ventricle, although the left ventricular wall or musculature is thicker than
that of the right ventricle, the output of the two ventricles are the same.
Heart Rate (HR)
the number of contractions/heart beats/cardiac cycles per
minute
Normal Value (normal resting adult): 75 beats per min.
Correlation of SV, EDV, ESV with the Ejection Loop
From point D to point A, the volume of blood increases in the
ventricles with little increase in pressure, this is the ventricular filing
time. At point A, the atrioventricular (AV) valves will close so that
whatever amount of blood will be present in the ventricles before closure
of the AV valves, that is now the end diastolic volume (EDV) which is a
little less than 150 mL, average of 130 mL.
From point A to point B, the ventricles will now start to
contract, but since all the valves are closed, there will be no change in
ventricular volume.
From point B to C, that is the period of ejection of blood from
the ventricles so the EDV will be decreased and the amount that will be
ejected is the stroke volume. At point C, the semilunar (SL) valves will
close, the ventricles will start to relax and the volume of blood that is now
in the ventricles is the end systolic volume (ESV).
Stroke volume is equal to EDV minus ESV or ESV + SV will be
the EDV.
CO = SV x HR
* In a normally functioning heart, the heart rate and rhythm are
determined by the activity of the SA node.
Stroke Volume (SV)
is the amount/quantity/volume of blood ejected by each
ventricle per contraction/per heartbeat/per cardiac cycle
SV = EDV – ESV
Normal Value: 70 mL
The stroke volume of the left ventricle is the same of that of the right
ventricle.
End Diastolic Volume (EDV)
is the amount/quantity/volume of blood in the ventricles at
the end of diastole, before systole = PRELOAD
Normal Value: 110-130 mL
* Whatever amount of blood that will be present in the ventricles after
the ventricular filling time, before contraction of the ventricle; that is the
end diastolic volume. It is the EDV that will exert force on the ventricular
wall stretching the ventricular wall before it contracts thus it is called
preload or the load of the ventricle that is needed to be ejected.
End Systolic Volume (ESV)
is the volume of blood in the ventricles at the end of systole
Normal Value: 45-50 mL
* ESV is the amount/quantity/volume of blood remaining in the
ventricles after contraction. No matter how strong the force of ventricular
contraction is, there will always be a certain amount of blood that will
remain in the ventricles.
EDV – ESV
Whatever factor that will affect EDV and ESV will also affect the
SV. Whatever factor that will affect the SV and HR will affect the CO. As
for the SV, this is determined mainly by the force of myocardial
contraction. So if the force of myocardial contraction increases, the SV
will increase. On the other hand, if the force of myocardial contraction
decreases, the SV will also decrease. We can therefore say that the HR, SV
as a reflection of the force of myocardial contraction are factors intrinsic
to the heart that will affect the cardiac output. But aside from factors
intrinsic to the heart, there are also factors outside the heart called
peripheral factors that may also affect the cardiac output.
What are the factors outside the heart that may affect the
cardiac output?
1.
Total blood volume
2.
Status of the venous sytem that will deter blood back to the
heart
3.
Status of the arterial system which is the opposing force to
ventricular contraction
All of these factors make up the vascular or circulatory system
so that means that the activity of the heart is dependent on the status of
the vascular system and vice versa – the status of the vascular system is
also dependent on the activity of the heart. The heart and the vascular
system are actually inter-dependent and that is because of the close
nature of the cardiovascular system.
End Diastolic Volume (EDV)
What are the factors that will influence the EDV? EDV is the
volume of blood in the ventricles after the relaxation phase, before
contraction.
PHOTO: Preload
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Shannen Kaye B. Apolinario, RMT|
Take note of where the black arrows are directed. These black
arrows represent the EDV. It is directed towards the ventricular wall so
the greater the volume or EDV, the greater the force that will be exerted
on the ventricular wall. If the force exerted on the ventricular wall is
greater, that will now stretch the ventricular wall and if the ventricular
wall is stretched, that will now increase the force of myocardial
contraction. So in other words, the greater the EDV, the more the
ventricular wall is stretched, the greater will be the force of contraction.
And if the force of contraction is increases, stroke volume increases,
cardiac output increases. So EDV is directly related to cardiac output.
Factors Affecting EDV
1.
Effective filling time
Filling time refers to the duration of the diastolic or relaxation
phase because that is when the ventricles are filled with blood.
FT 
EDV 
SV 
FT 
EDV 
SV 
FT 
EDV 
SV 
When the heart rate increases from 180 beats per minute and
above, the duration of the filling time is now severely compromised. And
sympathetic stimulation can no longer compensate on the very short
duration of filling time. So the increase in heart rate is now less than the
decrease in stroke volume so the cardiac output will now decrease. There
is a range wherein the cardiac output will start to decrease with an
increase in heart rate.
CO
One factor that will influence the duration of the filling time is
heart rate. When the heart rate increases, the duration of the filling time
will decrease – less time for ventricular filling so the EDV will decrease
and so will the SV and CO.
HR 
When the heart rate increases from 60-180 beats per minute,
the duration of the filling time is quite affected but still, the ventricles can
still be filled with blood because from 60-180 beats per minute, the
increase in heart rate is equal to the decrease in stroke volume so that the
cardiac output is maintained at a constant level.
CO
If the duration of filling time increases, there will be enough
time for the ventricles to accommodate a larger volume of blood so the
EDV increases. Again, if the EDV is greater, the greater the ventricular
wall is stretched, the greater the force of contraction so the SV as well as
the CO increases. All are directly directed.
HR 
Both of the equations are true but there is a range of heart rate.
The horizontal axis on the graph represents heart rate while the vertical
axis represents cardiac output. Based on the graph, when the heart rate
increases from 0–60 beats per minute, there is a corresponding increase
in cardiac output. They are directly related because when the heart rate
increases from 0-60, the duration of filling time is not yet compromised
because the normal heart rate is 75 beats per minute so that means that
the ventricles can still be filled with blood adequately so the cardiac
output increases. In the first phase, sympathetic stimulation increases the
heart rate. Sympathetic stimulation increases not only the heart rate but
also the force of contraction. When the heart rate increases, the stroke
volume increases therefore the cardiac output increases.
CO
The reverse is also true that when the HR decreases, the
duration of the filling time will increase, more EDV, SV and CO.
Increased HR decreases the CO and decreased HR increases the
CO but going back to the formula: CO = SV x HR, heart rate is directly
related to CO, meaning to say that an increase in HR will increase the CO.
Which among the formula is true?
In the formula, it is directly related and of course that is true. If
the HR increases, there will be an increase in the frequency of
depolarization on the sarcolemma of the cardiac muscle cell. So the more
the cardiac muscle is depolarized, the more Ca++ enters the cell and if
more Ca++ enters the cell, the greater the force of contraction, the more
the stroke volume increases, increased cardiac output. That is how an
increase in HR will increase the CO. What about the other equation?
If you will recall, if the heart rate is 75 beats per minute, the
duration of one cardiac cycle is 0.8 sec, the duration of the systolic phase
is 0.27 sec, and much longer is the duration of the diastolic phase which is
0.53 sec. The longer duration of the diastolic phase is important because
it is during the diastole that the ventricles are filled with blood and at the
same time, it is during diastole that perfusion of oxygen supply to the
cardiac muscle is better.
Cardiac Cycle Duration with Heart Rate
Duration
Heart Rate
75 beats/min
Cardiac cycle
0.80 sec
Systole
0.27 sec
Diastole
0.53 sec
Heart Rate
200 beats/min
0.30 sec
0.16 sec
0.14 sec
When the heart rate increases to 200 beats per minute, the
duration of cardiac cycle will decrease from 0.8 to only 0.3 sec but if you
will compare the decrease in the duration of systole and diastole, diastole
is more affected (bigger decrease in duration of diastole) from 0.53 to
0.14 sec which means that the filling time is really compromised and the
EDV is severely decreased.
2.
Effective filling pressure
EFP = CVP – ITP
EFP - effective filling pressure
CVP – central venous pressure
ITP – intra-thoracic pressure
Aside from the duration of the filling time, another factor that
may influence the diastolic volume is the effective filling pressure or
transmural pressure - pressure difference between the inside and
outside of the heart. Pressure inside the heart is the central venous
pressure while outside is the intra-thoracic pressure. The greater the
difference between the pressure inside and outside of the heart, the
greater the effective filling pressure. And when the effective filling
pressure is greater, that will now distend the ventricles, allowing the
ventricles to accommodate a larger EDP. The intra-thoracic pressure is
always negative or below atmospheric pressure and that will enable the
heart as well as the other dilatable structures in the thoracic cavity to be
distended so it can accommodate greater volume.
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Shannen Kaye B. Apolinario, RMT|
3.
Myocardial compliance
All elastic structures have the property of compliance and that
is the measure of distensibility or stretchability of an elastic structure.
C=∆V
∆P
Compliance is equal to change in volume over change in
pressure. For a structure to have an increase in compliance, the change in
volume should be higher or greater compared to the change in pressure.
And this is true for the ventricles, remember that the ventricles can
accommodate a large volume of blood with little increase in pressure and
that is because of the presence of the elastic tissue in the cardiac muscle
that will enable the ventricles to distend.
4.
Venous return
VR = CO
5 L/min
The most important factor that determines the EDV is the
volume of blood returning to the heart per minute and that is venous
return. Because of the closed nature of the cardiovascular system,
whatever volume of blood that will return to heart per minute, will be
effectively ejected or pumped by the heart per minute so that means
venous return is equal to cardiac output. The average venous return is
also 5 L or 5,000 mL per minute.
End Systolic Volume (ESV)
What is the major factor that will affect the volume of blood
remaining in the ventricles after contraction or ESV? It is the force of
contraction. So if the force of myocardial contraction increases, SV will
increase, ESV will decrease. If the force of myocardial contraction
decreases, SV will decrease, ESV will increase. In other words, force of
myocardial contraction is inversely related to the end systolic volume
(ESV).
Within physiologic limits, the force of myocardial contraction
will be determined by the initial muscle length that means resting length
of the cardiac muscle or length of the cardiac muscle before it contracts.
The force of contraction will depend on the length of the
cardiac muscle before it contracts so what will stretch the cardiac muscle
before it contract ? The force that will be exerted by the EDV. the greater
the EDV, the greater will be the force exerted on ventricular wall, the
more the ventricular wall will be stretched and that will now increase the
force of contraction and this is called heterometric autoregulation.
Autoregulation means that the heart itself can regulate its own force of
contraction. Metric is the length. Hetero - changes. So the change in the
length of cardiac muscle will enable the heart to regulate its own force of
contraction. Remember that this only happens within physiologic limits –
it does not stretch continuously when the EDV is increasing and more and
more powerful the force contraction becomes. There is a limit because
when the cardiac muscle is overstretched or distended, there will be less
overlapping between thin filaments and thick filaments so there will be
less myosin length that will bind on the actin active site so when it
contracts, it becomes weak.
Actin filament
Myosin filament
But remember that overstretching or overdistention of the
cardiac muscle does not occur in the first place because of the presence of
connective tissue. The connective tissue on the cardiac muscle and on the
pericardium prevents overdistention when the cardiac size increases
because connective tissue is less distensible while the elastic tissue
allows distension.
Factors that affect cardiac muscle length:

Stronger atrial contraction. Remember that most of the
ventricular filling will take place when the ventricles as well as
the atria are in a relaxed state. But during atrial systole, there
is an additional amount of blood that will be ejected to the
ventricles so the EDV increases. If the force of contraction in
the atria is greater, there will be more than the 20% that will
be added in the ventricular filing, the EDV will be more
increased.

Increased total blood volume. Total blood volume is actually
one factor that will affect venous return. So if the total blood
volume increases, venous return will increase, EDV will also
increase so that will stretch the ventricular wall.

Increased venous tone. One property of smooth muscle cells
present in the vascular wall as well as in the visceral wall is the
tone. For example, the stomach and the small intestinal wall
have a tone, the same is also true with blood vessels, arteries
and veins - their wall has a tone.
When the smooth muscle layer in the veins contract,
there will be veno-constriction, the blood cannot go back to the
heart. The veins are called capacitance vessels because the
smooth muscle layer is thin and it has elastic tissue so the
venous wall is highly distensible so it can accommodate large
volume of blood. If the venous wall is in a relaxed state, the
blood in the veins cannot go back to the heart. So what is
venous tone? Tone means state of partial contraction. One
property of smooth muscle is they can remain partially
contracted for a long time. If the wall of the veins is partially
contracted, there will be less capacity to accommodate blood
so the blood will go back to the heart thus increasing venous
return and EDV and that will stretch the cardiac muscle cell.
The normal systolic volume (red line) is about 70 mL but if the
force of myocardial contraction increases, SV increases so the remaining
part becomes smaller.
Since the force of myocardial contraction will affect the ESV,
what now are the factors that will influence the force of myocardial
contraction? What is the EDV and the relationship between EDV and force
of myocardial contraction is reflected in the Frank starling’s Law.
Factors Affecting ESV
a.
Force of myocardial contraction
1.
Frank Starling’s Law
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Shannen Kaye B. Apolinario, RMT|

Increased pumping of skeletal muscle. When you remain in
a standing position for a long time, blood pools in the veins of
the lower extremities. So again, if there is pooling of blood in
the veins of the lower extremities, the venous return will
decrease, EDV will decrease, and the cardiac muscle will not be
stretched. But once you move, the skeletal muscle will contract
and that will compress the veins. When the veins are
compressed, that will open up the venous valves. The opening
of the valves is directed toward the heart. So when the veins
are compressed by skeletal muscle contraction, venous valves
will open and blood will return to the heart.
* The three factors: increased total blood volume, increased venous tone
and increased pumping of the skeletal muscle will first influence venous
return. Venous return will then influence EDV, EDV is the one that will
exert force on the ventricular muscle to stretch the ventricular muscle.

Increased negative intrathoracic pressure. Increased
negative intrathoracic pressure allows the ventricles to
distend, so that will stretch the ventricular muscle.
All of these are factors will affect cardiac muscle length before
contraction. So if these factors will increase, cardiac muscle length will
increase before contraction so that during contraction, the force of
myocardial contraction will increase.
2.
Autonomics
Aside from cardiac muscle length another factor that will
influence the force of myocardial contraction is the autonomic
innervations:
sympathetic
that
will
release
catecholamine,
norepinephrine, epinephrine; and parasympathetic that will release
acetylcholine.
Sympathetic stimulation will increase the force of contraction
of both the atria and ventricles primarily because norepinephrine binds
with β1 receptors will increase membrane permeability to calcium
allowing more Ca++ to enter myocardial cell and that will increase the
force of contraction. But aside from this, sympathetic stimulation can also
increase the heart rate so the more frequent the myocardial cell is
depolarized, again, the more Ca++ will enter the myocardial cell and that
will increase the force of contraction.
In contrast, vagal or parasympathetic stimulation by releasing
acetylcholine will decrease the force of atrial contraction. It has no direct
effect on the force of ventricular contraction because there is very little, if
any parasympathetic or vagal innervation to the ventricles.
But that is not the end of sympathetic effects. It does not allow
Ca++ to always enter the cell because when it always depolarizes, more
Ca++ will enter the cell.
But hidni dun nagtatapos ang sympathetic effects. Hindi lang
basta nagpapapasok ng ca kasi malimit magdepolarize, mas madaming ca
na papasok
Another action of sympathetics is when norepinephrine and
epinephrine bind with β1 receptors in the heart, this will cause activation
of G-proteins. Activated G-proteins will activate the enzyme system adenylyl cylcase that will lead to the formation of an intracellular ligand
or a second messenger that is cyclic AMP (cAMP). As a second
messenger, cAMP will mediate the actions of catecholamines on the
cardiac muscle cell and one action of cAMP is to cause activation of
another intracellular enzyme that is protein kinase A (cAMP-PK). One
action cAMP-PK is to phosphorylate the Ca++ channels on the
sarcolemma. When it is phosphorylated, that will allow more Ca++ to
enter that will increase the force of myocardial contraction.
But take note that sympathetic stimulation will increase not
only the force of contraction; it will also facilitate relaxation of the cardiac
muscle by the action of cAMP-PK. So another action of cAMP-PK is to
phosphorylate troponin I so that troponin cannot bind with Ca++. If
troponin cannot bind with Ca++, the muscle will relax because troponintropomyosin complex will go back to cover the active site of actin due to
absence of troponin-Ca++ complex.
Another action of cAMP-PK is to phosphorylate an intracellular
protein called phospholamban. The normal action of phospholamban is
to inhibit the Ca++ pump on the sarcoplasmic reticulum. If the Ca++ pump
is inhibited, Ca++ will not return – it will remain bound to troponin C so
there will still be muscle contraction. But once phosphorylated by cAMPPK, the inhibitory effect of phospholamban will decrease so the Ca++
pump will be activated and when activated, it will actively transport Ca++
back to the sarcoplasmic reticulum so there will be no Ca++ that is
attached to troponin and the muscle will relax. So again, aside from
increasing the force of myocardial contraction, sympathetic stimulation
can also facilitate relaxation of the cardiac muscle.
3.
Calcium
Another important factor that will affect the force of
myocardial contraction will be the amount Ca++ available that will bind
with troponin C. In contrast to the skeletal muscle, there are two sources
of Ca++ for myocardial contraction: sarcoplasmic reticulum and ECF. That
means that the plasma Ca++ level will have an effect on the force of
myocardial contraction.
4.
Adequate coronary flow
Another factor is adequacy of the coronary arteries. Remember
that the coronary arteries supply blood and oxygen to the cardiac muscle
itself. So when there is an obstruction (e.g. thrombus or embolus) in one
of the branches of coronary arteries, there will be an area of that
myocardium that will be deprived of oxygen supply so the area will be
ischemic. If the ischemic area is not corrected, it will cause necrosis to the
tissue developing an infarct and that infarcted area cannot contract
anymore. Since there is an area in the myocardium that is not contracting,
the overall force of contraction will decrease and that will predispose to
ventricular or heart failure.
5.
PHOTO: Schematic diagram of the movement of calcium in excitation-contraction
coupling in cardiac muscle. Influx of Ca++ from interstitial fluid during excitation
triggers release of Ca++ form the sarcoplasmic reticulum (SR). The free cytosolic Ca++
activates contraction of the myofilaments (systole). Relaxation(diastole) occurs as a
result of uptake of Ca++ by the SR, by extrusion of intracellular Ca++ by the 3 Na+-1
Ca++ antiporter, and to a limited degree by the Ca++-ATPase pump. βR, β-adrenergic
receptor: cAMP-PK, cAMP-dependent protein kinase.
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Shannen Kaye B. Apolinario, RMT|
Heart rate
The force of myocardial contraction can also be influenced by
heart rate. It is mentioned earlier that when the heart rate increases, the
depolarization of cardiac muscle will be more frequent and remember
that with each depolarization, it allows more Ca++ to enter and that will
increase the force of contraction.
Factors that influence or regulate heart rate:

Autonomics. The most important factor. Sympathetic nerves
innervating the SA node and the effect of norepinephrine is to
increase membrane permeability to Na+ and Ca++ that will
make the SA node more excitable so the heart rate will
increase. On the other hand, parasympathetic or vagal
stimulation will make the SA node more permeable to K+ so
that will hyperpolarize the SA node making it less excitable,
decreasing the heart rate.

Hormones. Aside from the neurotransmitters released by the
autonomic nerves, heart rate can also be affected by several
hormones one of which is cortisol - corticosteroids from the
adrenal cortex. The effect of cortisol is to potentiate the effect
of epinephrine so that means increased corticosteroids may
increase the heart rate.
7.
Afterload
Afterload is the aortic pressure load, opposing force to left
ventricular contraction. Why in the aortic artery only and not in
pulmonary artery? Because remember that there is low/no pressure area
in the pulmonary circulation, not much resistance to right ventricular
contraction unless there is pulmonary hypertension. More of the
resistance happens in the left ventricle because there is high pressure
area in the arterial system. So when we say afterload, it is the pressure in
the aorta.
Other hormones are T3 and T4 – thyroid hormones.
Thyroid hormones directly stimulate the SA node so that one
clinical manifestation of hyperthyroidism is tachycardia.


6.
Neural reflexes. Heart rate can also be influenced by neural
reflexes that are centered on the medulla and that will include
reflexes that actually regulate arterial blood pressure: the
baroreceptor reflex and the chemoreceptor reflex. These
reflexes that regulate arterial blood pressure can also regulate
heart rate.
Bainbridge reflex. This time, when venous return increases,
the volume of blood in the right atrium will increase and that
will stretch the right atrial wall where you have the SA node.
When the right atrial wall is stretched, the SA node is
stimulated and that will increase the heart rate. So this
Bainbridge reflex is sensitive to an increase in blood volume
that will return to the right atrium.

Exercise. During exercise, heart rate increases for two
reasons: increased metabolism and increased sympathetic
stimulation.

Excitement and anxiety. Emotions like excitement and
anxiety will also increase the heart rate partly because of
increased sympathetic stimulation.

Temperature. Increased environmental temperature can also
increase the heart rate. Not only environmental temperature
but also body temperature so when there is fever, heart rate
increases.
PHOTO: Afterload
Remember the photo on preload, the arrows are directed on
the ventricular wall because the EDV exerts force on the ventricular wall
to increase the force of contraction.
When the ventricles contract, the blood or EDV goes in the
aorta so the direction is directed towards the aorta but the pressure in
the aorta counteracts the EDV so when the pressure is greater on the
aorte, EDV will have a hard time to go out. So if the aortic pressure
increases, stroke volume decreases, end systolic volume increases and
this is shown on the photo below:
Cardiac glycosides
Cardiac glycosides are given to patient suffering from
congestive heart failure. The main purpose of giving cardiac glycosides is
to increase the force of myocardial contraction.
When the muscle is relaxed, the Na-K pump is activated. Na-K
pump will extrude 3 Na+ in exchange for 2 K+ transported into the cell
creating a concentration gradient for Na that will now activate the Na+Ca++ pump. If the Na+-Ca++ pump is activated, 3 Na+ will go inside and
Ca+ will go outside decreasing the concentration of Ca+ inside the cell and
that is not ideal if there is congestive heart failure. It is needed for the
Ca++ to remain inside the cell to have an increased force of contraction.
So what the cardiac glycosides do is to inhibit the Na-K pump so there will
be no concentration for Na+ and that will not activate the Na-Ca pump. If
the Na-Ca pump is not activated, there will be no increase concentration
of Ca++ that will go out of the cell or Ca++ will remain inside the cell so
the force of contraction is increased.
The normal stroke volume is still represented by the red line.
When the aortic pressure increases, the tendency of the ventricles is to
increase its contraction because the pressure against it is stronger. That’s
why the pressure in the ventricles is increasing and increasing but
because the opposing force is greater, stroke volume is decreased and the
end systolic volume is increased.
So what is the consequence of that? There is much left so in
every venous return, what will happen in the EDV? There is much left but
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Shannen Kaye B. Apolinario, RMT|
even if there is less amount that goes out, some will still go back to the
heart, so what will happen to the EDV? EDV will increase because there is
much [blood] left and there was an additional amount added during the
relaxation phase. When the EDV is increased, the ventricular wall will be
stretched; its contraction will be increased. But even if the contraction is
increased but there is persistent increase in aortic pressure, less will still
be ejected so that eventually there will be pulling of blood in the left
ventricle and that will cause the left ventricle to dilate. Since the SV is less,
eventually the venous return will also be lessened because there is a
decrease in the amount ejected so less will go back or return to the heart.
To summarize the factors that will determine the cardiac
output, there are factors intrinsic to the heart and there are factors
outside the heart. Factors intrinsic to the heart will include the heart rate
and the force of myocardial contraction. Factors outside the heart or
peripheral/coupling factors will include the preload (factors that will
affect EDV) and afterload or aortic pressure load. These are the major
factors that will determine cardiac output
Effects of Various Conditions on Cardiac Output
Increase:
-
Anxiety or excitement (50-100%) – partly because of
sympathetic stimulation.
-
Eating (30%) – eating increases blood flow to the
gastrointestinal tract. Increase in blood flow increases venous
return and increases cardiac output.
-
Exercise (up to 700%) – increased metabolism, sympathetic
stimulation.
-
Increased environmental temperature
-
Pregnancy – due to increased blood volume that will increase
venous return.
-
Epinephrine
Decrease:
PHOTO: Pressure-Volume Loop. Cardiac output is the volume of blood pumped by the
heart each minute. In the steady state the output from both the right and left ventricles
is the same. The pressure-volume loop for the left ventricle is depicted here. The
cardiac output is calculated as: Cardiac output = Heart rate x stroke volume
where: stroke volume = end-diastolic volume – end systolic volume
Increases in venous return (increased preload) increase the stroke volume and thus
cardiac output. Increases in arterial pressure (increased afterload) decrease stroke
volume and thus cardiac output (lower panel).
8.
Sitting or lying down from a standing position (20-30%)
-
Rapid arrhythmias – heart rate of 200 beats per minute that
will severely compromise the duration of the filling time so
that will decrease the cardiac output.
-
Heart diseases – examples are congestive heart failure,
myocardial infarction, cardiac valve diseases, arrhythmias,
chronic hypertension all of these factors that will decrease the
force of myocardial contraction.
No change
-
Sleep
-
Moderate change in environmental temperature
Ejection Fraction (EF)
Stenosis
Another condition that will increase aortic pressure is stenotic
aortic valve. If the aortic valve hardens, even if the ventricular pressure is
greatly increased, the SV and cardiac output will still be diminished.
Blood will again accumulate in the left ventricle and eventually, the left
ventricle will dilate so the force contraction will decrease.
Cardiac factors:
Coupling factors:
Heart rate
Preload
Cardiac Output
Myocardial
contractility
-
Percentage of the EDV is ejected by the left ventricle per
contraction
EF = SV x 100
EDV
Normal value: 65-70%
The volume of blood that should be ejected per contraction
should be 65-70% of 130 mL that is why the average stroke volume is 70
mL.
Determinants of Cardiac Output
6
-
Afterload
Shannen Kaye B. Apolinario, RMT|
In patients suspected of having congestive heart failure, one
procedure that is requested is 2-D echocardiogram to determine the
ejection fraction (EF). Because if the EF falls below what is normal, it
means that the SV is decreased and it is decreased because the
ventricular contraction is weak.
Cardiac Index
-
Cardiac output per square meter or body surface area
Normal value: 3L/min/m2 of body surface area
Another factor that may influence cardiac output is body
surface area and the normal cardiac index is 3L/min/m2. It means that in
the elderly where the physical activity is less, the skeletal muscles
atrophy so the body surface area decreases and the cardiac output and
cardiac index is decreased. Compared to the athletes who have welldeveloped muscles, they have a bigger body surface area so the CO and
cardiac index is increased because what happens is that when there is
increased need (bigger muscles) to be supplied with blood, the heart
compensates so the CO increases.
Cardiac Reserve
-
Maximum percentage that cardiac output can increase above
normal (300-600%)
In certain conditions, the CO may be increased from 5L to 1315 L per minute and that is called a hypereffective heart. Hypereffective
because the heart can pump blood a volume that is greater than what is
normal. Hypereffective heart happens if there is sympathetic stimulation
and parasympathetic inhibition, during moderate to heavy exercise or
during athletic activities that will involve endurance (e.g. marathon
races). The opposite is a hypoeffective heart –the heart pumps blood
that is less than normal and that is brought about by cardiac diseases (e.g.
congestive heart failure, rapid arrhythmia, cardiac valvular diseases).
“Ask and it will be given to you; seek and you will find; knock and
the door will be opened to you. For everyone who asks receives; he
who seeks finds; and to him who knocks, the door will be opened.”
-Matthew 7:7-8
GOD BLESS YOU 
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Shannen Kaye B. Apolinario, RMT|
Circulatory or Vascular System
(Gloria Marie M. Valerio, MD)
The Circulatory System or Vascular System is made up of
different types of blood vessels that are arranged either parallel or in
series with one another forming a closed system of conduits or tubes that
will transport blood to and from the heart. Take note that the blood
vessels are not rigid tubes, they are distensible. The primary function of
the circulatory system is to service the needs of the tissues that is - by
transporting blood, it will transport essential substances like oxygen and
nutrients to the tissues and at the same time it will transport the waste
products of metabolism away from the tissues.
As what we have learned from the previous lecture, the
circulatory system is divided into two – pulmonary and systemic
circulation. The pulmonary circulation receives unoxygenated or
venous blood from the right heart and supplies blood to the lungs. On the
other hand, the systemic circulation receives arterial or oxygenated
blood from the left heart and supplies blood to almost all organs of the
body except for the lungs. Since the systemic circulation will supply blood
to almost all organs of the body, it is also called peripheral or greater
circulation.
Blood Vessels
In the different organs of the body, the arteries will divide into
smaller branches forming the arterioles. This time, the wall of the
arterioles contains more smooth muscle fibers than elastic tissue. In fact,
among all the different types of blood vessels, the arteriolar wall has the
thickest muscular layer so that when the smooth muscle layer of the
arteriolar wall contracts or if there is vasoconstriction, that will decrease
tremendously blood flow to the capillaries and to the tissues. On the other
hand, when the smooth muscle layer of the arteriolar wall relaxes or if
there is vasodilatation, that will now increase tremendously blood flow to
the capillaries and to the tissues. So one important function of the
arterioles is to regulate blood flow to the capillaries and to the tissues and
also because of its thick muscular layer, resistance to blood flow is
highest in the arterioles so the arterioles are called resistance vessels.
The smallest blood vessels are the capillaries. The capillary
wall is thin and porous - it allows exchange of fluids and some solutes
between intravascular and interstitial fluid compartments. The capillaries
are known as exchange vessels.
From the capillaries, blood will be collected by the venules
which will then coalesce to form the bigger veins. Comparing the wall of
the vein to that of an artery, the venous wall is thinner and more
distensible that is why the veins can accommodate a large volume of
blood with little increase in pressure and the volume of blood that is
contained in the veins is what we call unstressed blood volume because
of the low pressure area of the venous system. It means that the vascular
capacity is bigger and veins are also called capacitance vessels. There
are two functions of veins: one is to act as blood reservoir and another
one is to return blood back to the heart.
In the veins of the limbs or extremities, there are venous valves
present with openings of which are directed towards the heart. So that
when you move your limbs and the skeletal muscles contract that will
open up the venous valves and facilitate venous return.
Layers of the Blood Vessel
1.
2.
3.
Tunica intima
Tunica media
Tunica adventitia
PHOTO: Schematic diagram of the parallel and series arrangement of the vessels
composing the circulatory system. The capillary beds are represented by thin lines
connecting the arteries (on the right) with the veins (on the left). The crescent-shaped
thickenings proximal to the capillary beds represent the arterioles (resistance vessels).
On the right is the arterial system or distributing vessels. On
the left is the venous system or collecting vessels.
When the left ventricle contracts, blood is ejected to the aorta
and from the aorta to the arteries. The wall of the aorta and arteries is
strong and thick so it is able to transport oxygenated blood under high
pressure to the different organs of the body and we call the blood volume
that is contained in the arterial system as stressed blood volume. One
important characteristic of the aortic as well as arterial wall is that it
contains more elastic tissue than smooth muscle fibers. So that will make
the aortic and arterial wall highly distensible so during ventricular
systole, when blood is ejected to the aorta, the aortic wall will distend to
accommodate the large volume of blood. On the other hand, during
ventricular diastole, the aortic and arterial wall will recoil on the
contained blood.
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Except for the capillaries, the wall of the different blood vessels
is made up of the same structure. There are three layers of the vascular
wall. The innermost layer is the tunica intima which is made up of the
endothelium and basement membrane. The middle layer is the tunica
media which is made up of smooth muscle fibers. The outermost layer is
the tunica adventitia which is made up of connective tissue. Just like in
the heart, the presence of connective tissue in the vascular wall will
prevent overstretching or over distension of the vascular wall when
blood volume as well as blood pressure increases.
Properties and Characteristic of the Vascular Smooth Muscle
6.
2 types of Smooth Muscle
1.
2.
Multiunit
Single unit
PHOTO: Control systems of smooth muscle. Contraction (or inhibition of
contraction) of smooth muscles can be initiated by (1) the intrinsic activity of
pacemaker cells, (2) neutrally released transmitters, or (3) circulating or locally
generated hormones or signalling molecules. The combination of a neurotransmitter,
hormone, or drug with specific receptors activates contraction by increasing cell Ca++.
The response of the cells depends on the concentration of the transmitters or
hormones at the cell membrane and the nature of the receptors present. Hormone
concentrations depend on diffusion distance, release, uptake, and catabolism.
Consequently, cells lacking close neuromuscular contacts will have a limited response
to neural activity unless they are electrically coupled so that depolarization is
transmitted from cell to cell. A. Multiunit smooth muscles resemble striated muscles in
that there is no electrical coupling and neural regulation is important. B. Single-unit
smooth muscles are like cardiac muscle, and electrical activity is propagated
throughout the tissue. Most smooth muscles probably lie between the two ends of the
single unit-multiunit spectrum.
structures which are called calveolae. However, this calveolae are
actually analogous to the T-tubules.
Few mitochondria. There are fewer mitochondria in the smooth
muscle and the main source of energy for contraction is glycolysis.
7.
Sarcoplasmic Reticulum. The sarcoplasmic reticulum is less welldeveloped so that means it is not able to store large quantities of
calcium ions just like in the cardiac muscle cell so in order to
contract, there has to be another source of calcium ions and that is
the extracellular fluid (ECF). Also present on the membrane of the
sarcoplasmic reticulum are ryanodine receptors that will bind with
calcium coming from the ECF and there is also a calcium pump.
8.
Contractile Proteins. Contractile proteins are also present that will
include actin, myosin and tropomyosin but there is no troponin so in
order to contract, calcium will bind with another protein and that is
calmodulin so you have a calcium-calmodulin complex that will
initiate vascular smooth muscle contraction.
9.
Stimuli. Stimuli that will cause contraction of the vascular smooth
muscle. Remember that in the skeletal muscle, the primary stimulus
will be neural or nervous. You have an action potential for a somatic
nerve transmitted to the skeletal muscle cell that will depolarize the
skeletal muscle cell and that will now initiate the excitationcontraction coupling. In vascular smooth muscle, there are different
types of stimuli that can stimulate the vascular smooth muscle:
a.
The neurotransmitter agent that is released by
sympathetic nerves is norepinephrine. You also have
norepinephrine and epinephrine from the adrenal medulla so
that when either norepinephrine or epinephrine binds with
alpha-1 receptors that will cause contraction of the vascular
smooth muscle so there will be vasoconstriction. On the other
hand, when either norepinephrine or epinephrine binds with
beta-2 receptors, that will cause relaxation of the vascular
smooth muscle so there will be vasodilatation. Remember in
relation to beta-2 receptors, epinephrine has a greater effect
than norepinephrine.
There are two types of smooth muscles in the body: multi-unit
smooth muscle and single unit smooth muscle. In the visceral wall as well
as the vascular wall, the type of smooth muscle fibers present is mostly
the single unit type.
Characteristics of Smooth Muscle
1.
Smaller. Compared to the skeletal muscle cell, the smooth muscle
cell is smaller
2.
Involuntary. The activity of the vascular smooth muscle is not
regulated by the cerebral cortex.
3.
4.
5.
Resting Membrane Potential. The RMP is less negative, it is also
unstable. It ranges from -50 to -60 mv. The action potential
generated is brought mainly by opening of slow calcium channels so
that will make the duration of the vascular smooth muscle action
potential longer than that in the skeletal muscle. So that the duration
of the contraction-relaxation cycle in the vascular smooth muscle is
also longer.
Tonic contraction. Another important property of the vascular
smooth muscle - it can remain partially contracted for a long time
with little expenditure of energy and that is what we call tonic
contraction.
Sarcolemma. The vascular smooth muscle cell is also surrounded
by the sarcolemma and present on the sarcolemma are voltagegated as well as ligand-gated calcium channels. Also present is a
calcium pump, a sodium-potassium anti-porter, and a sodiumcalcium anti-porter. However, invaginations of the sarcolemma will
not form the T-tubules; instead the invaginations will form cave-like
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Neural. First is again neural so we have autonomic innervation
and the vascular smooth muscle is innervated mainly by the
sympathetic nervous system so you have sympathetic
adrenergic and sympathetic cholinergic. Sympathetic
adrenergic nerves innervate the blood vessels in the skin and
viscera while sympathetic cholinergic nerves innervate the
blood vessels in the skeletal muscle.
In sympathetic cholinergic, you have acetylcholine
binding with muscarinic receptors that will also relax the
vascular smooth muscle in the skeletal muscle so there will be
vasodilatation.
b.
Hormones. Aside from neural, the vascular smooth muscle can
also be stimulated by circulating hormones which could either
be vasoconstrictors or vasodilators. Among the circulating
vasoconstrictors are angiotensin 2 and vasopressin or
antidiuretic hormone (ADH). Among the circulating
vasodilators are bradykinin and histamine.
c.
Stretch. Stretch of the muscle will initiate a reflex action. For
example, when the blood volume and blood pressure
increased, that will now stretch the arterial wall that will
initiate a reflex action that will cause vasoconstriction.
d.
Local factors. Local factors for example actively metabolizing
tissue so there will be oxygen consumption and production of
carbon dioxide. So that oxygen tension (pO 2) will decrease and
pO2
pCO2
carbon dioxide tension (pCO 2) will increase, these two factors
will also cause vasodilatation.
pH = H+
Other local factors that will cause vasodilatation will
include a decrease in plasma pH so increase hydrogen, increase
lactic acid concentration. Increase potassium, increase
adenosine, all of these will produce vasodilatation.
Latch-Bridge Mechanism
Repolarization
Ca++  out
There are several factors that can either stimulate or
inhibit the vascular smooth muscle.
Myosin phosphatase
Dephosphorylation of myosin  relax
Contraction-Relaxation Cycle
M+A
On the other hand, with repolarization, Ca++ will be removed
either through the activity of the Ca++ pump on the sarcoplasmic
reticulum, Ca++ pump on the sarcolemma or Ca++-Na+ antiporter. In the
skeletal muscle as well as in the cardiac muscle, once Ca++ is unbound
from troponin, it is expected to relax but in this case, even if Ca++ is
removed from calmodulin, the vascular smooth muscle will remain
contracted that is why it is capable of tonic contraction with little
expenditure of energy. It will take some time before the muscle will relax
by activation of another intracellular enzyme called myosin
phosphatase. When activated, myosin phosphatase will cause
dephosphorylation of myosin. When myosin is dephosphorylated, it will
be unbound from actin and that will bring about relaxation and this is
called the latch-bridge mechanism.
Smooth Muscle Fiber
PHOTO: Regulation of smooth muscle myosin interactions with actin by Ca++stimulated phosphorylation. In the relaxed state, cross-bridges are present as highenergy myosin-ADP-Pi complex in the presence of ATP. Attachment to actin depends on
phosphorylation of the cross-bridge by a Ca++-calmodulin-dependent myosin-lightchain kinase (MLCK). Phosphorylated cross-bridges cycle until they are
dephosphorylated by myosin phosphatase. Note that cross-bridge phosphorylation at a
specific site on a myosin regulatory light chain requires ATP in addition to that used in
each cyclic interaction with actin.
Depolarization
Ca + calmodulin
Myosin light-chain kinase
Phosphorylation of myosin
Increased ATPase
M+A
contraction
If the membrane is depolarized, that will allow Ca++ to enter the vascular
smooth muscle cell. When the Ca++ enters, it will bind with calmodulin
which will now initiate the contraction process. What happens is that the
calcium-calmodulin complex will activate an intracellular enzyme that
is myosin light chain kinase. When activated, myosin light chain kinase
will cause phosphorylation of myosin which will then increase the
activity of ATPase. With increased activity of ATPase, myosin will now
form cross bridges with actin and that will bring about contraction.
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PHOTO: Apparent organization of cell-to-cell contacts, cytoskeleton, and
myofilaments in smooth muscle cells. Small contractile elements functionally
equivalent to a sarcomere underlie the similarities in mechanisms between smooth
and skeletal muscle. Linkages consisting of specialized junctions or interstitial fibrillar
material functionally couple the contractile apparatus of adjacent cells.
Smooth muscle is non-striated. There is no regular
arrangement of the actin and myosin filaments so that when you observe
the smooth muscle under the microscope, alternating thick and thin
filaments and alternating light and dark bands will not be seen. The
structure of a smooth muscle fiber is usually arranged in bundles.
Another characteristic, there is no Z line, instead of the Z line,
there are dense bodies attached to the membrane of the smooth muscle
which will also provide an attachment between the membrane of the
individual muscle fibers. So that force generated in one muscle fiber can
be transmitted to other muscle fibers as well.
Also, there are gap junctions present in the membrane
allowing ions to flow freely from one muscle fiber to the next so that
when an action potential is generated anywhere in a bundle, it can be
transmitted readily and that will cause the whole bundle to depolarize
and to contract as a single unit and that arrangement of the muscle fiber
is called synctitium. That is why the type of the smooth muscle is singleunit smooth muscle.
Attached to the dense bodies are the actin filaments and
interspersed within the actin filaments are the myosin filaments. And the
myosin filaments here form what we call side-polar crossbridges –
myosin on one side is attached to actin and it is attached to actin on the
other side. When activated, that means myosin can pull the actin filament
on one side in one direction at the same time pulling the other actin
filament on the other side in the opposite direction.
capillaries which is slower because it is numerous and smaller and that is
why the velocity is inversely related to the cross-sectional area.
As to radius, the vena cava actually has a bigger radius than the
aorta but the aorta has the thickest wall. Composition of the vascular wall
you have elastin, smooth muscle, collagen. Elastin and collagen
component is highest in the aorta but take note the smooth muscle
component is most abundant in arterioles. The capillary wall has no
elastin, no smooth muscle, and no collagen.
Differentiation of the Blood Vessels
Char.
Aorta
Arteriole
Capillary
Venules
Vena
cava
Number
in body
1
109
1010
3 x 108
2
4.5
300
5,000
4,000
18
12
0.010
0.004
0.02
17
Wall
thickness
(microns)
2
0.02
0.001
0.002
1.5
Elastin
+++
+
0
+
+
Smooth
muscle
++
+++
0
+
++
Collagen
+++
+
0
+
+
110
70
20
10
5
50
0.3
0.017
0.02
4.6
Crosssectional
area
Radius
(mm)
Trasmural
pressure
(mmHg)
Peak
velocity
(cm/s)
As for transmural pressure, this is difference in the pressure
between the inside and outside of a blood vessel and the transmural
pressure is highest in the aorta, lowest in the vena cava. It is mentioned
earlier that the arterial system is a high pressure area while the venous
system is a low pressure area.
PHOTO: Internal diameter, wall thickness, and relative amounts of the
principal components of the vessel walls of the various blood vessels that compose the
circulatory system. Cross sections of the vessels are not drawn to scale because of the
huge range from the aorta and venae cavae to capillary.
Let us now differentiate the blood vessels that make up the
circulatory system so you have the aorta, arterioles, capillaries, venules
and vena cava. Number in the body: there is only 1 aorta, 2 vena cava –
superior and inferior, millions of arterioles, millions of venules, and
billions of capillaries.
As to cross-sectional area, you will notice that although the
aorta is the biggest artery in the body, its cross-sectional area is small.
Compare it to the smallest blood vessel in the body which is the capillary,
it has the biggest cross-sectional area. What does cross-sectional area
mean? If you put the blood vessels side by side, there is one aorta, two
vena cava and billions of capillaries and if you spread all of those, which
among those blood vessels would occupy the most space. When we say
cross-sectional area, that is not the size of the blood vessel - you put the
blood vessels side by side then spread it, which among the blood vessels
will occupy the biggest space and of course that will be the most
numerous even though it is the smallest and that will be the capillaries.
Correlate it with the velocity of the blood flow. When we say
velocity of blood flow, that is the distance travelled by a volume of blood
per unit of time. As you can see, cross-sectional area is inversely related
to velocity. The aorta which has a small cross-sectional area has the
highest velocity of blood flow, in contrast, the capillaries with the biggest
cross sectional area has the lowest velocity of blood flow. Why did that
happen? You will learn later on that again because of the closed nature of
the circulatory system, blood flow is equal to cardiac output equal to
venous return so that means the blood flow in every blood vessel per unit
of time is the same. So if blood flow is 5L/min, in a big blood vessel like
the aorta, it can easily fill up 5 L. What about the capillaries? It is small
and numerous, it is slower to fill up the 5L so although the volume is the
same in both, the blood flow in the aorta is faster compared to the
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PHOTO: Phasic pressure, velocity of flow, and cross-sectional area of the
systemic circulation. The important features are the inverse relationship between
velocity and cross-sectional area, the major pressure drop across the small arteries
and arterioles, and the maximal cross-sectional area and minimal flow rate in the
capillaries. AO, aorta; ART, arterioles; CAP, capillaries; LA, large arteries; LV, large
veins; SA, small arteries; SV, small veins; VC, venae cavae; VEN, venules.
This graph will show you again the relationship between crosssectional area and velocity of blood flow. So to summarize, cross-sectional
area increases from the aorta to the capillaries, it decreases from the
capillaries to the vena cava. For the velocity of blood flow, it is highest in
the aorta so it decreases from the aorta to the capillaries; it increases
from the capillaries to the vena cava. As to pressure, again, pressure is
high in the arterial system, highest in the aorta and then it progressively
decreases towards the vena cava but the biggest drop in pressure is in the
arterioles.
Velocity

V=D
T
The formula for velocity is distance over time and the unit is
centimetres per second. As said earlier, when we say velocity, that is the
distance that is travelled by a volume of blood in a blood vessel.
V=Q
X
Where:
Q = blood flow
X = area
What is the difference between velocity and blood flow
because the two are directly related? Velocity is equal to blood flow over
cross-sectional area. The two are directly related so if the blood flow is
increased, velocity is also increased. When you say velocity, again, that is
the distance that a volume of blood will travel per unit of time in a blood
vessel (unit: cm/s). But when you say blood flow that is the
volume/quantity/amount of blood that will pass through a blood vessel
per unit of time (unit: mL/unit of time). And again, the two are directly
related. We already explained why velocity is inversely related to crosssectional area.
Distribution of Blood Volume
How much quantity of blood that can be stored in a given portion
the circulation for each millimeter of mercury pressure rise.
How come that the venous system can accommodate large
volume of blood with little increase in pressure? When we say compliance
or vascular capacity or capacitance, that is the measure of the degree of
stretching or distensibility of an elastic structure. So a structure can be
distensible because of the presence of elastic tissue and compliance is
equal to change in volume over change in pressure or how much blood
can be accommodated in a blood vessel for every mmHg increase in
pressure.
Vascular Distensibility
Which of the two will have more elastic tissue, artery or vein?
Arteries have more elastic tissue and the elastic tissue is responsible for
the distensibility of a blood vessel.
Which is more distensible, artery or vein? It is supposed to be
the artery but the arteries are 8x less distensible than the veins. So how
did that happen? The artery has more elastic tissue so we expect it to be
more distensible than the vein but how come that it is 8x less distensible?
The veins has higher vascular capacity, it can accommodate a large
volume of blood compared to the artery. There are more elastic tissue in
the arterial wall than in the venous wall but the venous wall is thinner.
Meaning to say, if you have an artery and a vein of the same size, both can
accommodate the same volume of blood but in order to stretch the
arterial wall which is thick and strong, that volume of blood will exert a
greater pressure or force. Compare it to the same volume of blood in the
vein, whose wall is thin and also distensible so the same volume of blood
will exert less force or pressure to distend the venous wall. So the venous
wall being thinner that also has elastic tissue, it is more distensible, it can
accommodate a large volume of blood with little increase in pressure.
Arteries are 8x less distensible than the veins i.e. a given increase in
pressure causes about 8x as much increase in blood in a vein as in
on artery of comparable size.
Veins = increase V
little P
Arteries = increase V
higher P
In the case of the veins, increase in volume but there is only
little increase in pressure. In the arteries, same volume and increase in
pressure. So the compliance is higher in veins.

PHOTO: Distribution of blood (in percentage of total blood) in the different parts of
the circulatory system.
Percentage
39 %
25 %
8%
5%
2%
5%
7%
9%
Parts of circulatory system
Large veins
Small veins and venules
Large arteries
Small arteries
Arterioles
Capillaries
Heart
Pulmonary circulation
At any point in a cardiac cycle, about 65% of the blood is
contained in the venous system, 13% in the arteries, 2% in the arterioles,
5% in the capillaries, 7% in the heart and 9% in the pulmonary
circulation.
Vascular Compliance or Capacitance
Where:
C=ΔV
ΔP
Δ V = change in volume
Δ P = change in pressure
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PHOTO: A to D, When the arteries are normally compliant, blood flows through the
capillaries throughout the cardiac cycle. When the arteries are rigid, blood flows
through the capillaries during systole, but flow ceases during diastole.
At the top, is a normal artery or aorta. Below, you have a rigid
aorta or artery. Still we are discussing compliance or stretchability of the
arterial or aortic wall.
A - During ventricular systole, blood will be ejected to the aorta so that
the volume of blood in the aorta will increase and under normal
conditions, the aortic wall will distend. At the same time, during
ventricular systole, that volume of blood will be transported under high
pressure to the arteries, to the arterioles, capillaries and therefore to the
tissues.
B - Now, during ventricular diastole (ventricles are not ejecting), the
aortic wall being distensible, it can now recoil on the contained blood.
And because of the recoil of the aortic wall, that will still push blood to the
arteries, arterioles, capillaries and to the tissues so that means although
the ejection of blood from the ventricles to the arterial system is pulsatile,
the transport of blood to the tissues is continuous so there is still
transport of blood to the tissues during diastole.
C - What will happen if the arterial wall becomes rigid for example there
is atherosclerosis which is common in the elderly. So that will make the
arterial wall less distensible. During ventricular systole, blood will be
ejected to the aorta, it can still be transported under high pressure to the
arteries, arterioles, capillaries and to the tissues but as you can see here,
it is not distended anymore. . .
D - So that during ventricular diastole, because the walls are already rigid,
it can no longer recoil. Nothing will push the blood towards the arteries,
arterioles, capillaries and tissues so that means if the arterial wall
becomes rigid i.e. atherosclerosis, that will already compromise blood
supply to the tissues during ventricular diastole.
Large artery
Capillary
In the case of the capillary, there is less tension on the wall so
that means less pressure is needed to balance the tension on the wall so
its transmural pressure is also less. That is why the capillary wall is not
prone to rupture. Compare it to a large artery, its wall is strong, so the
wall tension is high so that the pressure needed to balance the wall
tension is also high so that will make the transmural pressure high also
that is why a large blood vessel like an artery or aorta is more prone to
rupture.
Blood Flow

Volume of blood that passes through a specific point in the
circulatory system per minute

Approximately equal to CO and VR
Blood flow is the amount/quantity/volume of blood that will
pass through a specific point in the circulatory minute per minute. It is
equal to cardiac output and venous return so that means the average
blood flow is 5,000 mL or 5L/min.
Ohms Law
Volume flow = Δ Pressure
Resistance
Laplace equation
According to Ohms law, blood flow is equal to pressure
gradient over resistance.
A
PHOTO: Diagram of a small blood vessel to illustrate the law of Laplace: T = Pr, where
P = intraluminal pressure, r = radius of the vessel, and T = wall tension as the force per
unit length tangenital to the vessel wall. wall tension acts to prevent rupture along a
theoretical longitudinal slit in the vessel.
T=Pr
Where:
T = tension on the wall
P = transmural pressure (pressure inside blood vessel)
r = radius of the vessel
Laplace equation that is wall tension is equal to the product of
distending pressure and radius of a blood vessel. Tension is tension on
the wall and pressure is inside a blood vessel. So they are directly related.
How come a small blood vessel like a capillary is less prone to rupture
while in large vessel i.e. artery or aorta is more prone to rupture.
B
Let’s say this (above) is a blood vessel with point A and point B.
So for blood to flow from point A to point B, there has to be difference in
pressure between point A and point B. the greater the difference in
pressure, the greater will be the blood flow so that if the pressure in point
A is equal to that in point B, there will be no blood flow, it becomes
stagnant.
As for resistance, that is the impediment to blood flow and
there are two types of resistance depending on the arrangement of the
blood vessels. For example, there are blood vessels arranged in series or
arranged in parallel with one another.
Series:
artery arteriole capillary venule vein
TR =
T
resistance
P
P = distending pressure
T = wall tension
T
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In in series arrangement, let’s say you have an artery
connected to an arteriole, connected to a capillary and then you have a
venule and finally a vein. If the arteriole will constrict, resistance to blood
flow will increase and so will resistance in the capillaries, venules, and
vein because no blood will flow. So that means that when the blood
vessels are arranged in series, the total resistance is equal to the sum of
all the resistances in individual blood vessels.
Parallel:
resistance
TR <
On the other hand, an artery will give rise to several arterioles
arranged in parallel with one another. Each arteriole can function
independently of the others so that if one arteriole will constrict, the
resistance will increase only in this (arrow) arteriole so the total
resistance this time will become less than the resistance in one blood
vessel.
One type of blood flow is laminar flow wherein blood flows at
a constant rate. When we say laminar flow, the layer of blood that is in
close contact with the vascular wall hardly moves. The next layer which is
a little farther away from the vascular wall will flow at a low velocity. The
next layer will move at a higher velocity. That means the highest velocity
will be at the center and that will be the direction, that will be the rate
along a blood vessel meaning to say, when the blood reaches the end of
the blood vessel it cannot be that the one in contact with the blood vessel
wall will have the highest velocity and the one at the center will have the
lowest velocity. The direction is straight at a constant rate so that laminar
flow is also called stream line and this type of blood flow is silent, it
creates no sound.
2.
Turbulent Flow
The sum of all the resistances to blood flow in the systemic or
peripheral circulation is what we call total peripheral resistance (TPR).
Factors that will increase resistance to blood flow:
Poiseuille’s Equation
Resistance = Length x Viscosity x 8
Π r4
Factors that will increase resistance to blood flow are expressed in
Poiseuille’s equation. So resistance is directly related to length of a blood
vessel. The longer the blood vessel is, the higher the resistance to blood
flow. It also related to blood viscosity. Remember that blood is 3-4x more
viscous than water and there are two factors that make blood viscous:
haematocrit/concentration of red blood cells and concentration of plasma
proteins. In polycythemic patients, there is increase RBC production,
increase RBC count, increase haematocrit that will make blood more
viscous so resistance to blood flow is increased. On the other hand, the
opposite is true to anaemic patients, decrease RBC count, decrease
haematocrit that will make blood less viscous so that the rate of blood
flow increases.
When blood flows in different directions, it creates a sound and
that is what we call a turbulent flow and the sound that is produced by
turbulent flow is a bruit. In the heart, the abnormal sound is a murmur;
in the blood vessel it is called a bruit.
What are the conditions that will predispose to a turbulent
type of blood flow?
Another important factor related to resistance but this time
inversely related is the radius of a blood vessel and not just the radius,
radius to the 4th so that will make it a very important factor. Meaning to
say, during vasoconstriction, if the lumen of a blood vessel will decrease
twice its normal size, that means blood flow will decrease 4x. or if during
vasodilatation, the lumen or the radius of a blood vessel will increase
twice its normal size, that means blood flow will increase 4x normal. So
the radius of the blood vessel is very important in regulating resistance to
blood flow.
1.
If the velocity of blood flow increases.
2.
If the blood passes over a rough surface. Remember that
endothelial lining of a blood vessel is smooth. But if there will
an injury on the blood vessel wall or if there will be
atherosclerotic plaques deposited on the blood vessel wall, that
will make the endothelial lining rough and when blood passes
over a rough surface, the direction of blood flow is disturbed.
3.
If there is an obstruction. So along a blood vessel, blood flows
laminar then suddenly there is a thrombus, that will again
change the direction and the rate of blood flow will be
disturbed
4.
When the blood vessel makes a sharp angle, that will again
predispose to a turbulent type of blood flow.
Reynold’s Number
2 Types of Blood Flow
1.
Re = Diameter x Velocity x Density
Viscosity
Laminar Flow
The factors that will increase the tendency of blood flow to
become turbulent are expressed in Reynold’s number. The factors that
are directly related to the Reynold’s number are diameter of blood vessel,
velocity of blood flow, and density of the fluid or medium whereas blood
viscosity is inversely related to the Reynold’s number.
When will turbulent flow occur? If the Reynold’s number is
below 2,000, blood flow is laminar and there is very little turbulence but
it will easily die out. Between 2,000 to 3000 is the transition from laminar
to turbulent flow but above 3000, blood flow is definitely turbulent
0
1
Velocity
2
PHOTO: When flow is laminar, all elements of the fluid move in streamlines that are
parallel to the axis of the tube; the fluid does not move in a radial or circumferential
direction. The layer of fluid in contact with the wall is motionless; the fluid that moves
along the central axis of the tube has the maximal velocity.
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Venous Return


Volume of blood that goes back to the heart per minute
5,000 mL/min
Venous return is the amount/quantity/volume of blood that
will return to the heart per minute. It is equal to cardiac output and equal
to blood flow so it is 5,000 mL or 5L/min.
long time, there will be pulling of blood on the lower
extremities. Since the venous return cannot be facilitated
because of the damaged venous valves, the accumulation of
blood in the lower extremities will now cause stretching or
distension on the wall of the veins and that will cause
varicosities.
Factors that Regulate Venous Return
VR = MCSFP – CVP
RV
Where:
MCSFP = Mean Circulatory Static Filling Pressure
CVP = Central Venous Pressure
RV = resistance in veins
Venous return is equal to mean circulatory static filling
pressure (MCSFP) – the measure of the degree of filling of the systemic
or circulatory system. Meaning to say, when blood blow in the systemic
circulation stops the pressure exerted by the volume of blood in the
systemic circulation is what we call MCSFP – how much blood is present
in the systemic circulation when blood flow stops. It is actually directly
related to the total blood volume (TBV).
Where:
MCSFP = TBV
VC
TBV = total blood volume
VC = vascular capacity
So increase in the total blood volume will increase the MCSFP
and therefore increase the venous return but it is inversely related to
vascular capacity. Remember there is increase capacitance if the venous
wall is in a relaxed state because the veins will accommodate a large
volume of blood and that blood will not return to the heart so with
sympathetic stimulation, you increase the tone of the venous wall that
will now increase the veins vascular capacity and therefore increase
venous return. So, sympathetic stimulation increase venous tone,
decrease vascular capacity, and increase venous return.
CVP is central venous pressure or more specifically pressure
in the right atrium which is normally 0 mmHg. For venous return to
increase, CVP should be lower than the pressure in the venous system.
When will the right atrial pressure or CVP increase? There are
factors:
1.
Rate of venous return increases. When the rate of venous
return increases above normal so that will easily fill up the
right atrium so that is increased volume blood in the right
atrium will increase the CVP.
2.
Pumping capacity of heart. The other factor is the pumping
ability of the heart. If the pumping ability of the heart is
normal, the volume of blood in the right atrium will be ejected
to the right ventricle and on to the pulmonary circulation.
What if there is right-sided heart failure? So the pumping
ability of the right heart is depressed so the blood in the right
atrium will back up in the venous system and that will now
increase the venous pressure so that one clinical manifestation
of right-sided heart failure will be distension of the neck veins.
3.
Resistance in veins. Next is resistance in the veins which is
quite low because remember that the veins are low pressure
area but resistance may increase if the intra- abdominal
pressure increases because for example during pregnancy or if
there is tumor in the abdominal cavity or if there is ascites
(accumulation of fluid in the abdominal cavity), that will now
compress the veins so the resistance in the veins will increase
and that will decrease venous return.
4.
5.
Venous pump. Other factors that may influence venous return
will be the venous pump or activity of the venous valves. We all
know that when you move your limbs, the venous valves will
open and that will facilitate venous return. What will happen
when the venous valves are damaged? When you stand for a
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Negative intra-thoracic pressure. A negative intra-thoracic
pressure that will allow the veins and the heart to dilate so that
will facilitate venous return and allow more blood to be
accommodated in the heart.
Arterial Blood Pressure

Force exerted by the volume of blood on the arterial wall
When you get your BP: 120/80, what does that mean? What do
you mean by arterial blood pressure? That is the force exerted by the
volume of blood on the arterial wall. It is expressed as systolic pressure
over diastolic pressure.
Blood Pressure:
Systolic Pressure (SP) = is the highest pressure in the aorta at systole
Systolic pressure is the highest pressure recorded in the aorta
during ventricular systole. Why will the pressure in the aorta increase
during ventricular systole? Because when blood is ejected into the aorta,
the volume of blood in the aorta will increase and that will exert pressure
on the aortic wall to distend the aortic wall. in the elderly, systolic
pressure is usually high (higher than normal – 130, 140 and the average
is 120 mmHg) because of atherosclerosis that will cause hardening of the
aortic wall so the volume of blood ejected by the left ventricle will have to
exert a greater force to stretch the already rigid aortic wall.
Diastolic Pressure (DP) = is the lowest pressure in the aorta at diastole
Diastolic pressure is the lowest pressure recorded in the aorta
during ventricular diastole. Why will pressure in the aorta decease during
ventricular diastole? Because there is no more ejection of blood from the
ventricles and the volume of blood that is present in the aorta will drop
off to the arteries, arterioles, capillaries and tissues and the aortic wall
will recoil.
PHOTO: Arterial systolic, diastolic, pulse, and mean pressure. Mean arterial pressure
(Pa) represents the area under the arterial pressure curve.
Pulse Pressure = SP – DP
Where:
SP = systolic pressure
DP = diastolic pressure
The difference between the systolic pressure and diastolic
pressure is the pulse pressure. Again, in the elderly with atherosclerosis,
what will happen to the pulse pressure? It will increase because the
systolic pressure, the diastolic pressure will not change so that will now
increase the pulse pressure.
recoils, the volume of blood is still high and that will increase the diastolic
pressure.
What about during moderate to heavy exercise? The
sympathetic nervous system is stimulated so that will increase the heart
rate, increase the stroke volume, and increase the cardiac output. When
the cardiac output increases, the systolic pressure increases. What
happens to the diastolic pressure? During exercise, with increased
metabolism, there is increase heat production. Increase heat production
will cause vasodilatation decreasing the total peripheral resistance (TPR).
With a decrease in TPR, diastolic pressure decreases so that will widen
the pulse pressure.
To summarize, here are the factors that affect the arterial
blood pressure:
The pulse pressure can actually be influenced by two factors:
one is stroke volume – greater stroke volume, increase systolic pressure,
no change in diastolic pressure so that will increase the pulse pressure.
The other factor is compliance of the arteries. So again, when the arterial
wall becomes rigid, its compliance will decrease and that will again
increase the systolic pressure, no change in diastolic pressure so that will
widen the pulse pressure.
Another condition is in hyperthyroidism. Thyroid hormones
can directly stimulate the SA node and the myocardial cell so increase
heart rate, increase stroke volume, increase cardiac output, increase
systolic pressure. But at the same time, thyroid hormones can increase
intracellular metabolism. Again, that will increase heat production,
vasodilatation, decrease TPR, decrease diastolic pressure. So in
hyperthyroidism, you have an increase systolic pressure, decrease
diastolic pressure that will widen or increase the pulse pressure. So
hyperthyroid patients are prone to what we call high cardiac output
failure.
Factors that Affect ABP
1.
Blood volume. How come we always say that if there is
hypervolemia, there is hypertension or if there is hypovolemia,
there is hypotension? If blood volume increases, that will
increase initially the MCSFP. When increased, MCSFP will
increase venous return. The effect of an increased venous
return on the heart increases the following parameters: end
diastolic volume that will stretch the ventricular wall, increase
force of contraction, increase stroke volume, increase cardiac
output, and increase blood pressure.
2.
Compliance of arteries. When the compliance of the arteries
decreases, it increases mainly systolic pressure.
3.
Cardiac output. Increase in cardiac output will increase
mainly systolic pressure.
4.
Total peripheral resistance. Vasoconstriction that will
increase TPR will increase mainly diastolic pressure.
Mean Arterial Pressure (MAP)
MAP = DP + 1/3 (SP-DP)
Where:
MAP = mean arterial pressure
DP = diastolic pressure
SP-DP = pulse pressure
The average pressure in the circulatory system in one cardiac
system is the mean arterial pressure (MAP). Remember that this is not
the average of systolic and diastolic pressure. This is the average pressure
in the circulatory in one cardiac cycle. And it is equal to the diastolic
pressure plus one third of the pulse pressure. Why diastolic pressure?
Because 60% of the cardiac cycle is diastole, only 40% is systole.
ABP = CO x TPR
Where:
ABP = arterial blood pressure
CO = cardiac output
TPR = total peripheral resistance
The formula for arterial blood pressure (ABP) is cardiac
output (CO) times total peripheral resistance. If for example TPR is
normal, CO increases, which will be affected more, will it be the systolic
pressure or diastolic pressure? Systolic pressure because if the stroke
volume increases, increase CO, increase volume of blood in the aorta that
will exert a greater force on the aortic wall.
Now, if the TPR increases, which will be affected more? It is
diastolic pressure but why? What causes an increase in TPR?
Vasoconstriction. Remember that during diastole, supposed to be there is
peripheral run off blood to decrease the volume of blood in the aorta and
the aortic wall will recoil. What if there is vasoconstriction? Increase TPR,
blood cannot runoff to the capillaries, to the tissues etc. so there will be
pulling of blood in the arterial system so that when the arterial wall
“Trust in the Lord with all your heart and lean not on your own
understanding; in all your ways acknowledge him, and he will make
your paths straight.”
-Proverbs 3:5-6
GOD BLESS YOU 
9
Shannen Kaye B. Apolinario, RMT|
ELECTROCARDIOGRAPHY
Dr. Barbon and Dra. Cundangan
 Procedure to detect and obtain electrical activities coming
from the heart.
 Berne and Levy: enables physicians to infer the course of the
cardiac impulse by recording the variations in electrical
potential at various loci on the surface of the body.
o
Located at the junction of Superior Vena Cava with the
right atrium
▪
▪
o
Why is it considered as the pacemaker of the heart?
▪ Because it discharges the fastest among all other
origins of electrical activities of the heart
▪ SA node normally discharges most rapidly, with
depolarization spreading from it to the other regions
before they discharge spontaneously.
▪ Its rate of discharge determines the rate at which the
heart beats
▪
CARDIAC CONDUCTION SYSTEM
SA node  Internodal Trunk/ Internodal pathways  AV node 
Bundle of His  Right and Left bundle branches  Apex  Purkinje
fibers (all parts of ventricular myocardium)  Base



o

Internodal Atrial Pathways
o From the SA node, the impulse will travel to the AV node
via the internodal trunk. They are almost sumltaneous in
activation
o Anterior internodal tract of Bachmann – distribute the
impulse going to the left atrium
o Middle internodal tract of Wenkebach – utilized as a
bridge from the SA node to the AV node; activate the
middle, interatrial septum
o Posterior internodal tract of Thorel – distribute impulse
to the right atrium. All right are activated by the posterior
tract

Atrioventricular node
o Located in the right posterior portion of the interatrial
septum
o Next to discharge the fastest
o The only that impulses can be transmitted from atrium to
ventricle is through the AV node
o Atrionodal zone  Nodal zone  Nodal His zone
▪ Smallest fibers are at the Nodal zone
o Common site of AV block
o AV nodal delay
▪ Fewer gap junction
▪ Smaller fibers so the discharge is slower and
there is greater resistance to impulse flow
▪ Fewer striations
Atrial Muscle: 1st to
depolarize is the 1st
to repolarize
Ventricular muscle:
1st to depolarize is
the last to repolarize
Sinoatrial node
o Conduction in the heart originates from the SA node
known as the pacemaker.
P cells - actual pacemaker cells in the SA node and, to a
lesser extent, in the AV node which are small round cells
with few organelles and connected by gap junctions
Indistinct boundaries
Purpose: atrium will contract first before the
ventricle; for effective ventricular filling
Decremental conduction
 While atrium and ventricles are in relaxed state, you have
continuous ventricular filling. While it is relaxed (atrium and
ventricle), you fill the ventricle up to 70% of its volume.
 For it to reach the maximum filling, the atrial muscle must
contract. Once it reaches the maximum filling, the impulses
from the AV node will now proceed towards the ventricles.
 The first to activate is the Bundle of His  bundle branches.
The part of the ventricle first to be activated—Interventricular
septum (depolarizing current).
 What part of the ventricle was last activated?
o Purkinje fibers will go back towards the base. And the
last parts of the ventricle activated on depolarize the
base. When the heart contracts and the atrial muscle
contracts it will contract downward because the
activity will starts upward.
 When the ventricle contracts, it is initiated in upward
direction. The first to activate is the septum and it will contract
into smaller size  apex  base.
o Purpose: all contains blood (pulmonary artery and
aorta)—located in the basal region.
o Atrium will give blood to the ventricles, while the
ventricles will give blood to the systemic and
pulmonary circulation.
o The opening is located at the base - mechanical
activity. But before mechanical activities happen,
electrical activities must come first.
Impulse transmission and direction:
 Right atrium (where SA node is located)  AV node
o Direction: to the left
o First to depolarize in the atrial wall: endocardium to
epicardium
 Interventricular septum
o 1st part of the ventricle that is activated
o Aka: Ventricular septal activation
o Left bundle branch to right bundle branch
o Direction: to the right
o


Depolarization of the ventricular muscle starts at the left
side of the interventricular septum and moves first to the
right across the mid portion of the septum. The wave of
depolarization then spreads down the septum to the apex
of the heart.
Apex
o Direction: to the left
Movement of depolarizing current: Endocardium to Epicardium

In the ventricle:
o Depolarization: endocardium to epicardium
o Repolarization: epicardium to endocardium

Posterobasal activity
o From right ventricle  base
o The last parts of the heart to be depolarized are the:
▪ Posterobasal portion of the left ventricle
▪ Pulmonary conus
o Direction: to the right
Cardiac Vector – average direction of current flow or flow of impulses;
allow synchronized activity of the heart
o Normal Direction R  L going down
o ECG axis follow cardiac vector
ECG MACHINE
-
-
-
To record electrical activity of the heart
Connected by electrical cable to the patient or target body
Electrodes: capable of gathering electrical impulses from the
patient’s body; placed in specific body parts (RA, LA, LL)
Electrical conduction will be determined and seen in the monitor
or tracing in the ECG paper
Use body fluids which functions as volume/fluid conductors
Extracellular electrical activities: conducted by the body fluids
(INTERSTITIAL FLUIDS) towards the skin and the electrodes are
attached to the skin to gather electrical impulses
Body fluids are good conductors (body is a volume conductor),
fluctuations in potential that represent the algebraic sum of the
action potentials of myocardial fibers can be recorded
extracellularly.
ECG machine: responsible on which lead is to be recorded. Leads
will depend on what electrodes are being activated. The one
activating this is the ECG. Electrodes exhibit a color coded form. It
is in standard form:
o RA - Red
o LA - Yellow
o RL – Black (ground electrode)
 Because heart is not the only one that makes the
action potential, it can be smooth muscle, skeletal
muscle. You must remove the said other action
potential that are not coming from the heart, for
the tracing to be clean.
o LL – Green
Electrodes must be placed in the correct body part for you to
have a correct ECG tracing
o Electrodes must also be placed at the same level on both
sides of the body (mirror image) so that impulses will travel
the same length towards the electrodes
Resting ECG
o Most common procedure done; usual position
o patient is lying down
o cables are commonly on the chest and not in the
extremities
o remove all metals that will interfere with the transmission
of impulses
o Actual: there is electrode also in the RL (ground)
▪ Purpose: to remove other electrical activities not
originating from the heart or non-cardiac
▪ Other tissues that can also generate electrical
activities: Skeletal muscle (Diaphragm); Smooth
muscle (GIT, ureter); Neurons
Stress/Exercise ECG/Treadmill test
o Electrodes are directly connected to the machine.
Complete electrodes
o Detects the heart’s electrical activity; At least 3 chest
electrodes are used
o the patient is exercising in treadmill or stationary bicycle
and ECG is attached to the patient
o with modified attachment because it cannot be attached
to the hands and feet while running
▪ No more chest electrodes because the extremity
electrodes are placed on the chest
o
to determine any presence of abnormality that is not
detected in normal ECG (example, in patients complaining
with chest pain but normal in resting ECG)
▪ Some cardiac problems are only manifested if you
allow the patient to have extra activity like running
▪ But there are still times when even if you conduct
stress ECG, you still cannot detect the cardiac
problem
Holter Monitoring
o There is a portable ECG attached to the patient’s body for
24-48 hours continuously
o aka Event recording
o Indicated for patients who always complain of palpitation
but are not seen in normal ECG tracing
o Not necessarily that the patient will not move; The patient
can still do normal daily routine and they will be provided
with a diary (to write the start of ECG recording and write
if ever the patient will experience palpitation, the time
must be recorded in the diary)
o Example, to correlate the presence of arrhythmia
recorded in the ECG which is simultaneous with the
palpitations or abnormalities experienced by the patient
Continuous Loop recording
o Applied much longer; for 4 months
BASIC LEADS USED IN ECG


Common recording of ECG: 12 ECG leads
o Bipolar limb leads: 1, 2, 3
o Unipolar limb leads: aVR, aVL, aVF
o Unipolar chest leads: V1-V6
Bipolar/Extremity limb leads
o “Bipolar”: there are 2 active electrodes. 1
electrode connected to the negative terminal of
the machine and the other to the positive terminal
of the machine
In bipolar limb leads, it has negative and positive sign:
o RIGHT SIDE - always negative
o LEFT SIDE - always positive, except in bipolar in lead III
(left arm-negative) , but in lead I (left arm-positive)
o
o
o
o

Lead 1: RA (-) to LA (+)
▪ determines the condition of the basal region
of the heart
Lead 2: RA (-) to LL (+)
▪ determines the condition of the right side of
the heart
▪ the highest wave because it follows the wave
of cardiac vector; equals the value of Lead I
and Lead III
Lead 3: LA (-) to LL (+)
▪ determines the condition of the left side of the
heart
gives a 3-D picture of the heart
Unipolar limb leads
o Unipolar extremity leads or Augmented
o Only 1 active electrode which is attached to the positive
terminal of the machine
o aVR – augmented vector to the right arm
▪ from the axis to the RA
▪ shows what is happening in the right uppermost
part of the heart (right atrium)
▪ mostly the limb lead that is always presenting mostly
negative deflected waves
o aVL – augmented vector to the left arm
 shows the left uppermost part of the heart (left atrium
and basal portion of left ventricle)
o
o
o
o
o
aVF – augmented vector to the left foot
▪ shows what is happening in the apex
together with bipolar limb leads produce 6-D picture of the
heart (HEXAGONAL REFERENCE SYSTEM)
when 2 lead are combined, the result is neutral
Limitation of Extremity Leads: it is only looking at the anterior
portion of the heart (Ventral plane)
o
o
o
o
 Ex. If the patient has inferior wall problem or apical
problem, it can be seen in the L1, L3 and aVF
Chest leads: horizontal or transverse plane; determines
happening laterally and posteriorly
Extremity Leads: anterior part of the heart (front only)
Limitation: those happening in the frontal
plane
 HEXAGONAL REFERENCE SYSTEM (Frontal plane –
Vertical)
o
o
o










V1: 4th ICS; Right Sternal Margin
▪ right anterior side of the heart; Red
V2: 4th ICS Left Sternal Margin
▪ right anterior side of the heart; Yellow
V3: midway between V2 and V4
▪ left anterior wall; Green
V4: 5th ICS, Left midclavicular line (apex of the heart)
▪ left anterior wall; Brown
V5: 5th ICS, Left anterior axillary line
▪ left lateral wall; Black
V6: 5th ICS (same horizontal level as V5); Left Mid axillary line
▪ posterolateral wall; Violet
V7: 5th ICS, posterior axillary line
V8: 5th ICS (same horizontal level as V5); Left midscapular line
V1 and V2 – right anterior portion of the heart
V3 and V4 – left anterior portion of the heart
V2 and V3 – middle portion of the heart
V5 and V6 – lateral portion of the heart
V7 and V8: for monitoring the posterior aspect of the heart;
posterior wall of the heart
To detect posterior heart problems
aka Esophageal electrode
Not commonly used because problems of the heart in the most
posterior portion is one in a million
You will allow the patient to swallow the electrode which is
connected to the wire (Flag ceremony )
Unipolar chest leads/ Pre- cordial leads
 If the problem is still not detected by ECG, use other modalities like
CT Scan, MRI, and specific determination of cardiac enzymes


There is no Q wave in V1 and V2, and the initial portion of the QRS
complex is a small upward deflection
o Ventricular depolarization: mid portion of the septum
from left to right toward the active electrode  down the
septum  into the left ventricle away from the electrode
 moves back along the ventricular wall toward the
electrode, producing the return to the isoelectric line.
o Large S wave
In left ventricular leads (V4–V6)
o initial small Q wave (left to right septal depolarization)
o large R wave (septal and left ventricular depolarization)
o moderate S wave (late depolarization of the ventricular
walls moving back toward the AV junction).
 RA is always negative except for aVR
o When there is activity, it will depolarize and the inside
will become positive
o When the heart has an electrical activity, there will be an
initial change extracellular (becomes negative) in the right
uppermost portion where the SA node is located
 LL is always positive
o Because the ECG is recording the happenings on the
outside of the heart (EXTRACELLULAR)
o Electrical activity of the heart:
▪ Any excitable cell that is resting is negative inside
and positive outside
 LA is positive in Lead 1 and aVL but it is negative in Lead 3




Hexagonal system for determining the frontal plane of the heart
Using the bipolar limb lead
Formula: L2 = L1 + L3
o The potential in Lead 2 is the sum of the potential of Lead
1 and Lead 3
o Margin of error: +/- 2
Lead 2 has the highest amplitude or voltage
o Because Lead 2 is towards the left and most of the
impulses of the heart are directed toward the left; it
follows the cardiac vector
RELATIONSHIP OF CHEST LEADS TO R and L Ventricles


aVR
o Atrial depolarization, ventricular depolarization, and
ventricular repolarization move away from the active
electrode
o P wave, QRS complex, and T wave = all negative (downward)
deflections
aVL and aVF
o deflections are predominantly positive or biphasic.
greater works compare to the right ventricle.
 Left ventricle is the one working for the whole systemic circulation while
the right ventricle works on the pulmonary circulation.
Review: Action potential in ventricular muscle
EINTHOVEN’S TRIANGLE


 Common problem of the heart: left side; because left ventricle has
 Chest lead- horizontal plane of the heart
 Limb and augmented limbs – vertical plane of the heart or frontal
plane

Phase 0
o rapid depolarization
o The initial depolarization is due to Na+ influx through
rapidly opening Na+ channels
 Phase 1
o initial rapid repolarization
o The inactivation of Na+ channels
 Phase 2
o plateau
o Ca2+ influx through more slowly opening Ca2+ channels
 Phase 3
o slow repolarization process
o net K+ efflux through multiple types of K+ channels.
 Phase 4
o return to the resting membrane potential
Why is it different from the action potential seen of ECG paper?
Because the ECG machine detects electrical activities outside
the tissues and uses interstitial fluid while the action potential
shown above detects activities inside the cardiac tissues
Normal: move from right going down to the apex (Cardiac vector)
 If the depolarizing current in the ECG (Cardiac vector) follows the
ECG axis = (+)
o Atrial depo: P wave
o R wave: endo to epi; towards the ECG axis
 If the depolarizing current moves in the opposite direction to the
ECG axis = (-)



o Ventricular septum: Q wave
In repolarizing current, if the vector of the repolarization is
following the axis = (-)
In repolarizing current, if the vector of the repolarization is moving
opposite to the axis = (+)
o T wave: in the ventricle; moving opposite to the axis
Normal recording of atrial repo (though it is not normally recorded)
= (-)
o Atrial T wave = 2nd degree AV block
▪ Activity starts at the right side goes towards the left
going down
For depolarization current:
 Upward deflection (+) – flow of the electrical current is going to
the positive side


Downward deflection (-) : away from the positive side
Isoelectric line
o horizontal straight line
o reference line to determine which are positive and which
are negative
o Anything above is positive while anything below is negative
o Normally (+) waves or Depolarizing waves: P, R, and T
waves
o Normally (-) waves or Repolarizing waves: Q and S

P wave
o atrial depolarization
QRS complex / Depolarization wave
o corresponds Phase 0
o ventricular depolarization
o to know if there is problem in the conducting fibers in the
ventricle (Bundle of His and Purkinje fibers)
o if the duration is longer than normal = Bundle branch block
ECG WAVE
Depolarization moving toward an active electrode in a volume
conductor produces a positive deflection, whereas depolarization
moving in the opposite direction produces a negative deflection.
U wave - secondary to a much slower repolarization of papillary
muscle
o Papillary muscle – to prevent backflow from ventricle to
atrium; to prevent eversion of the AV valve
o If prominent, it is called SIGNIFICANT U WAVE
▪ if it is as tall or half the height of T wave
▪ indicates hypokalemia

For repolarization current – occur in opposite direction; the first to
depolarize will be the last to repolarize

The machine will detect higher/greater electrical activity
which is ventricular depo that is overshadowing atrial
repo
o The atrial repolarizing wave is buried in the QRS
In analyzing ECG, we have to determine the normally positive
waves and the normally negative waves

Standard speed of the movement of ECG paper = 25 mm/sec
 Upright/ Vertical line: amplitude / voltage (strength of electrical
activity; gaano kalakas yung kuryente ng puso)
 Horizontal line: time which determine the duration of intervals
(gaano katagal yung electrical activity ng puso)


o
ECG PAPER
Downward: Atrial T wave; going to positive

There is no wave for atrial depo because it occurs simultaneous
with ventricular depo. Since atrial muscle is thinner than the
ventricular muscle, ventricular depo mask the atrial repo


Q wave
o
o
o
o
o

septal depolarization; seldom to be seen
Normally negative
Lead II
When impulses reaches bundle of his and transmitted
to the interventricular septum the impulses will move L
to R (opposite cardiac vector so Q wave is negative)
Represents depo of interventricular septum
Parameters used in determining when atrial repo and ventricular depo
starts includes the following:
o
PR segment
o
PR interval

R wave
o
o
o
o
apical depolarization
+ wave
Wave representing what is happening in the apex
Apex( impulses is R-L going down moving towards
positive electrode—follow axis/ current flow
S wave
o Postero - basal depolarization
o Normally negative
o Represent the part of the ventricle depolarized last
(base)
T wave/ Repolarization Wave
o part of ventricular repolarization; phase 3
o If repo follows ECG axis/ cardiac vector → negative
deflection
o It repo does not follow cardiac vector → positive
deflection
o Total duration of repolarization
▪ start from end of S to end of T
o Duration of T wave
▪ does not give the total duration of ventricular
repo
o In obtaining the total duration of ventricular repo
▪ Measured from the end of S to the end of T
o T interval → end of S to beginning of T
HEART RATE
ST segment
o initial repo; corresponds Phase 1 and 2
o From the end of QRS to the beginning of T wave
o At isoelectric line, while cell is repolarizing; since the
machine only records electrical changes in phase II there
is no electrical change(efflux of K is balance by the influx
of Ca), so it is recorded at the isoelectric line but that cell
is said to be repolarizing
PR segment
o From the end of P wave to the beginning of QRS wave
o Represents AV nodal delay
PR interval
o P wave + PR segment
o Atrial depo + AV nodal delay
o To tell if there is AV block; conduction delay
o beginning of P to beginning of Q
QRS interval
o beginning of Q to end of S
QT interval
o From the beginning of Q to the end of T
o Action potential
o To know if the patient experience tachycardia (shorter
duration of action potential) or bradycardia (longer
duration of action potential)
ST interval
o end of QRS to end of T
o measures the whole period of latent repolarization
o to know the total duration of ventricular repo

NORMAL INTERNAL VALUES

J point
o Reference point for ST elevation and ST depression
o It is the time at which all ventricular muscle has been
repolarized
o To know if there is ischemia or myocardial infarction
R-R interval (duration) – measure the big squares



60 / (5*0.2) = 60 bpm
The equation is only used for regular rhythm of the heart; not for
irregular rhythm because there is variable R-R interval
 Hash marks
o duration is 3 sec then multiply to 20
o Count the number of R waves in a given duration to get
the heart rate for irregular heart rhythm
o Small vertical lines on top of the ECG paper
If you have hard time dealing with decimal numbers: 
o 300 / number of big squares
o 1500 / number of small squares
VECTORCARDIOGRAPHY



Mean cardiac vector: average direction of the cardiac electrical
activity (san papunta yung takbo ng activity sa puso)
In vector analysis, aside from the direction, what other
parameters should be considered?
o Magnitude/strength of electrical activity (gaano kalakas yung
kuryente ng puso) – measured by the length of the vector
Because the standard limb leads are records of the potential
differences between two points, the deflection in each lead at any
instant indicates the magnitude and direction in the axis of the
lead of the electromotive force generated in the heart (cardiac
vector or axis).
Cardiac vector calculation
o R = (+)
o S = (-)
o Get the sum of R and S but by getting the total, you are
actually subtracting the values because they have opposite
signs
Draw horizontal line and arrow where it intersects and measure
the angle = Axis of the heart
o Line parallel to Lead 1 passing to the center of the triangle
= 0 angle
o Then draw a line going to the common intersection of the
Leads
o Get the angle between the two lines = Cardiac vector
To get the magnitude:
Get the length of the arrow multiply to 0.1 mV
Alternative:











 not used for diagnostic purposes
 used for annual check-up in companies; for screening purposes
only
Determination of the Axis of the Heart
o Get the number of mm for upward (+) and downward (-)
deflection
o Plot in triangle (must be equilateral and equiangular = 60
degrees)
o Get the center of the triangle. Midpoint of the sides are
marked as 0
o Draw perpendicular line in reference to the plotted leads
Point of intersection = Vector = Mean QRS axis
o To know if you have the correct analysis, Lead 2 must be
plotted in the intersection of Lead 1 and Lead 3
Normal values of axis
 Asians: 0 to 90 degrees
o Vertical position
▪ Payat na matatangkad ; puso na parang parol
o Horizontal position
▪ For obese and pregnant people
o Intermediate position
▪ Anatomical position of the heart
 Americans: -30 to +110 degrees (due to bigger thoracic cage that
allows their heart to move in a bigger area)
 Common cardiac vector: 59 degrees


o R and S wave = ventricular vector; commonly used
o T wave = atrial vector
Mean cardiac vector indicates average or mean direction of flow
in the heart
Length will determine the thickness and activity in the muscle
o If it hypertrophy, greater voltage is generated
▪
▪
▪
o
peak energy; peak/prominent T wave because during
repolarization, K will enter the cell. If there is
increased amount of K then more K will go into the
cell.
At higher K+ levels, paralysis of the atria and
prolongation of the QRS complexes occur. Ventricular
arrhythmias may develop.
The resting membrane potential of the muscle fibers
decreases as the extracellular K+ concentration
increases. The fibers eventually become unexcitable,
and the heart stops in diastole.
▪
Hypokalemia
▪ prolonged of the PR interval, prominent U waves, and
late T wave inversion in the precardial leads
o
2nd degree (Incomplete)
progressive lengthening of the PR interval and
absence of QRS (2:1 ratio of P wave : QRS wave)

▪
▪
not all atrial impulses are conducted to the ventricles
Dropped beat: there will be an atrial P wave but no
QRS-T wave
Abnormalities Determined in ECG
 Cardiac problems diagnosed using the ECG are cardiac problems
wherein there is alteration in deterioration and conduction of
impulses.

Arrhythmia
o Bradycardia < 60
o Tachycardia > 60
o Junctional rhythm like AV node rhythm
 Abnormal pacemakers – other potential pacemakers will
discharge impulses
 Myocardial ischemia – ST depression; lack of blood flow;
Ventricular strain
 Myocardial Infarction – ST elevation; T wave inversion
 Cardiac enlargement – Since it is larger and thicker, it has a
tendency to produce greater contraction and voltage.
o Higher R wave
o Deep S wave
o Longer duration of QRS > 0.10 sec
o Right ventricular hypertrophy
▪ Tall R waves in V1; deep S waves in V6
o Left ventricular hypertrophy
▪ Tall R waves in V6; deep S waves in V1
Electrolyte/Ionic imbalance
o Hyperkalemia

o

Hypocalcemia
▪ prolonged ST segment and QT interval; phase 2
involves Ca conductance
▪ bradycardia
AV block – block at AV node
o 1st degree
▪ prolonged PR interval > 0.2 sec
▪ P-QRS interval normal
▪ P waves
 there are repeated sequences of beats in which the PR interval
lengthens progressively until a ventricular beat is dropped
(Wenckebach phenomenon)
o
3rd degree (Complete heart block)
▪ no impulse travels from the SA node AV node
ventricles; complete dissociation
▪ May sariling mundo na yung ventricle caused by the
activity of Purkinje fibers. Hindi na nya hinihintay si
atrium.
▪ Ventricles beat at a low rate (IDIOVENTRICULAR
RHYTHM) independently of the atria


Bundle branch block – prolonged QRS > 0.10 sec
o Longer transmission in the ventricular muscle
o Left bundle branch is blocked so Right bundle branch will be
activated first
o Since left bundle branch is also a potential pacemaker, it will
produce its own depolarization which will overlap with the
previous depolarization that reached the right bundle
branch.
o 2 R waves (one to the right and one to the left)
o Due to heart enlargement (Cardiomegaly) which requires
longer time to transmit impulses in the ventricles which are
bigger than normal

Cardiac Enlargement
o Very tall R waves
o Very deep S waves
o QRS interval > 0.10s

Right ventricular hypertrophy
o Tall R waves in V1; deep S waves in V6
Left ventricular hypertrophy
o Tall R waves in V6; deep S waves in V1


Are all cardiac disorders diagnosed using the ECG? NO
o Useful in cardiac disorders wherein there is disturbance
in impulse generation and conduction
ECG
o
o




ECG can only detect electrical activity of the heart. It cannot
identify structural abnormalities so, use other modalities like
echocardiography.
o 2D-echo ultrasound of the heart; problems in blood flow
Cardiac problems that are not associated with the alteration,
generation, or transmission of cardiac impulses are not detected
in ECG.
Not diagnosed by ECG:
o Valvular disorders/defect
o Stenosis
o Septal defects - Congenital heart disease; ASD, VSD
o Coronary heart disease – ECG can suggest but it cannot
quantify how much is the obstruction in the coronary artery
o Cardiac chamber disorders
o Cardiomyopathies – weakening of heart muscle
o Cardiac masses
o Pericardial disorder
Not only diagnose cardiac problems but also electrolyte
problems → electrolyte problems affect cardiac activity
Diagnose cardiac problem with alternation in
electrolyte activities
Echocardiography
o Can diagnose cardiac problems not associated with
alternation of electrical activity
Cardiac masses
o Abnormal growth in the cardiac tissue
Pericardial disorders
o Even injuries affecting pericardial sac
o Initially not diagnose in ECG → they are not causing
changes in the electrical activity of the heart
o Problems in this conditions →BLOOD FLOW (diagnose
using echocardiography
Originally by (Combined): CKRP, Dela Rosa, Mauro, AJRU
Updated by: CDMD, RMT 
Electrocardiography R wave Apex Depolarization Electrocardiography -­‐
Procedure used to record electrical activity of the human heart QRS Complex Ventricular Depolarization AJRU ST Segment Plateau S wave Posterobasal Depolarization PR Interval Atrial Depolarization + AV Nodal Delay T wave Ventricular Repolarization P wave Atrial Depolarization PR Segment AV Nodal Delay Q wave Interventricular Septum Depolarization -­‐ Fewer gap junctions -­‐ Smaller diameter fibers QT Interval Ventricular Depolarization + Ventricular Repolarization U wave Slow repolarization of the papillary muscles. If the height of the T wave is equal to the height of the U wave, it may indicate Hypokalemia in the patient. Impulse Conduction Rule #1: Depolarization following direction of impulses Rule #2: Depolarization away from direction of impulses Rule #3: Repolarization following direction of impulses Rule #4: Repolarization away from direction of impulses -­‐
-­‐
= Positive Deflection = Negative Deflection ^ v = Negative Deflection = Positive Deflection v ^ SA Node generates an impulse o Atrial Depolarization occurs § P wave § Depolarization direction • Downward Follows Rule #1 • Right to left Impulse is transmitted to the AV node o AV Nodal Delay § PR Segment § Isoelectric line (no electrical activity noted) Direction of Impulses à Downward à Right to Left Electrocardiography -­‐ Atrial Repolarization occurs (Unseen in the ECG) o Repolarization Direction § Downward Follows Rule #3 § Right to left -­‐ Impulse is transmitted to the Ventricular Conduction System o Ventricular Depolarization Occurs § QRS Complex • Q Wave o Interventricular Septum Depolarization § Depolarization direction • Downward Follows Rule #2 • Left to Right • R Wave o Cardiac Apex Depolarization § Depolarization Direction • Downward Follows Rule #1 • Right to Left • S Wave o Posterobasal Depolarization § Depolarization direction • Upward à Follows Rule #2 -­‐ Ventricular Repolarization occurs o Q Wave § Depolarization direction • Upward à Follows Rule #4 Automatic Cells -­‐
-­‐
-­‐
Sinoatrial (SA) Node o Node of Keith and Flack o Primary pacemaker of the heart o Suppresses automaticity of other automatic cells § Overdrive suppression Atrioventricular (AV) Node o Node of Kent and Tawara o AV Nodal delay o Slow velocity of impulse conduction (0.05 m/s) Purkinje system o Bundle of His o Left and Right bundle branch o Purkinje Fibers ECG Procedure -­‐
Types o Resting ECG § Most common procedure done § Remove all metal items § Usually uses all leads o Exercise ECG / Stress test / Treadmill test § Detects the heart’s electrical activity changes during activity § At least 3 chest electrodes are used AJRU Atrial Muscle The first part to Depolarize will be the first part to Repolarize. Ventricular Muscle The first part to Depolarize will be the last part to Repolarize. The last part to Depolarize will be the first part to Repolarize. Electrocardiography AJRU -­‐ Application of electrode gel -­‐ Leads o Method discovered by Dr. Einthoven o Ground Lead § Eliminates non-­‐cardiac electrical activities § Right leg (Black) o Bipolar Limb Leads § Lead I • Records electrical activities in the base of the heart • Right Arm (Red) to Left Arm (Yellow) § Lead II • Records electrical activities from the base going to the apex on right side of the heart • Follows cardiac vector • Right Arm (Red) to Left Leg (Green) § Lead III • Records electrical activities from the base going to the apex on left side of the heart • Left Arm (Yellow) to Left Leg (Green) o Unipolar Limb Leads § aVR • Center to the right uppermost part of the heart § aVL • Center to the left uppermost part of the heart § aVF • Center to the apex of the heart o Unipolar Chest Leads § V1 4th Intercostal Space, Right Sternal Border § V2 4th Intercostal Space, Left Sternal Border § V3 In between V2 and V4 § V4 5th Intercostal Space, Left Mid Clavicular Line § V5 5th Intercostal Space, Left Anterior Axillary Line § V6 5th Intercostal Space, Left Mid Axillary Line § V7 5th Intercostal Space, Left Posterior Axillary Line Rarely used th
§ V8 5 Intercostal Space, Left Mid Scapular Line o Esophageal Leads § Rarely used § Most posterior portion of the heart § Patient is asked to swallow the leads -­‐ Body fluids transmit conduction from heart -­‐ Einthoven’s Equation o (Lead II) = (Lead I)+ (Lead III) § Lead II shows the tallest recording in the ECG Electrocardiography AJRU ECG Reading -­‐
-­‐
Vertical Reading o Amplitude (millivolts) Horizontal Reading o Time (seconds) 5mm = 0.5 mv 5mm = 0.2 s 1mm = 0.1 mv 1 Hash Mark Equivalent to 3 seconds (15 big boxes) 1mm = 0.04 s -­‐
Interpreting the Heart Rate o Only for ECG readings with a regular rhythm o Count the number of small boxes in between the RR intervals o Multiply number of small boxes by 0.04 seconds Heart Rate = 60 seconds RR Interval Example 1 5 10 12 o
12 x 0.04 = 0.48 60 seconds . = 125 bpm 0.48 seconds Shortcut! (Only for exact RR Intervals) -­‐
5 small boxes (1 big box) = 300 -­‐
10 small boxes (2 big boxes) = 150 -­‐
15 small boxes (3 big boxes) = 100 -­‐
20 small boxes (4 big boxes) = 75 -­‐
25 small boxes (5 big boxes) = 60 -­‐
30 small boxes (6 big boxes) = 50 -­‐
35 small boxes (7 big boxes) = 43 -­‐
40 small boxes (8 big boxes) = 37 ECG Intervals PR Interval QRS Interval QT Interval ST Interval Normal Duration Common Range 0.18 s 0.12 – 0.21 s 0.08 s 0.08 – 0.10 s 0.40 s 0.40 – 0.43 s 0.32 s 0.12 – 0.21 s Electrocardiography Cardiac Abnormality Detection in ECG -­‐
-­‐
-­‐
-­‐
-­‐
Arrhythmias o Bradycardia § RR < 60 bpm o Tachycardia § RR > 100 bpm o Pacemaker abnormalities o Heart Blocks § 1st degree • Prolonged PR Interval § 2nd degree • PQRS – P – PQRS (2:1 / 3:1) § 3rd degree • P waves found in many parts Myocardial Ischemia / Injury / Infarction o Ischemia § Depressed T wave T↓schemia o Injury Injur↑ST § ST segment elevation infarQtion o Infarction § Pathologic Q wave Hyperkalemia o T wave Hypokalemia o Prominent U wave Hypocalcemia o Narrow QRS Interval (Tischemia) (injuryST) (infarction) Vectocardiography -­‐
-­‐
-­‐
Determination of the electrical axis of the heart Mean cardiac vector (angle) indicates the average direction of current flow in the heart o Normal (Local) Deviation from the normal axis § 0 to 90° may indicate Cardiomegaly o Normal (Western) § -­‐30 to +110° o Average / Common Vector / Common Axis § 59° 2 methods o Method 1 § Lead I and aVF o Method 2 § Lead I, Lead II and Lead III AJRU Electrocardiography (ECG)
Dr. Barbon
ECG
-
This is a procedure were we are trying to detect and
obtain electrical activities coming from the heart.
now in the AV node. There will be normal AV nodal delay. Its
purpose is for the atrium to contract ahead of the ventricle. It
cannot undergo simultaneously. Why? Because you must fill the
ventricle to maximum or almost maximum. And, what will cause
almost maximum filling of ventricle? You allow the muscles to
contract ahead. When it contracts, AV valves are open. While
atrium and ventricles are in relaxed state, you have continuous
ventricular filling. While it is relaxed (atrium and ventricle), you
fill the ventricle up to 70% of its volume. But, it is not yet full. For
it to reach the maximum filling, the atrial muscle must contract.
Once it reaches the maximum filling, the impulses from the AV
node, it will now eventually proceed towards the ventricles. The
first to activate is the Bundle of His, then bundle branches.
So, when you are asked what part of the ventricle was first
to be activated—it’s the Interventricular septum (these are
depolarizing current). You need to depolarize the ventricle for it
to contract. Like the atrium, first it should be depolarize, and
then activates the SA node, intermodal tracts; then, there will be
delay in the AV node. And if the atrium is fully depolarizing it will
now contract. Next, activates the ventricles, apex, and then
Purkinje fibers.
If you follow the activity it starts from the right atrium,
because it is the pacemaker. From the right atrium the impulses
are then transmitted towards the whole atrial muscles: right and
left. What will transmit impulses if the SA node is in the right
atrium? We will utilize the different intermodal tracts. The
anterior tract of Bachmann, middle tract of Wenckeback and
posterior tract of Thorel are almost simultaneous in activation.
1
Your posterior tract will eventually activate the whole right
atrium. All right are activated by the posterior tract. The anterior
tract of Bachmann will activate the entire left atrial region. Then,
the middle tract of Wenckeback will activate the middle, the
interatrial septum. And this all happens simultaneously. They
will proceed now towards the AV node. So, what will happen
What part of the ventricle was last activated? The
Purkinje fibers will go back towards the base. And the last parts
of the ventricle activated on depolarize the base. When the
heart contracts and the atrial muscle contracts it will contract
downward (pababa). Why downward? Because the activity will
starts upward (pataas).
When the ventricle contracts, it is initiated in upward
direction. The first to activate is the septum and it will contract
into smaller size, then apex, lastly base. Purpose: all contains
blood (pulmonary artery and aorta)—located in the basal region.
Atrium will give blood to the ventricles, while the ventricles will
give blood to the systemic and pulmonary circulation. The
opening is located at the base -- that’s mechanical activity. But
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
before mechanical activities happen, electrical activities must
come first.
In ECG, direction of electrical activity is needed. The
flows of current are through: Electrical changes happening in the
atrial and ventricular muscles. Depolarization of atrium will
proceed on this direction going through the SA node towards
the AV node.
In the ventricle, first is the interventricular septum.
Then, the electrical activity is of the same direction and current
flow. The depolarizing current will moved in the direction
moving towards the right side. Next to activate is the apex, then
moving to the left side. Last part to depolarize is the base.
Depolarization and repolarization are used in recording
ECG. Following repolarization, in the atrium, the first to
depolarize is the first to repolarize. Therefore, the direction of
repo and depo in the atrium is the same.
In the ventricle, the first to depo is the last to repo. The
direction of repo in the ventricle is moving in opposite direction.
If depo is moving towards left, repo is moving towards right.
towards the left (depo) and that is also the repo. The first to
depolarize in the atrial wall is endocardium to epicardium.
(Same in repo)
Phase 2- continuous repolarization; almost no change in the
electrical activity of the ventricle—Plateau phase
Phase 3- rapid return to normal resting membrane potential
Phase 4- returning back to the RMP
In the ventricle, the first to depo is endocardium to
epicardium, but in repo it will start in the epicardium towards
the endocardium.
Average direction of the current flow of the heart:
movement is from right to left. The first to contract is atrium
then ventricle.
The purpose of AVR contraction: for the blood in the
atrium to be emptied in the ventricle. Then, the blood from the
ventricle will be released to the aorta and pulmonary artery.
When the ventricle contracts, it will not totally empty the
ventricular chambers. There is remaining blood—ESV. There is
no total emptying of ventricular chambers.
This is what the ECG needs to record. The machine
must be connected to the subject using the wires. And that wire
is connected to the machine and to the subject. Electrodes are
the one being attached to the subject. It includes:
o Right arm electrode
o Left arm electrode
o Chest electrode
o Left leg Electrode
2
If you look at the ventricular wall and atrial wall, you
follow the depolarization. In the atrium, the movement is
Phase 0- depolarization period
Phase 1- start of repo
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
Right leg electrode- it is the ground electrode. Because
the heart is not the only one that makes the action potential, it
can be smooth muscle, skeletal muscle. You must remove the
said other action potential that are not coming from the heart,
for the tracing to be clean.
ECG machine is the one responsible on which lead is to
be recorded. Leads will depend on what electrodes are being
activated. The one activating this is the ECG. Electrodes exhibit a
color coded form. It is in standard form:
 Right arm- red
 Left arm- yellow
 Right leg- black (ground electrode)
 Left leg- green
The one attached in the chest are labeled 1, 2, and 3,4,5,6. Then,
th
 V1 – 4 ICS, right sterna margin
th
 V2- 4 ICS, left sterna margin
nd
th
 V3- middle of 2 and 4 (V2 and V4)
th
 V4- 5 ICS, Midclavicular line
th
 V5- 5 ICS, axillary line
th
 V6- 5 ICS, midaxillary line
ECG can be done as:
Resting
Exercise


In exercise: electrodes are directly connected to the
machine. Complete electrodes
In resting: cables are commonly on the chest and not in
the extremities
Common recording of ECG: 12 ECG leads



Bipolar limb leads: 1, 2, 3
Unipolar limb leads: aVR, aVL, aVF
Unipolar chest leads: V1-V6
They are called extremities leads because we are using extremity
electrodes.



Lead I- electrical activity of heart recorded by right arm
and left arm electrodes
Lead II- RA and LL (record right side of the heart)
Lead III- LA and LL (record left side of the heart)
Bipolar- because it uses two electrodes
Unipolar- uses one active electrode



Develop by Einhoven’s using bipolar limb leads
aVR- active is right arm (upper most right side of the
heart)
aVL- left electrode (left extremity leads)
aVF- left leg (lower most portion of the heart—apex)
Remember: In the normal tracing, aVR is mostly the limb lead
that is always presenting mostly negative deflected waves.
Chest leads: horizontal or transverse plane
Extremity Leads: anterior part of the heart (front only)
Limitation: those happening in the frontal plane
V1, V2: mostly on the right side of the heart
V3, V4: middle heart
V5, V6: left side, lateral side
V7, V8: posterior of the heart (rare)
3
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
The electrical activity recorded to Lead II is equals to
the sum of the electrical activity recorded to lead I and lead III.



aVR- active is right arm
aVL- active is left arm
aVF- active is left leg
In unipolar chest leads, there is no negative and positive,
the electrodes are all positive. When you interconnect them this
is the arrangement.



This is the relationship to the heart; it’s the hexagonal
reference system of the procedure.
If you are using the extremities lead, it’s the frontal plane
(front only), and you cannot see the back portion so you need to
use the unipolar chest leads.
Lead I- RA (-) and LA (+)
Lead II- RA (-) and LL (+)
Lead III- LA (-) and LL (+)
In bipolar limb leads, it has negative and positive sign:
 Right side- always negative
 Left side- always positive, exceptin bipolar in lead III
(left arm-negative) , but in lead I (left arm- positive)
When you look at the ECG, you are not looking at a three
dimensional picture it is already six dimensional pictures: Lead I,
II, and III, aVR, aVL and aVF; six dimensions, heart is the center
Locate V1-V6:
th
 V1 – 4 ICS, right sternal margin
th
 V2- 4 ICS, left sternal margin
nd
th
 V3- middle of 2 and 4 (V2 and V4)
th
 V4- 5 ICS, Midclavicular line
th
 V5- 5 ICS, axillary line
th
 V6- 5 ICS, midaxillary line
nd
st
First palpable is the 2 ICS not the 1 ICS.


4
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
Chest leads- horizontal plane; determines happening
laterally and posteriorly
Extremities lead- frontal plane
ECG waves:




P wave- atrial depo
QRS- ventricular depo
T wave- ventricular repo
U wave- activity of papillary muscle, seldom seen due to
slow repo happening in the papillary muscle—not
strong to generate electrical activity that can be
recorded at the machine
P, R, S, and T wave- common waves seen
Q wave- seldom to be seen
To know the problem at the back of the heart: look for
the most posterior portion of the heart—esophageal leads. It is
seldom used. It allows the patient to swallow electrode.
Esophagus is right behind the heart in determining what’s
happening posteriorly.
V7-V8- if you want to see the back portion. Rare problems are
seen in this part because seldom problems can be seen at the
posterior part of the heart.
5
Common problem of the heart: left side; because left
ventricle has greater works compare to the right ventricle. Left
ventricle is the one working for the whole systemic circulation
while the right ventricle works on the pulmonary circulation.
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
Once depolarize next will be repolarization. There is no
ECG wave representing atrial repo because it happens
simultaneous with the ventricular depo (QRS).
Isoelectric Line
-
Straight line
Any recording above line (+)  upward deflected wave
Any recording below line (-)  downward deflected
wave
Normally: there are only 2 negative waves
Q wave- seldom although it is a negative deflected
wave
S wave- commonly recorded downward deflection
Parameters used in determining when atrial repo and ventricular
depo starts includes the following:
 PR segment
 PR interval
RS- commonly seen
Q wave- start of ventricular depo
-
only present part of ventricular repo due to phase III
only telling us the duration of phase III
When cell repolarizes, it is immediately observes after end of
repolarization, once depolarization ends it begins to repolarize
(starT from the end of S)
Total duration of repolarization
start from end of S to end of T
Duration of T wave
does not give the total duration of ventricular repo
In obtaining the total duration of ventricular repo
 it is measured from the end of S to the end of T
Dr. Eithoven said that the value of Lead II is equals to the value
of Lead I and Lead III. Lead II has the highest wave because it
follows the wave of cardiac vector.
Flowing in the same direction with the cardiac vector you obtain
the positive wave where the electrical activity is a depolarizing
wave.
Atrial T wave
Activity starts at the roght side goes towards the left
going down
Follows the cardiac vector
If the ECG axis is opposite to the cardiac vector downward
aVR
T interval  end of S to beginning of T
ST segment
end of S to beginning of T
represent phase II
normally at the isoelectric line while cell is repolarizing;
since the machine only records electrical changes in
phase II there is no electrical change(efflux of K is
balance by the influx of Ca), so it is recorded at the
isoelectric line but that cell is said to be repolarizing
Positive waves  P, R, S, and T waves (common)
NO
 QRS- ventricular depo
 In the lecture, Phase 0- ventricular depo
 T wave- ventricular repo
 Phase 1 going to phase 3- ventricular repo in the lecture
6
T wave
always mentioned as to ventricular repo
does not give the total duration of ventricular repo
ST interval
measures the whole period of latent repolarization
Cardiac vector
normal direction R  L going down
ECG axis follow cardiac vector
R  L going down
Lead II- follows cardiac vector, moving from the RA  LL
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
-
opposite to the cardiac vector
Normally negative deflected
Q wave
Normally negative
That is Lead II
When impulses reaches bundle of this and transmitted
to the interventricular septum the impulses will
move L to R (opposite cardiac vector so Q wave is
negative)
Represents depo of interventricular septum
R wave
+ wave
Wave representing what is happening in the apex
Apex( impulses is R-L going down  moving towards
positive electrode—follow axis/ current flow
Apical depolarization
S wave
Normally negative
Represent the part of the ventricle depolarized last
(base)
-
So the flow of impulse is transmitted upward
opposite to the cardiac vector  negative deflection
Postero-basal region of the ventricle is depolarize
T wave
Repolarization (recording is opposite with depolarizing
current)
If repo follows ECG axis/ cardiac vector negative
deflection
It repo does not follow cardiac vector positive
deflection
Atrium
st
1 to depo, is also the first to repo
Ventricle
st
1 to depo, is the last to repo
From the basal portion
Movement:
Endo epi (depo)
Epi endo (repolariing current  flow is opposite ECG
axis  upward)
T wave (+)
In the ventricle  flow of repo is counter to the flow of
repo but not in the atrium because the flow of depo
current follow the flow of repo
Hash works
Equals to 3 sec duration
For determination of heart rate
ECG paper
Calibrated
Amplitude:
 1 small square= 1 mm= .1mV
 1big square= 5mm= .5mV
Time:


1 small square= 1mm= 40 milliseconds= 0.04s
1big square= 5mm= 200 milliseconds= 0.2 s
Duration/ time
Represented by horizontal line
Unit: seconds
Electrical activity
Represented by vertical line
Unit: mV
7
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
Heart rate
Use only for regular rhythm
In reporting HR it is always per minute
If irregular:
Count big square enclosing R-R interval x .20sec
Big square = 0.20sec
Ex: if 6 sec x 10 = 60 sec
1 big square= 0.20s
60/ 0.20s= 300
Limitations: Use only for regular rhythm. It can’t be used if the
HR is irregular
Lead II
- follow the flow of heart
- RA  LL




P wave- atrial depo
QRS- ventricular depo
T wave- ventricular repo (part only) phase III
PR Interval- duration of atrial depo + AV nodal delay

Intermodal tracts
o will activates the atrial muscles
o during PR interval, it is active







PR segment- AV nodal delay; end of P beginning of QRS
Q wave- septal depo
R wave- apical depo
S wave- depo of base
ST segment- after depo of ventricle; phase II
T wave- phase III
ST interval- total duration of ventricular repo (phase II,
T wave and phase III)
QT interval
o ventricular depo and repo (ventricular muscle
of action potential)
o will help approximate the duration of
ventricular contraction ( when depo it will
immediately contract, the if already finish it
will repo)
o also known as the electrical systole of the
heart

Duration that depolarize before repolarize LATENT PERIOD
(the excitable muscle is depolarizing)
8
J point
end of depo, start of repo
normally, this period is always at the isoelectric line
once not on the isolectric line it is now called ST
segment elevation (up) and ST segment depression
(down)  suffering from ischemia
elevation-  myocardial ischemia
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
When you are a doctor use:
Lead I and aVF
Vector
Purpose: tells the direction of the electrical activity of
the subject and also the magnitude (how strong is the
said current)
Purpose: common point of all values from the different leads.
From the common point start doing horizontal line passing to
the center of the triangle to lead warns. Get the center of the
triangle and that is zero. From that zero point, draw an arrow
going to the common point of the lines, from the values of leads
I, II, and III cardiac axis of the patient. This is the direction of
the current flow. To get the angle, use protractor and that will
be the cardiac vector. Every millimeter times 1mV.
To check if the ECG technician is correct used:
Lead I and aVF (easy way)
Plot lead I (+5) and Lead III (+3.5)
For diagnosis used:
Leads I, II and III
You will compute for the R wave (+6.5) and S wave (1.5), the unit is distance; next compute for the Lead III.
The total should be equal to sum the of leadIII and lead
I.
After getting the values, make the triangle. Use the
Eithovens triangle and get a protractor. Get the center (from the
apex going to the opposite side). Each center of each side mark
it zeros. Lead I (+ 5) and lead III (+3.5)
9
Once you record it, draw a line perpendicular to the lead study.
The calibration is millimeters. There will be intersection. Then
get now Lead II (+8.5). It should be exact.
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)

Not all abnormalities can be diagnosed by ECG.
Common axis: 59 degrees
Position of the heart: intermediate
SA node (pacemaker)  Sinus rhythm
Not SA node, but is controlled by AV node
 AV nodal rhythm/ Junctional rhythm
Easy way:
1. Get aVF and Lead I.
2. Lead I  RA- LA
3. Get and draw the value of Lead I (+5) and aVF (+6.5)
4. Then after plotting, see the common intersection. From the
intersection draw an arrow, that is the vector and you can get
the cardiac axis.
10
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
Prominent Q wave previous infarction
 Elevation: ischemia
 Depression: infarction
st
1 degree heart block
P-QRS interval normal
P waves
PR interval are longer
nd
2 degree heart block
1:1 ratio is not normal because QRS are not seen
- 2:1 or 3:1 ratio
rd
3 degree heart block
Ventricle is independent of atrial activity
Bundle Branch Block
Longer and wider QRS
11
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
Right ventricular hypertrophy
Tall R waves in V1; deep S waves in V6
Left ventricular hypertrophy
Tall R waves in V6; deep S waves in V1
ECG
-
Not only diagnose cardiac problems but also electrolyte
problems electrolyte problems affect cardiac activity
Diagnose cardiac problem with alternation in
electrolyte activities
Tall T wave (peaked T wave)
Echocardiography
Can diagnose cardiac problems not associated with
alternation of electrical activity
Action potential is longer  phase II
Prominent U wave  HYPOKALEMIA
12
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
Cardiac masses
Abnormal growth in the cardiac tissue
Pericardial disorders
Even injuries affecting pericardial sac
Initially not diagnose in ECG  they are not causing changes in
the electrical activity of the heart
Problems in this conditions BLOOD FLOW (diagnose using
echocardiography
13
MAURO, REJANE D. 1E ( ELECTROCARDIOGRAPHY- DR. BARBON)
Microcirculation
(Gloria Marie M. Valerio, MD)
Example is a photo of an endothelium. There are individual
endothelial cells. Inside is the intravascular compartment and outside is
the interstitial compartment so in other words, the capillary wall or
membrane separates intravascular from interstitial fluid compartment. In
the vascular wall, the endothelial cells or membrane of the endothelial
cells are connected by protein attachments but between the protein
attachments are spaces called slits or pores or clefts. And these slits,
pores or clefts can allow water molecules as well as small water soluble
molecules to pass through. Although not shown in the picture, there are
also vesicles present on the membrane. These vesicles will coalesce to
form cave-like structures called calveolae that can allow macromolecules
to pass through.
Comparison of Intravascular and Interstitial Fluid
PHOTO: Composite schematic drawing of the microcirculation. The circular structures
on the arteriole and venule represent smooth muscle fibers, and branching solid lines
represent sympathetic nerve fibers. The arrows indicate the direction of blood flow.
When we say microcirculation, this will involve the activity or
function of the smaller blood vessels that will include the arterioles,
capillaries, and venules. In the different organs of the body, an artery will
divide 6-8x giving rise to smaller branches called arterioles with an
internal diameter of 10-15 µm. The arterioles themselves will divide
several times giving rise to yet smaller branches with an internal
diameter of 5-9µm. The terminal branch of an arteriole is a metarteriole
which will then connect with the capillary. The wall of the metarteriole
contains a smooth muscle layer but it is not continuous. However at the
junction between a metarteriole and a capillary is a layer of smooth
muscle forming what we call the pre-capillary sphincter. The precapillary sphincter is not innervated by sympathetic nerves but it can still
respond to circulating vasoconstrictors. From the capillaries, blood will
then be collected by the venules that will coalesce to from the bigger
veins.
In some areas of the body like for example in the finger tips,
palm of the hand, and in the earlobes, the arteriole is directly connected
to the venule bypassing the capillary forming what we call an
arteriovenous anastomosis or shunt. The function of the arteriovenous
anastomosis or shunt is to regulate body temperature – it transports heat
away from the body.
We mentioned that the capillaries are exchange vessels
because of the thin and porous capillary wall or membrane, it allow
exchange of fluid and some solutes between intravascular and interstitial
fluid compartment.
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Shannen Kaye B. Apolinario, RMT
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Intravascular fluid is the liquid portion of blood or plasma.
Plasma contains 91-92% water, solutes suspended dissolved in the
plasma which include plasma proteins; electrolytes like Na+, K+, Cl- etc.;
nutrients like glucose, amino acids, fatty acids; gases like oxygen and
carbon dioxide; waste products of metabolism like urea; hormones; and
enzymes – all are in the plasma plus the formed elements in the blood.
The intravascular fluid contains formed elements and more proteins in
the plasma.
Present in the interstitial fluid is not only water but also two
solid structures that will provide tensile strength for the tissue and these
are collagen fibers and proteoglycans. In the interstitium, the fluid is
not free flowing, it is a gel-like structure because of the presence of the
collagen fibers and proteoglycans and there is very little amount of the
free flowing fluid.
Functions of the Endothelium / Endothelial Cells
1.
Physical lining. It lines the blood vessel wall.
2.
Permeability barrier and transport regulator. As what have
mentioned earlier, it provides a permeability barrier as well as
regulator of transport of water molecules and some solutes.
3.
Secrete paracrine substances acting on smooth muscle. It can
also secrete paracrine substances that can act on the vascular
smooth muscle examples include nitric oxide that will cause
vasodilatation and endothelin that will cause vasoconstriction.
4.
Mediated angiogenesis. The endothelial cells can also mediate
angiogenesis. Angiogenesis means formation of new blood vessels
from existing blood vessels and that is made possible when the
endothelial cells secrete the vascular endothelial growth factor
(VEGF).
5.
Produce growth factors in response to damage. The endothelial
cells can also produce growth factors that will repair the damage in
the vascular wall.
6.
Secrete substances that regulate platelet clumping, clotting and
anti-clotting, It can also secrete substances that will regulate
platelet clumping, clotting, and anti-clotting. One substance that is
secreted by the endothelial cells that will increase platelet
adhesiveness and regulate the formation of clotting factor VIII is the
von Willebrand factor.
7.
Secrete cytokines in immune response. The endothelial cells also
secrete cytokines in response to an immune reaction.
Transcapillary Exchange
How solutes and water molecules are transported across the
capillary membrane?
1.
Diffusion
One mechanism is by simple diffusion and this is true for small
water soluble substances as well as for lipid soluble substances. For small
water soluble substances, they can diffuse to the clefts/pores/slits
present on the capillary membrane. For lipid soluble substances, they can
easily diffuse across the membrane.
What are the factors that may influence diffusion rate?
S = DC x SA x ΔC
Where:
Surface area: if the surface area available for diffusion is big,
the more substances that can be diffused.
The diffusion coefficient is dependent on two factors:
molecular weight or size of the substance which is inversely related to
diffusion and the other factor that will affect diffusion coefficient is
temperature which is directly related to the diffusion rate.
For small water soluble molecules, diffusion is said to be flowlimited, meaning to say, it will depend on blood flow. When the blood
flow is fast, more substances can diffuse but for large water soluble or
lipid insoluble substances, the limiting factor is its molecular weight or
size so they are called diffusion-limited.
Pinocytosis
Some macromolecules can be transported by way of calveolae
or vesicles. The mechanism is either through pinocytosis/endocytosis or
transcytosis.
3.
IN
Plasma colloid osmotic pressure
(Пp)
Interstitial fluid pressure
(Pif)
To bring about filtration and absorption, there are four forces
involved and we call them Starling’s forces. Forces when increased will
favour movement of fluid out or filtrations are the capillary hydrostatic
pressure and interstitial fluid colloid osmotic pressure. On the other
hand, forces when increased will favour absorption of fluid are plasma
colloid osmotic pressure and interstitial fluid pressure.
Capillary hydrostatic
pressure (Pc)
Plasma colloidal
osmotic pressure (Пp)
DC = diffusion coefficient
SA = surface area
ΔC = concentration gradient
So for diffusion of substances to take place, there has to be
difference in concentration and the substances will be transported from a
high concentration area to a low concentration area.
2.
OUT
Capillary hydrostatic pressure
(Pc)
Interstitial fluid colloid osmotic
pressure (Пif)
Filtration or Absorption
Two other mechanisms will allow transport of water across the
capillary membrane: one is filtration and the other one is absorption.
Arterial
Venous
Intravascular
Interstitial
Filtration
Absorption
For example this is a capillary; there is an arterial end and a
venous end, an intravascular compartment and an interstitial
compartment. What does filtration mean? How is it different from
diffusion?
The filtering membrane is the capillary membrane. Filtration
is transport of water molecules and some solutes from a high pressure
area to a low pressure area and that usually happens at the arterial end of
a capillary. At the venous end, water molecules will be absorbed from the
interstitial to the intravascular compartment. So when we say
absorption, the water goes back to the intravascular compartment. What
will attract water back into the intravascular compartment? There has to
be the presence of osmotically active substances specifically the plasma
proteins. So you have filtration at the arterial end of a capillary and
absorption at the venous end.
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Shannen Kaye B. Apolinario, RMT
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Interstitial fluid
hydrostatic pressure
(Pif)
Interstitial fluid
osmotic pressure
(Пif)
Capillary hydrostatic pressure is the force exerted by the
volume of water on the capillary wall. So that when it is increased, this is
the one that will push water out into the interstitial space.
Plasma colloid osmotic pressure is determined by the
number of concentration of plasma proteins. Plasma proteins are
osmotically active and when increased, they can attract water molecules
into the intravascular space by osmosis. Why proteins? Because of its
large size and the capillary membrane is impermeable to these plasma
proteins (if the capillary wall is permeable, plasma proteins will go in and
out of the space and there will be water absorption. Water will go where
the proteins are). When the concentration or number of plasma proteins
increases, plasma colloid osmotic pressure will increase and that will
attract water back into the intravascular compartment.
Capillary hydrostatic pressure and plasma colloid osmotic
pressure are the most important of the four forces that will regulate
transcapillary exchange of fluid. The other two are less important.
Interstitial fluid hydrostatic pressure is the force exerted by
the volume of fluid in the interstitial space. It is less important because it
does not change under normal conditions because any excess of fluid in
the interstitial space will be collected by the lymphatic vessels and
returned into the circulating blood. If there is an excess interstitial fluid, it
means that there is edema and that will now push the fluid into the
intravascular compartment.
The other one is interstitial fluid osmotic pressure so that in
now determined by the number or concentration of proteins in the
interstitial space. Remember we mentioned that the interstitial space is
not purely water, there is little amount of proteins but it is also less
important because the proteins in interstitial space will not increase
(under normal conditions), it will only increase when the capillary
membrane is destroyed that will allow plasma proteins to pass through
so when the plasma proteins go out, it will go together with water. When
the interstitial fluid osmotic pressure increases, that will attract water
molecules.
Net Filtration Pressure (NFP)
NFP = (Pc – Pif) – (Пp – Пif)
(+) = favour filtration
(- ) = favour absorption
The net filtration pressure (NFP) is equal to capillary
hydrostatic pressure minus interstitial fluid pressure minus plasma
colloid osmotic pressure minus interstitial fluid osmotic pressure. If the
value that you will get is positive, that will favour filtration. If the value
that you will get is negative, there will be absorption.
To put in another way: 15 + 3 = 18. The factors that will favour
absorption are still the same. Again, you have a difference of 10 but the
factors that will favour absorption is now higher so that is at the venous
end.
Increased Capillary Hydrostatic Pressure (CHP)
Capillary Filtration Coefficient (Kf)
Remember that characteristic of the capillary membrane will
vary from one organ to another like for example in the brain. In the brain,
the endothelial cells lining the capillaries are joined by tight junctions
that is why only the smallest substances can pass through. The opposite is
true in the liver wherein the clefts are wide open that even proteins can
pass through so that aside from the net filtration pressure, we also have
to take into consideration the number and size of pores that are present
on the capillary membrane as well as the number of active capillaries in a
tissue. The more actively metabolizing a tissue is, the greater the number
of active capillaries.
1.
Arteriolar dilatation. One factor is arteriolar dilatation that will
increase blood flow to the capillaries, increasing the volume of blood
in the capillaries therefore increasing the force exerted by that
volume of blood on the capillary wall.
2.
Venoconstriction. Remember that blood in the capillaries should
flow into the venous system. If the venous system is constricted,
blood cannot flow into the veins, blood will pull into the capillaries
and that will again increase the CHP.
3.
Increased venous pressure. The venous system normally is a low
pressure are but if there is congestive heart failure, the pumping
action of the heart is compromised, blood will back up in the venous
system, venous pressure will increase so the blood cannot flow from
the capillaries to the veins so CHP will increase.
4.
Increased arterial blood pressure. An increase in arterial blood
pressure that will increase blood flow to the capillaries.
FR = Kf x NFP
Where:
FR = filtration rate
Kf = capillary filtration coefficient
NFP = net filtration pressure
So that when we say filtration rate, it is actually the product of
capillary filtration coefficient and net filtration pressure.
Arterial end
Pc = 35
j
Pif = 0
Venous end
Пp = 28
Пif = 3
Pc = 15
Pif = 0
5.
Пp = 28
Пif = 3
NFP = (35-0) – (28-3)
= 10 mmHg
= favouring filtration
NFP = (15-0) – (28-3)
= -10 mmHg
= favouring absorption
35
3
38
15
3
18
28
0
28
*** Two ways: increase venous pressure and increase arterial blood
pressure will increase the capillary hydrostatic pressure.
28
0
28
The capillary hydrostatic averages 35 mmHg at the arterial
end, remember that the arterial system is a high pressure area, the
venous system is a low pressure area and the average capillary
hydrostatic pressure at the venous end is only 15 mmHg. For the plasma
colloid osmotic pressure, it is the same at the arterial and venous ends of
a capillary average of 28 mmHg. For the interstitial fluid pressure, almost
0mmHg on both the arterial and venous end as well as the interstitial
fluid osmotic pressure, both are 3 mmHg. The one that often change is the
capillary hydrostatic pressure.
Decreased Plasma Colloid Osmotic Pressure
1.
Now we go at the venous end, so same formula: NFP = (Pc –
Pif) – (Пp – Пif). The answer is still 10 mmHg but this time, it is negative
so it will favour absorption.
3
Shannen Kaye B. Apolinario, RMT
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Decreased plasma protein level
Plasma colloid osmotic pressure is determined by the number
or concentration of plasma proteins so that any condition that will cause
hypoproteinemia will decrease the plasma colloid osmotic pressure and
that is one cause of edema. The fluid cannot be absorbed in the
intravascular compartment so it accumulates in the interstitial space. So
what are the conditions that will cause hypoproteinemia?
Why is there filtration on the arterial end? Let us go back to the
formula of net filtration pressure (NFP): NFP = (Pc – Pif) – (Пp – Пif). You
get positive 10 and if the answer is positive, it favours filtration.
To put in another way, what are the forces when increased will
favour filtration? It is the capillary hydrostatic pressure and interstitial
fluid osmotic pressure. On the other hand, what are the forces when
increased will favour absorption? It is the plasma colloid osmotic
pressure and interstitial fluid pressure. You have a difference of 10 and
the factor that will favour filtration is bigger so at the arterial end, you
have filtration.
Increased total blood volume. Another one is an increase in total
blood volume which will initially affect venous return – it will
increase. With increased venous return, cardiac output will increase.
With increased cardiac output, arterial blood pressure will increase
so will the CHP.

Poor production. Liver diseases will cause hypoproteinemia
because proteins are produced in the liver

Protein losing conditions. Kidney or renal diseases that will
increase excretion of proteins.

Decrease substrate. Malnutrition or starvation will cause
hypoproteinemia because there are no substrates for protein
synthesis.
Increased Interstitial Fluid Osmotic Pressure
1.
Increased capillary membrane permeability. The interstitial fluid
osmotic pressure will increase with increased capillary membrane
permeability. When the capillary membrane is damaged, it allow
proteins to pass through that will increase the interstitial fluid
osmotic pressure attracting fluid from the intravascular to
interstitial fluid compartment.
Causes of Increased Interstitial Fluid Volume (Edema)
1.
Increased filtration pressure. The capillary hydrostatic pressure
is too much so the water goes out in the interstitial space.
2.
Decreased absorption. Decreased absorption because of
hypoproteinemia that would decrease the plasma colloid osmotic
pressure (PCOP).
3.
Increased capillary permeability. Increased capillary membrane
permeability that will increase the interstitial fluid osmotic
pressure.
4.
Inadequate lymphatic flow. More importantly, obstruction in the
lymphatic circulation or inadequate lymphatic flow because
remember that the primary action of the lymphatic vessels is to
collect excess fluid from the interstitial space so if the lymphatic
circulation is inadequate, it cannot collect the excess fluid in the
interstitial space so there will be accumulation causing edema.
metabolites will accumulate. When you release the occlusion, blood flow
will increase rapidly and that increase in blood flow will continue until
the oxygen supply is replenished and the metabolites are washed away.
So in active hyperemia, the tissue is active. In reactive
hyperemia, the tissues react first to the occlusion.
2.
Myogenic Theory
Ohm’s law (Q) = ΔP
R
Where:
Blood Flow
We go back to blood flow to the different organs of the body.
Why is it in the cardiac output of 5,000 mL/min, almost 20-21% goes
straight to the kidneys? Why there are organs that is increased in blood
flow and why are there organs with less blood flow?
Regulation of Blood Flow
a.
Autoregulation
The first mechanism that regulates the blood flow is
autoregulation. When we say autoregulation that means the tissue
themselves regulate their own blood flow. It determines whether the
blood flow should be increased or decreased.
1.
The other mechanism is myogenic. Remember Ohm’s law –
blood flow is equal to pressure gradient over resistance. So we expect
that when the blood pressure increases, blood flow increases. If the blood
pressure continues to increase, blood flow will also continue to increase
but it is not the case because we have what call an autoregulatory range
wherein an increase in blood pressure will maintain a constant blood
flow. And that autoregulatory range is between 75-175 mmHg. So when
blood pressure increases from 75-175 mmHg, there is very little increase
in blood flow so the normal blood flow is maintained. When the blood
pressure is high, the arterial wall is stretched. Stretching of the arterial
wall will stimulate the receptors present on the arterial wall and that will
initiate a reflex action causing vasoconstriction. So increased blood
pressure, blood flow will increase initially then there will be
vasoconstriction then decreased blood flow. From increased blood flow, it
will decrease then it will be maintained a constant level.
But outside of the autoregulatory range, let’s say the blood
pressure drops below 75 mmHg, blood flow decreases. When blood
pressure rises above 175 mmHg, blood flow increases. But within the
autoegulatory range, the blood flow is maintained at a constant level with
an increase in blood pressure.
b.
Metabolic Theory
Decreased pO2
Increased pCO2
Increased H+, Lactic Acid (dec. pH)
Increased K+, Adenosine
Vasodilators
At the same time, actively metabolizing cells produce carbon
dioxide. Aside from carbon dioxide, actively metabolizing cells also
produce hydrogen ions, as well as lactic acid. Other metabolites produced
include potassium as well as adenosine. All of these are vasodilators.
What happens when the cell is active, there are two factors: hypoxia and
production of metabolites that are vasodilators so there will be
vasodilatation, increased blood flow, increase oxygen supply to replenish
the oxygen lack. Also, increased blood flow will wash away the
metabolites so the oxygen will increase, the metabolites are gone,
vasoconstriction.
Now, that is what we call active hyperemia – increased blood
flow during active metabolism.
What is reactive hyperemia? This time, when you occlude a
blood vessel temporarily, there will be no blood flow, no oxygen,
Shannen Kaye B. Apolinario, RMT
Release of vasoactive substances from the endothelium
Vasodilators:
- Prostacyclin
- NO2
For actively metabolizing cells, they consume oxygen so that
will cause a decrease in the oxygen tension in the blood. The vascular
smooth muscle needs oxygen to contract so if the oxygen has been used
up by the tissue, oxygen tension is decreased so there will be hypoxia or
lack of oxygen and that will cause the vascular smooth muscle to relax so
there will be vasodilatation, blood flow is increased, oxygen supply will
also increase. When the oxygen supply is increased, vascular smooth
muscle will have something (oxygen) to use, it will contract so there will
be vasoconstriction. With vasoconstriction, blood flow is decreased,
oxygen supply is decreased, vasodilatation. It is like a reflex action.
4
ΔP = pressure gradient
R = resistance
|
Vasoconstrictors:
- Endothelin
- TXA2
Aside from autoregulation, there are local vasoactive
substances secreted mainly by the endothelial cells that can act on the
vascular smooth muscle and this will include vasodilators like
prostacyclin and nitric oxide, vasoconstrictors like endothelin, you also
include thromboxane A2. So these are local vasoactive substances
produced by the endothelial cells.
c.
Humoral control of blood flow
Vasoconstrictor agents:
- Norepinephrine/epinephrine
- Angiotensin II
- Vasopressin
- Endothelin
- Serotonin
Aside from local vasoactive substances, we also have
circulating vasoactive substances and this will include norepinephrine
and epinephrine - norepinephrine from sympathetic nerves and the
adrenal medulla, epinephrine from the adrenal medulla. Another very
potent vasoconstrictor is angiotensin II and we will discuss more of
angiotensin II later when we go to mechanisms that regulate arterial
blood pressure. The antidiuretic hormone (ADH) or vasopressin
synthesized by the hypothalamus, stored and released by the posterior
pituitary gland. Other vasoconstrictors are again, you have endothelin
and serotonin.
Vasodilator agents:
- Bradykinin
- Histamine
Aside from autoregulation, local vasoactive substances,
circulating vasoactive substances we also have the vasodilators
bradykinin and histamine. Now these two, aside from causing
vasodilatation, they can also increase capillary membrane permeability in
response to a hypersensitivity or allergic reaction.
1.
R-A-A system
Neural:
Low Pressure Receptor Mechanism
d.
Effect of ions and other chemical factors
Increased Ca++
Increased K+
Increased Mg++
Increased H+
Increased CO2
Vasoconstriction
Vasodilatation
We have several ions that can also act on the vascular smooth
muscle. Calcium for vasoconstriction then potassium, magnesium,
hydrogen ion, carbon dioxide will cause vasodilatation.
e.
Autonomic innervation
In the blood vessel of the skin and viscera, innervation is
autonomic adrenergic. The neurotransmitter agent released is
norepinephrine and from the adrenal medulla, norepinephrine and
epinephrine. So when these two binds with alpha-1 receptors there will
be vasoconstriction. When they bind with beta-2 receptors, there will be
vasodilatation.
In the blood vessel of the skeletal muscle, innervation is
sympathetic cholinergic so you have acetylcholine binding with
muscarinic receptors that will bring about vasodilatation.
f.
Angiogenesis
Now, in growing tissues, to meet their metabolic needs, there
has to be formation or proliferation of new blood vessels from existing
blood vessels and this is stimulated by the vascular endothelial growth
factor (VEGF) secreted by the endothelial cells.
So these are the factors that regulate the blood flow. In most
instances, autoregulation and metabolic will override the other
mechanisms.
Arterial Pressure Control Mechanisms
Mechanisms that regulate arterial blood pressure:
a.
Acting within seconds or minutes
b.
These receptors are present on the atrial wall as well as on the
arterial wall and they are more sensitive to an increase in blood volume
rather than an increase in blood pressure.
Under this, we have the Bainbridge reflex. Remember the SA
node is in the right atrium. Now, when the volume of blood in the right
atrium increases, that will stretch the right atrial wall and directly
stimulates the SA node increasing the heart rate. With increase in heart
rate, blood will be ejected from the right atrium to the right ventricle on
to the pulmonary circulation so the volume of blood will be decreased on
the right atrium. But at the same time, stretching the wall of the right
atrium will initiate a reflex action transmitted by the vagus nerve to the
medulla where you have the vasomotor center. And from the vasomotor
center, back to the SA node in the right atrium again increasing the heart
rate so that blood will be ejected from the right atrium, to the right
ventricle and to the pulmonary circulation. So the end result of this
Bainbridge reflex is to increase heart rate so that the increase volume of
blood in the right atrium will be ejected immediately.
When the right atrial wall is also stretched, the atrial muscles
secrete a hormone that is the atrial natriuretic peptide (ANP) that will
cause natriuresis. Meaning to say, this hormone will act on the renal
tubules to increase excretion of sodium. When the sodium is excreted,
water goes along with it so the blood volume will decrease. This reflex is
stimulated by an increase in blood volume specifically on the right atrium
and its result is to decrease blood volume.
Inc. in atrial pressure - dec blood vol
First, for immediate regulation of blood pressure, we have
mostly neural mechanisms and this will include:
1.
2.
3.
4.
PHOTO: Intravenous infusions of blood or electrolyte solutions tend to increase the
heart rate via the Bainbridge reflex and to decrease the heart rate via baroreceptor
reflex. The actual change in heart rate induced by such infusions is the result of these
two opposing effects.
Baroreceptor Feedback Mechanism
Baroreceptor feedback mechanism
CNS ischemic mechanism
Chemoreceptor mechanism
Low pressure receptor mechanism
Acting after many minutes or hours
We also have mechanisms that can act after many minutes or
hours and this will include:
1.
2.
3.
c.
Stress-relaxation mechanism
Capillary fluid shift
Renal fluid shift
Actin g on several hours
For long term regulation of blood pressure we have the renin –
angiotensin – aldosterone system.
5
Shannen Kaye B. Apolinario, RMT
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PHOTO: Diagrammatic representation of the carotid sinus and carotid body and their
innervation.
Carotid sinus can be stimulated either by an increase or
decrease in blood pressure as long as there is a change in blood pressure.
The difference is if the stimulus is an increase in blood pressure, the rate
of firing of action potential is also increased but if a stimulus is a decrease
in blood pressure, the rate of firing of action potential will also decrease.
On the other hand, the aortic sinus is stimulated only by an increase in
blood pressure, it is not stimulated by a decrease in blood pressure and
you need a higher increase in blood pressure to stimulate the aortic sinus.
Comparing the two, the carotids sinus is more sensitive to changes in
blood pressure.
Functional areas of the vasomotor center
The areas present in the vasomotor center (remember that this
is in the medulla):
PHOTO: Anterior view of the aortic arch showing the innervation of the aortic bodies
and baroreceptors.
1.
Vasoconstrictor region (C-1). Tonically active, it
responsible for maintatining the tone of the vascular wall.
is
2.
Vasodilator region (A-1). The vasodilator region inhibits the
vasoconstrictor region so that will bring about vasodilatation.
3.
Sensory region. In the vasomotor center there is also a
sensory region that will detect what are the changes in blood
pressure.
4.
Cardiac center.
Baroreceptor Reflex Path
Baroreceptors (carotid and aortic arch sinus)
Glossopharyngeal nerve and vagus nerve
Baroreceptor Reflex
Increased
MAP
Vasomotor center
Vasomotor center
Sympathetic and parasympathetic fibers
The receptors are baroreceptors or pressoreceptors stimulated
when the arterial is stretched. There are two types of baroreceptors:
carotid sinus and aortic sinus.
In the photo, you will see the right and left common carotid
arteries that will bifurcate to form the internal and external carotid
arteries. The carotid sinus is located immediately above the bifurcation
in the wall of the internal carotid arteries while the aortic sinus is
concentrated on the wall of the aortic arch.
When the arterial wall is stretched, the carotid and aortic sinus
will be stimulated. When stimulated, they will generate impulses
transmitted by cranial nerves IX and X. Cranial nerve IX will transmit
impulses from the carotid sinus while cranial nerve X will transmit
impulses from the aortic sinus. The impulses are brought to the
vasomotor center which is located in the medulla and from the vasomotor
center, efferent or motor impulses will be transmitted by autonomic
nerves to the heart and blood vessels. So these are the components of the
baroreceptor reflex.
Baroreceptor Discharge Range
Carotid baroreceptor
Aortic
baroreceptor
50
100
150
200
Baroreceptor pressure (mmHg)
250
6
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Shannen Kaye B. Apolinario, RMT
Error
detect
Set
point
Barorecptor
Heart and blood vessels
0
Carotid sinus
CSM
firing
Inc.
stretch
sympathetic
sympathetic
parasympathetic
Heart
Dec.
rate &
contractility
Vasc.
smooth
musc.
Dec.
TPR
Inc. vol.
Let us now see how the baroreceptor reflex regulates the blood
pressure. Let’s say that our stimulus is an increase in blood
pressure/mean arterial pressure (MAP) that will stretch the arterial wall
that will stimulate both the carotid and aortic sinuses depending on what
is the increase in blood pressure. When the arterial wall is stretched, it
will stimulate the receptors, they will generate impulses transmitted by
cranial nerves 9 and 10 to the vasomotor center where the sensory
region will detect what is the stimulus – either an increase or decrease in
blood pressure. The blood pressure is increased so the efferent output is
decreased sympathetic outflow, increased parasympathetic outflow first
to the heart. Now remember that the formula for arterial blood pressure
is cardiac output x total peripheral resistance (ABP = CO x TPR). TPR
increases with vasoconstriction, decreases with vasodilatation while the
cardiac output will depend on the stroke volume and heart rate.
Let’s look on how will it decrease the blood pressure.
Decreased sympathetic outflow to the heart decreases heart rate and
decreases force of myocardial contraction so the stroke volume will also
decrease so when it decreases, decreased cardiac output, decreased
arterial blood pressure. Increasing parasympathetic outflow to the heart
will also decrease the heart rate therefore decreasing the cardiac output,
decreasing the arterial blood pressure.
Other effector organs are the blood vessels specifically the
arterioles and veins. In sympathetic outflow to the arterioles will
decrease so there will be vasodilatation and that will decrease the total
peripheral resistance, decrease arterial blood pressure. In sympathetic
outflow to the veins will decrease venous tone and vascular capacity will
increase. With increase vascular capacity, venous return will decrease
and so will the arterial blood pressure.
CNS Ischemic Response
Now let’s reverse. For example there is a decrease in blood
pressure, how will it increase the blood pressure? For example, lying
down for a prolonged period of time then suddenly gets up, due to the
effect of gravity, there will be pulling of blood to the lower extremities so
decrease venous return as well as blood supply to the brain resulting to
dizziness and fainting. But that does not happen because when the blood
pressure decreases, the baroreceptor reflex will work immediately.
Within seconds, it will increase the blood pressure, in what way? A
decrease in blood pressure stimulates the carotid sinus but there is less
firing of impulses that will reach the vasomotor center then it will be
detected by the sensory area that there are less impulses so the blood
pressure will decrease. This time, sympathetic outflow will increase,
parasympathetic will decrease. So with increase sympathetic outflow to
the heart, heart rate will increase, the force of myocardial contraction will
increase, increased stroke volume and cardiac output. With decreased
parasympathetic outflow to the heart, heart rate will increase so
everything will increase the cardiac output, arterial blood pressure. Then
you have increased sympathetic outflow to arterioles – vasoconstriction,
increasing total peripheral resistance, increased venous tone, decreasing
vascular capacity, increasing venous return, cardiac output and arterial
blood pressure.
But take note that the baroreceptor reflex can provide only
short term regulation of blood pressure. Effectivity is only up to two days
after which the baroreceptor will reset. If they were exposed to blood
pressure of let’s say 150, it can work until 150 only. It resets that’s why it
is only a short term regulation of blood pressure.
Decreased blood flow to the brain
(+) VMC
Ischemia
Increased sympathetic
Increased pCO2
Increased ABP
So again, when blood pressure decreases, blood flow to the
brain decreases, oxygen supply will decrease, carbon dioxide will
accumulate, the vasomotor center (VMC) is stimulated to increase
sympathetic outflow to heart and blood vessels increasing the arterial
blood pressure (ABP).
Cushing’s Reaction
Increased ICP > ABP
Ischemia
Compress arteries
CNS ischemic response
Decreased blood flow
Another mechanism is the Cushing’s reaction. Let’s say there is
fluid accumulation in the brain or there is a tumour in the brain that will
increase the intracranial pressure (ICP). If the intracranial pressure
exceeds the arterial blood pressure (ABP), that will compress the arteries.
So again, the blood flow will decrease, decreased oxygen supply,
accumulation of carbon dioxide and it will enter again the CNS ischemic
response.
Chemoreceptor Reflex
Decreased ABP
Decreased Arterial PO2
Carotid bodies
CN 9
Aortic bodies
CN 10
(+) VMC
Increased sympathetic
Heart
Increased ABP
Blood Vessel
3 stimuli:

Decrease pO2

Increase pCO2

Increase H+ concentration (decrease pH)
We have two kinds of chemoreceptors: carotid and aortic
bodies which have the same location as the aortic sinus and carotid sinus.
Chemoreceptors are the receptors sensitive to changes in the blood gases
and this will include hypoxia, increase carbon dioxide, increase hydrogen
ion concentration or a decrease in plasma pH - these are the three stimuli
that will stimulate the chemoreceptors. So when the blood pressure
decreases, blood flow decreases, oxygen supply decreases and that will
cause the accumulation of carbon dioxide and hydrogen ions so that will
now stimulate the chemoreceptors sending impulses to the vasomotor
center (VMC). The vasomotor center will respond by increasing
sympathetic outflow to the heart and blood vessels therefore increasing
blood pressure, blood flow, oxygen supply, washing away carbon dioxide
and hydrogen.
7
Shannen Kaye B. Apolinario, RMT
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PHOTO: Schematic diagram illustrating neural input and output of the vasomotor
region (VR). IX, glossopharyngeal nerve; X, vagus nerve.
Other Mechanisms:
Alteration in Glomerular Filtration Rate (GFR)
Capillary Fluid Shift
Dec. ABP
Increased BP
Increased CHP
Decreased BV
Dec. glomerular CHP
Filtration
Decreased MCSFP
Decreased CO
Dec. RBF
Decreased filtration
Decreased urine formation
Na & H2O retention
Preservation of BV
Improve VR & CO
Increased ABP
Decreased VR
Return ABP to normal
Any condition that increases the arterial blood pressure will
increase the capillary hydrostatic pressure (CHP) that will push the width
out of the blood vessels therefore decreasing the blood volume. With a
decrease in blood volume (BV), it will arrive in the formula for venous
return. Mean circulatory static filling pressure (MCSFP) will decrease,
venous return (VR) will decrease, cardiac output (CO) will decrease and
that will return or decrease blood pressure to normal. It will not decrease
below normal because initially, it is above normal so if it decreases, it will
go back to normal.
Do the reverse if the blood pressure is decreased. Capillary
hydrostatic pressure is decreased, less filtration, so increased blood
volume, venous return, cardiac output, increased blood pressure.
Stress-Relaxation
Decreased ABP
Decreased distending pressure
Elastic recoil
Decreased vascular capacity
When blood pressure decreases, renal blood flow will decrease
so that blood flow to the glomerular capillaries will decrease. In the
nephron, the functional unit of kidney, one set of capillaries is the
glomerulus. So if the glomerular capillary hydrostatic pressure (CHP)
decreases, filtration of plasma will decrease so the filtrate that will go to
the renal tubules (which are supposed to be excreted in the urine) will be
less also. So you have decreased urine formation, sodium and water are
retained in the body that will preserve the blood volume (BV), improve
venous return (VR) and cardiac output (CO), increasing the arterial blood
pressure (ABP).
If the blood pressure increases, renal blood flow increases,
glomerular capillary hydrostatic pressure increases so there will be more
that is filtered in the plasma resulting to an increased urine formation,
blood volume will decrease, venous return will decrease, cardiac output
and arterial blood pressure will decrease. But the kidneys are one of the
organs that have strongest autoregulatory mechanism so within the
autoregulatory range, it will not readily increase the blood pressure,
increase blood flow and increase urine formation.
Renin-Angiotensin-Aldosterone System (RAAS)
Inc. MCSFP
Inc. VR
Inc. CO
Inc. ABP
Dec. ABP
When the blood pressure decreases, distending pressure of the
vascular wall will decrease and that will cause recoil of the vascular wall.
If the vascular wall recoils, vascular capacity decreases, so the venous
return will increase, cardiac output (CO) will increase, increasing blood
pressure to normal.
Dec. RBF
(+) JG cells
Renin
Angiotensinogen
AI
A II
ACE
Renal Fluid Volume Shift
Remember that the most important function of the kidneys is
excretion. It removes excess water as well as the products of metabolism
away from the body by means of urine formation.
PHOTO: The nephron and its component parts.
8
Shannen Kaye B. Apolinario, RMT
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Another renal mechanism that will provide long term
regulation of blood pressure is the renin-angiotensin-aldosterone system.
So when the blood pressure decreases, renal blood flow decreases. This
will now stimulate the juxtaglomerular cells in the nephron to secrete an
enzyme renin. Renin will catalyse the activation of angiotensinogen to
angiotensin I (AI). But angiotensin I is less vasoactive, it has to be
converted to its more active form and that is angiotensin II (A II) and the
reaction is catalysed by the enzyme angiotensin converting enzyme
(ACE).
PHOTO: Renal concentration.
Actions of Angiotensin II
*** Assignment: Read on special circulation
A II
VC
(+) adrenals
Inc. TPR
aldosterone
Inc. Na reabsorption
DCT and CD
Inc. ABP
ADH
Hypothalamus
Inc. H2O reabsorption
DCT and CD
Inc. TBV
Inc. VR and CO
Inc. MCSFP
What are the actions of angiotensin II? There are three. First, it
is a potent vasoconstrictor substance. So there will be vasoconstriction
(VC), increased total peripheral resistance (TPR), increased arterial blood
pressure.
Angiotensin II can stimulate the adrenal cortex to secrete
aldosterone. Aldosterone is a hormone that acts on the distal convoluted
tubule (DCT) and collecting ducts (CD) of the nephron to increase sodium
reabsorption. If sodium will be reabsorbed, water follows so that will
increase blood volume, venous return, cardiac output and arterial blood
pressure.
At the same time, angiotensin II can stimulate the
hypothalamus to synthesize vasopressin or antidiuretic hormone (ADH).
This will also act on distal convoluted tubule and collecting duct of the
nephron to increase water reabsorption further increasing blood volume,
venous return, cardiac output and blood pressure. But aside from
increasing water reabsorption, antidiuretic hormone (ADH) or
vasopressin can also cause vasoconstriction increasing the total
peripheral resistance.
In summary, there are three actions of angiotensin II:
vasoconstriction, stimulate the adrenal gland to secrete aldosterone and
stimulate the hypothalamus to synthesize antidiuretic hormone.
Aldosterone’s action is to increase sodium reabsorption in the distal
convoluted tubule and collecting duct. For antidiuretic hormone, there
are two actions – increase water reabsorption in the distal convoluted
tubule and collecting duct and vasoconstriction.
PHOTO: Algorithm of the Renin-Angiotensin-Aldosterone System (RAAS)
“ “For I know the plans I have for you,” declares the Lord, “plans to
prosper you and not to harm you, plans to give you hope and a
future. Then you will call upon me and come and pray to me, and I
will listen to you. You will seek me and find me when you seek me
with all your heart. I will be found by you,” declares the Lord.”
-Jeremiah 29:11-14
GOD BLESS YOU 
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Shannen Kaye B. Apolinario, RMT
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Vascular Physiology Part 1 –Dr. Olivar
Circulatory System
----------------------------------------------------------------------------Main Function of Circulation:
-Service the needs of tissues
-Bring nutrients to the cell
-Remove waste products
-* maintain appropriate environment for optimum
survival and functioning of cells
Rate of blood flow into tissue
-regulated by the need of tissue
-if need of tissue is much (highly metabolic cell) = rate of
blood flow is increased (vasodilatation)
-if need of tissue is small-vasoconstriction: to redirect
flow of blood to area which needs more blood
-higher centers: help regulate cardiac output and
circulation
Review:
Pathway of blood flow:
Veins: converge to form 2 large veins (SVC and IVC)
SVC- collects blood from head and extremities at level of
heart
IVC-collects blood from all structures below level of heart
Both SVC and IVC empty to R atrium
Blood from R atrium transmitted to R ventricle via
Tricuspid valve
Blood exits R ventricle to pulmonary artery via pulmonic
valve-divides to R and L – to pulmonary capillaries
(oxygenate blood) – empty to pulmonary vein to L atriumL ventricle
Characteristics of the Vascular System
1. Aorta and large arteries
-very elastic structure
-contain large amount of elastin
Elasticity: blood vessels expand when they receive blood
and recoil back
Purpose of elasticity: (at aorta) first sends blood back to L
ventricle but it cannot flow back because aortic valve is
closed; blood will go forward into systemic circulation
-Elasticity is lost usually during old age.
2. Arterioles
-amount of elastin is decreased; largely replaced by
smooth muscles
Smooth muscle: functions as sphincters- can regulate
blood flow going into capillaries
-Classified as resistance vessels
3. Capillaries
-exchange area
arteriolar end: filtration of nutrients and gas
venular end: metabolic products go back to circulation
-classified as exchange vessels
Heart: 2 pumps connected in series
Left side of heart: composed of L atrium connected to L
ventricle by Mitral valve
Contraction of L ventricle: pumps blood to systemic
circulation
Blood exits L ventricle via aortic valve into aorta (artery –
carries blood away from heart and towards periphery)
Aorta: divides to smaller arteries-arterioles-capillaries
(where exchange of nutrients and gases occur)
Capillaries merge to become venules-merge to become
veins (veins-blood vessels that carry blood from periphery
back/towards right side of heart)
4. Veins
-diameter is larger than artery
-more distensible (ability of blood vessels to expand)
-contain more blood than arteries
*How does blood go back to R side of heart if they are not
elastic? They contain smooth muscles-contract and blood
is transmitted back to heart.
-contain valves
84% of blood- in systemic circulation
64% - veins
13% - arteries
7% - arterioles and capillaties
16% of blood: heart and lungs
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 1
Differences between series and parallel connection
Aorta – arteries – arterioles: series
Arterioles only: parallel
Blood Flow
-quantity/volume of blood passing through a specific
point in circulatory system per minute
All blood vessels are similar in structure EXCEPT
capillaries:
3 layers
1. Tunica Intima
-inner layer
-single layer of endothelial cells
2. Tunica Media
-middle layer
-circular layer of smooth muscle
-arteries have thicker T.m. than vein
3. Tunica adventitia
-outer layer
-elastin and collagen fibers
-add structural integrity to veins and arteries
Capillaries
-only composed of single layer of endothelial cells
Total Cardiac Output= 5000ml/min
(CO=Stroke Volume x HR)
-amount of blood pumped by aorta per minute
Factors Determining Blood flow
1. Pressure Difference
-pressure gradient/force pushing blood from point 1 to
point 2
2. Vascular Resistance
-impediment to blood flow
Cause of resistance: as blood moves around vessel, it
creates friction- the resistance to blood flow
Summary:
Blood Flow- could be Laminar or Turbulent
HEMODYNAMICS AND MICROCIRCULATION
Hemodynamics
-study of the physical variables related to containment
and movement of blood in CVS
Laminar Flow
-flows in streamline when blood is allowed to flow
steadily in a smooth and long vessel
-each layer of blood-same distance from vessel wall
-velocity of blood layer at center is greater/faster than
blood layer nearer to wall
-layer closer to wall is barely moving; creates friction with
vessel wall
-blood flow creates parabolic profile
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 2
-happens when flow is steady and vessel is long and
smooth
Turbulent Flow
-rate of flow is too rapid; with obstruction; vessel makes a
sharp turn; rougher vessel
-blood is along the vessels, crosswise; creates whirls/
eddy currents-adds to resistance; adds friction to vessel
wall
-tendency for turbulence can be predicted by knowing the
Reynolds’ Number
Velocity
-speed by which blood flow is displaced
Smaller x-sectional area=faster velocity
Higher x-sectional area= slower velocity
Peak velocity of aorta = fastest because it has smallest xsectional area
Capillary velocity = slowest because x-sectional area is
largest
-slow because exchange of substance occurs here
If rate is too high=Re increased=turbulent
Big diameter=Re increased=turbulent
Viscosity increased=Re decreased=laminar
(Amount of Blood-determines Viscosity)
Polycythemia=Re decreased-=laminar
Anemia=Viscosity decreased=increased velocity=turbulent
Physiological conditions causing turbulence:
1. Proximal part of aorta
-velocity is high
-turbulent flow
2. Carotid artery
-turns sharply
-turbulent
Pathologic conditions causing turbulence:
1. Aortic stenosis
-hindrance/obstruction
-murmur-turbulent flow
2. Atherosclerosis
-build-up of plaque along vessel walls
-smoothness is disturbed
-narrowed lumen
Resistance
-increased when:
-vessel diameter is decreased
-turbulent blood flow
-can’t be measured directly
-unit: PRU – peripheral resistance unit
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 3
*L side of the heart usually first to fail during heart failure
Blood from L side can’t be pumped to systemic
circulation, blood will go to lungs-Pulmonary Congestion.
If lungs can’t contain blood-blood goes to R atriumR side starts to fail.
*Systemic blood circulation has greater resistance than
pulmonary circulation
Conductance
-a measure of blood flow through a vessel for a given
pressure difference
-reciprocal of resistance
-diameter of vessel can change its conductance
Pressure from artery to vein= 100 mmHG
Blood flow/ Cardiac Output= 100 ml/sec
PRU=1
Vasoconstriction (through sympathetic
stimulation)=pressure increases; blood flow decreases;
PRU increase to 4
Vasodilatation=pressure decreases; blood flow increases;
PRU decrease to 0.2
Without sympathetic effect/stimulation, PRU=1
P at L atrium=2 mmHg
P at Pulmonic Vein= 16 mmHg
Difference= 14mmHg
PRU=0.14
*PRU at Pulmonary Circulation is lower than at Systemic
circulation
*therefore, HIGHER resistance at the Systemic circulation!
-Change in diameter is only slight, but increase of blood
flow is tremendous.
-In a vessel with large diameter, blood near the wall is
barely moving, blood closer to the center moves faster. At
the center blood moves very rapidly.
*At smaller diameter vessels, central layer of blood does
not exist. Only the layer of blood that is barely moving.
Blood moves slower.
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 4
-explained by…
(Pwaswis? Law :D)
-blood flow is directly proportional to change in pressure
and radius of vessel raised to 4th power and indirectly
proportional to viscosity of blood and length of vessel
-resistance is directly proportional to viscosity of blood
and length of blood vessel and therefore indirectly prop
to change in pressure and radius of vessel
*Effect of arterial pressure to blood flow:
P=50 mmHg; Blood flow=1
If P is increased to 100 mmHg (50% increase)
Increase of blood flow is not from 1 to 2
If pressure is increased to 100, blood flow increases to 4
Not just an effect of the pressure
*If pressure is increased in a vessel, pressure also distends
diameter of vessel. Increased diameter, blood flow is
increased raised to the 4th power. Tremendous increase in
blood flow.
Inhibit sympathetic stimulation= vasodilatation; higher
blood flow; lower pressure
Sympathetic stimulation =vasoconstriction; low blood
flow; high pressure
Transmural Pressure
-pressure within a vessel whenever it is filled with blood
Distensibility
-ability of vessel to increase its volume whenever pressure
is increased times original volume
Example:
*Increased Hct=increased viscosity
-blood flow is decreased
Artery- stronger because of elastin and collagen
Vein- 8x more distensible than artery
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 5
-pressure within vessel tends to rip apart the vessel if not
only for the opposing pressure brought about by the walls
of arteries and veins.
-opposing pressure of tendency of blood vessel to
rapture-tension
-in capillaries, vessels don’t rapture because radius is too
small. Tension is lower.
-thin walled vessels can withstand high pressure because
of their small radius.
Compliance > Distensibility
Vein
-8x more distensible, therefore could contain 3x more
blood volume than artery
-24x more compliant than artery
Clinical Correlation (Effect of aging on vascular
distensibility & compliance)
-When ventricle contracts, aorta distends, but because of
elasticity, blood recoils back. Even when ventricle is fully
relaxed, there is forward flow of blood into capillaries.
-When elasticity is lost, distensibility and compliance is
decreased (in aging). When ventricle contracts, blood flow
into capillaries, but it does not distend on ventricular
systole because of lost elasticity, there is no recoiling. No
flow of blood during ventricular diastole.
-in older people- no blood flow to extremities/ peripheral
blood vessels; Bluish discoloration; State of hypoxia.
-Blood vessels (aorta) are rigid/not elastic. No flow during
ventricular diastole. Healing is not good. Wound at
hands/feet may progress to gangrene = decreased
compliance and distensibility.
-same with cardiac output (CO); blood that is pumped by
the heart must go back to the right side of the heart.
-veins do not recoil
-Contraction of veins via smooth muscles-brings back
blood to right side of heart
-mean circulatory systemic filling pressure (MCSFP):
pressure within the veins = 7mmHg
-pressure inside atrium= 0mmHg, so blood from veins will
just flow from veins to the atrium
-Increased R atrial pressure (greater than MCSFP)-blood
will not be able to drain into R atrium- this is what
happens when L side of heart fails (blood can’t flow to
systemic circulation-goes to back to lungs-goes back to R
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 6
side of heart= blood from S/IVC can’t flow to R atrium
because pressure is higher)
Congestive heart failure
-jugular vein pulsates because blood would like to go
down to the heart but goes back up again because
pressure in R atrium is higher
-blood draining from IVC goes back=increased venous
pressure- extends to capillaries=Edema!
CVP (central venous pressure)=0 mmHg
Increased MCSFP- increased venous return
Increased resistance to venous return- venous return
decreases
*If more blood is in venous circulation, mean systemic
pressure increases (MCSFP) =venous return increases
Increase venous compliance (distensibility)=decrease
pressure=decrease venous return
Increase venous tone (contract smooth blood
vessel)=venous return increases
Increase venous compliance=decreased venous return
Increase blood volume=MSCFP increase=increase venous
return
R arterial pressure= 0mmHg normally
Increaser resistance=Venous return decrease
Decrease resistance=Venous return increase
Pressure
-generated on walls of the blood vessels (BP)
- (BP) fluctuates because heart contracts and relaxes
Example:
BP= 120/80
Pulse Pressure= 40
Elevated SP
(in elderly)-rigid aorta
-blood vessels are constricted
-aorta cannot distend
-generate very high SP
-DP is the same
*if high SP and same (did not differ) = pulse pressure:
greater than normal
Profuse bleeding
-decreased blood volume
-SP decrease= pulse pressure is narrow
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 7
MAP
-average pressure in arterial system measured over time
-close to the DP
-only composed of a single layer of endothelial cells
-with small slits for filtration and reabsorption of
substances
Arterial Blood Pressure
-increased stroke volume, heart rate= increase ABP
Four Forces that Determine Fluid Movement in the
Capillary
Aorta
-highest pressure because it receives blood directly from L
ventricle
Terminal Arterioles
-biggest drop in the BP
-arterioles can constrict/contract, allowing/not allowing
blood to flow
Venules, Small veins, VC’s
-pressure is no longer significance because of compliance
of veins
Pulmonary Circulation
-pressure is very small because of little resistance
1. Capillary Hydrostatic Pressure
-try to push fluid into the interstitial space
2. Interstitial Fluid Pressure
-prevent fluid from flowing into the interstitial space
If Pif is POSITIVE= prevents fluid from flowing to
interstitial space
If Pif is NEGATIVE=attracts fluid into interstitial space
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 8
3. Plasma colloid osmotic pressure
-primarily imparted by plasma proteins
-holds on to fluid to remain inside blood vessel
4. Interstitial fluid colloid osmotic pressure
-proteins in interstitial fluid will attract fluid into
interstitial space
How do you know if fluid will be filtered/reabsorbed in
the capillaries?
-compute net filtration pressure
Filtration-arterial end
Reabsorption-venous end
Excess of 0.3mmHg
-if it accumulates=edema
-accumulation does not occur because of the lymphatics
-if lymphatics is blocked= edema
Conditions that will produce EDEMA:
-anything that increases Capillary Hydrostatic Pressure
(CHP) and decreases plasma capillary oncotic pressure
(PCOP)
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 9
Lymphatics
-all excess (0.3mmHg) will go to the lymphatic system,
because the pressure between capillary and interstitial
fluid will always be greater than the capillary.
-direction of movement will always be to the capillary
-Lymphatic vessels up to the point of thoracic duct- all
capillaries drain into the thoracic duct and then to the
venous system via- subclavian vein
-if blocked-effect is accumulation in interstitial
space=edema
Burn Patients
-increased capillary membrane permeability
-proteins go to interstitial space
-Edematous
*When someone is standing still, because of force of
gravity, the pressure in veins, supplying the feet =
99mmHg. If the person will not move, pressure within the
vein will be greater than that of the capillary (20mmHg).
If pressure of capillary is lower than in the veins, blood
cannot drain into the venous systems=Edema.
Normal Valve
-unidirectional
-prevent backflow of blood
Abnormal Valve
-vein is too distended
-blood goes back to vein even when it closes
*nutrients and oxygen will not be able to go to the cell; if
not resolved, tissues will become necrotic and gangrenous
Causes of increased interstitial volume and Edema
-anything that increase CHP, decrease PCOP
-anything that increase Capillary permeability
-anything that can cause inadequacy in lymphatic flow
Manuel, Marie Eleonor B. 1A-Medicine ‘18 Page 10
PHYSIOLOGY A – Vascular Physiology Pt.2
Dr. Olivar
Adenosine
INTRODUCTION
Regulations in the Vascular System
-Under Basal conditions, the blood flow to the different
organs is different.
Organ
Brain
Heart
Bronchi
Kidneys
Liver
Muscle(Inactive)
Bone
Skin(Cool Weather)
Thyroid Gland
Adrenal Gland
Other Tissues
TOTAL
%cardiac output
14
4
2
22
27
15
5
6
1
0.5
3.3
100
ml/min
700
200
100
1100
1350
1050
300
750
50
25
175
5000
ml/min/g
50
70
25
360
95
4
3
3
160
300
1.3
b. Oxygen Theory/Nutrient Lack Theory – Oxygen and
nutrients are required for the smooth muscles to contract.
Therefore, the absence of oxygen would cause the smooth
muscle to relax and dilate the vessel. We must then recall
that dilation of blood vessels will cause an increase in blood
th
flow to the 4 power (Poiseuille’s Law)
-Take note of the large amount of blood flow to the
Kidneys (360ml/min/g),
Adrenal Gland (300ml/min/g), and
Thyroid Gland (160ml/min/g)
-Take note of the very little blood flow to the
Inactive Muscle (4ml/min/g)
Question: Why is blood flow not always increased in every
organ, in such a way that it would always be enough to meet
the needs of the tissue whether the activity of it is less or
great?
Answer: It is simply because the heart is unable to handle
that much more blood flow than normal. Studies have also
shown that if blood is regulated in such a way (as presented
in the table above), almost all tissue will not suffer from
oxygen deprivation or nutrient deficiency, with the heart also
kept at minimal workload.
LECTURE OUTLINE
I. Local and Humoral Control of Blood Flow
II. Nervous Regulation of the Circulation and Arterial Pressure
I.LOCAL AND HUMORAL CONTROL OF BLOOD FLOW
A. LOCAL
1. Acute Control (Happens in seconds to minutes)
a. Vasodilator Theory - If the rate of metabolism is increase,
it is accompanied by an immediate increase in blood flow.
This is because when a tissue is highly metabolic, it is
excreting a lot of metabolites and by-products which cause
the vessels to dilate. The most commonly associated byproduct is adenosine.
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Examples of Situations
-this theory presents in people high altitude. Due to the low
supply of oxygen, vessels are dilated and blood flow is
increased to the organs. (People from Baguio with fair
complexion have reddish cheeks)
-In Carbon Monoxide Poisoning, the hemoglobin is more
attached with carbon monoxide rather than CO2 and oxygen.
Patients with this poisoning have severely low oxygen in
blood vessels, which trigger massive vasodilation. These
patients will therefore present with reddish skin all over the
body.
-Cyanide Poisoning is another condition which prevents o2
utilization (ETC). The ultimate effect is that oxygen perfusion
to organs will decrease, and the vessels will dilate causing the
reddish discoloration.
Page 1
c.1 Reactive Hyperemia is appreciable when applying
tourniquet. Blocking the blood for a prolonged period of time
will cause a momentary hypoxia to the tissues initiating vessel
dilation. Release of the tourniquet would then cause blood to
flow back to the dilated vessels at a more rapid rate because
of its dilation. This is a compensation of the blood
oxygenation lost during the time of blockage.
c.2 Active Hyperemia is similar to vasodilator theory. It states
that when a muscle is at rest, the blood vessels are
constricted, and when the muscle or tissue is active, the
blood vessels will dilate. This is because of the metabolites
that cause vasodilation. This explains why you are flushed
whenever you are exercising.
The same theory applies when the blood pressure is
decreased. It causes the blood flow to decrease, and there
will be less oxygen reaching the cells. The blood vessel then
dilates and the blood flow returns to normal.
↓BP - ↓BF - ↓O2perfusion- Smooth Muscles
Relaxation – Dilate Vessel – Regulate Blood Flow
Autoregulation according to the Myogenic Theory is based on
the observation that sudden stretch of small blood vessels
causes the smooth muscle of the vessel wall to contract for a
few seconds.
Therefore, it has been proposed that when high blood
pressure stretches the vessel, this in turn causes the wall to
react by constricting. This reduces blood flow nearly back to
normal.
↑BP – Momentary ↑BF - Sudden Stretch – Smooth
Muscle Contraction – Regulate Blood Flow
Conversely, at low pressures, the degree of stretch of the
vessel is less, so that the smooth muscle relaxes and allows
increased flow.
↓BP - ↓BF – Less Degree of Stretch - Smooth Muscle
Relax – Regulate Blood Flow
The importance of Autoregulation is evident in cases when
the blood pressure is increased. When there is increased
blood pressure, the capillaries will increase Hydrostatic
Pressure causing increased filtration. GFR will also increase
because it is triggered by the increase in blood pressure.
Therefore whenever there is a rise in blood pressure, you will
urinate.
d. Autoregulation
Autoregulation is defined as the Capability of the blood
vessels to maintain normal blood flow despite fluctuations in
the blood pressure.
In any tissue of the body, an acute increase in arterial
pressure causes immediate rise in blood flow. But, within less
than a minute, the blood flow in most tissues returns almost
to the normal level, even though the arterial pressure is kept
elevated. This return of flow toward normal is called
autoregulation of blood flow.
When the blood pressure increases, the blood vessel will
dilate. Therefore, the blood flow increases as well. The
oxygen delivered to the tissue will increase and this will cause
the smooth muscles to contract. The blood flow ultimately
returns to normal. This is termed as Autoregulatiion
according to the Metabolic Theory.
↑BP - ↑BF - ↑O2perfusion – Smooth Muscle
contraction – Contract Vessel – Regulate Blood Flow
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Between 75-175mmHg, the blood flow is regulated
2. Long Term Control(Days to Months,but more complete)
a. Increased Tissue Vascularity
When requirement of oxygenation is high for a prolonged
period of time, the number of blood vessels in the tissue will
actually increase. On the other hand, if oxygenation
requirement is low, some blood vessels will disappear, or will
not form any more.
Page 2
When there is bacterial infection in the bone, this will require
longer time for healing. This also requires prolonged
metabolic process and therefore requires more oxygen
perfusion. Blood vessels will therefore start to increase in the
sites of the bone that are infected. This continues until the
bone is healed, at which point we notice that the blood
vessels will also disappear from the previous sites of
infection.
Recap:
A. Local
1. Acute Control (Happens in seconds to minutes)
a. Vasodilator Theory
b. Oxygen Theory/ Nutrient Lack Theory
c. Reactive and Active Hyperemia
d. Autoregulation (Metabolic & Myogenic)
2. Long Term Control (Days to Months, but more complete)
a. Increased Tissue Vascularity
b. Formation of Collateral Circulation
B. Humoral
1. Vasoconstrictors
Long term control is also seen in babies born prematurely.
These babies lack surfactant which is essential for proper
ventilation. An immediate management is to give high dose
oxygen. This can act on the retina of the babies’ eyes,
preventing blood vessels from forming, or even degenerating
formed blood vessels. Upon cessation of the high dose O2
(When the baby can now ventilate on its own), there will be
an overcompensated perfusion of blood in the retina which
can reach up to the vitreous humor of the eye (Retrolental
Fibroplasia, or in this case Retinopathy of Prematurity).
Ultimately, this can cause blindness.
Agent
Norepinephrine
(more potent) and
Epinephrine
Angiotensin ll
Where Produced
-from the Sympathetic Nerve Endings
or Adrenal Medulla)
Vasopressin (ADH;
potent
vasoconstrictor)
Endothelin
produced by the hypothalamus, and
stored in the posterior pituitary
-component in the RAAS (renin
angiotensin aldosterone system)
-Produced in the endothelial cells of
blood vessels
Serotonin
2. Vasodilators
Agent
Bradykinin
Histamine
b. Formation of collateral circulation
When an artery or a vein is blocked in virtually any tissue of
the body, a new vascular channel usually develops around the
blockage and allows at least partial resupply of blood to the
affected tissue.
The most important example of the development of collateral
blood vessels occurs after thrombosis of one of the coronary
arteries. Almost all people by the age of 60 years have had at
least one of the smaller branch coronary vessels close. Yet
most people do not know that this has happened because
collaterals have developed rapidly enough to prevent
myocardial damage.
Where Produced
released by mast cells, basophils
Effect of Ions & Other Chemical Factors
Ion
Effect
Calcium
Vasoconstriction
Potassium
Vasodilatation
Mmagnesium
Vasodilatation
H+
Vasodilatation
Carbon Dioxide
Vasodilatation
* no need for a recap.. 
II. NERVOUS REGULATION OF THE CIRCULATION AND
ARTERIAL PRESSURE
-Regulation that is confined in the autonomic nervous system,
specifically
the
sympathetic
nervous
system
(Vasoconstriction).
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Page 3
Sympathetic
Vasoconstriction
Sympathetic vasomotor nerve fibers that leave the spinal
cord immediately pass through the sympathetic chain, and
the sympathetic nerves pass to supply the heart as well as the
peripheral vessels. The sympathetic nerves supply all vessels
except the capillaries and the metaarterioles.
The effect of sympathetic stimulation on the arteries and
arterioles is constriction, thus regulating blood flow to the
capillaries.
The effect of sympathetic stimulation on the veins and
venules is increase in vasomotor tone, also constricting veins.
Remember that the veins are more compliant than the
arteries. They propel blood when the smooth muscles
contract. Therefore when the venous tone increases, the
veins will cause the blood to flow back to the right side of the
heart.
Vasomotor Center
It is located bilaterally in the reticular substance of the
medulla in the lower third of the pons. These centers send
sympathetic impulses to the heart and to the blood vessels.
They also send parasympathetic impulses but only to the
heart, not the blood vessels.
Sympathetic
Heart - ↑Heart Rate (Pulse Rate)
Blood Vessels – Vasoconstriction
Parasympathetic
Heart - ↑ Heart Rate
Blood Vessels – there is no parasympathetic supply to the BV
The reason why there is no parasympathetic vasodilation in
the blood vessels is because the main mechanism of causing
vasodilation is when the Sympathetic impulse is shut off. A
blood vessel at rest is dilated, and the only reason why it is
constricted is because of the effect of the sympathetic
impulse.
JOSE ALFONSO A. ROQUE, 1E-MD 2014
The Vasoconstrictor Area once again is responsible for
sending impulses that cause vasoconstriction to the blood
vessels and increase the heart rate of the heart.
The Vasodilator Area inhibits the vasoconstrictor area thus
causing vasodilation.
A sensory area (The third center) located bilaterally in the
tractus solitarius in the posterolateral portions of the
medulla and lower pons. The neurons of this area receive
sensory nerve signals from the circulatory system mainly
through the vagus and glossopharyngeal nerves, and output
signals from this sensory area then help to control activities
of both the vasoconstrictor and vasodilator areas of the
vasomotor center, thus providing “reflex” control of many
circulatory functions. An example is the baroreceptor reflex
for controlling arterial pressure.
To clarify, the impulse received by the sensory area in the
tractus solitarius will affect the activity of either the
vasoconstrictor area or the vasomotor area.
ARTERIAL PRESSURE (BP) CONTROL MECHANISMS
Acting within seconds or minutes or days
1. Baroreceptor feedback mechanism
2. Chemoreceptor mechanism
3. Central nervous system ischemic mechanism
4. Low pressure receptor mechanism
Acting after many minutes or hours
1. Stress- relaxation mechanism
2. Capillary fluid shift
3. Renal fluid shift
Acting after several hours
1. Renin –angiotensin –aldosterone system (RAAS)
ACTING WITHIN SECONDS OR MINUTES OR DAYS
1. BARORECEPTOR REFLEX
To understand the BR, we must first recall the parts of the
reflex arc:
Receptor (Baroreceptor) – the area that receives the stimulus
Sensory Neuron – sends signal from the receptor to the
center
Center (in the Tractus Solitaries) – analyzes the impulse and
gives it off towards the motor neuron
Motor Neuron – receives impulse from the Center
Effector – where impulse
Page 4
This can also happen the other way around…
The Baroreceptors are located in the Aortic Arch or Carotid
Sinuses. They are stretched receptors, meaning that they are
stimulated when they are stretched. The increase in blood
pressure causes this stretch. The sensory neurons can either
be the Glossopharyngeal Nerve for the Carrotid Sinus or the
Vagus Nerve for the Aortic Arch. The Center is the Tractus
Solitarius at the Vasomotor Center, and the efferent neurons
could either be the parasympathetic fibers or the
sympathetic fibers. The effectors could either be the heart of
the blood vessels.
Baroreceptors ( Carotid
sinus & Aortic Arch)
↓
Glossopharyngeal and
Vagus Nerve
↓
Vasomotor Center
↓
Sympa/Parasympathetic
Fibers
↓
Heart and Blood Vessels
Among the two receptors, the Carotid Baroreceptors have
the wider range of response. This means that the Aortic Arch
only responds to high pressure, whereas the Carotid
Baroreceptors can be stimulated even if the pressure is not
that high.
Scenario 1:
Your Physiology Professor suddenly enters the room to
announce that there will be an examination in a few minutes.
This caused you to have a sudden increase in blood pressure.
This causes the stretch of the Baroreceptor. This stretch
initiates them to send impulse towards the Center. Aortic
Arch sends through the Vagus and the Carotid Sinuses
through the Glossopharyngeal Nerve. Your Tractus Solitarius
recognizes the sudden increase in blood pressure and acts by
shutting of your sympathetic nervous system. This
parasympathetic impulse is sent off using the efferent
neurons towards the Heart. This causes the heart rate to
decrease. Without any stimulation going to the blood vessels,
they will dilate. So the pressure decreases.
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Scenario 2:
A medical student who had an examination at 7 am woke up
at 7:15 am. Startled, he suddenly stood up from bed. This
caused a sudden pooling of blood in the lower extremities
due to gravity (Orthostatic Hypotension). The abrupt pooling
of blood in the lower extremities doesn’t really stretch any
baroreceptor response because they are located away from
the lower extremities. This then causes the sympathetic
nervous system to predominate. This then causes the heart
rate to increase, and the vessels to constrict, allowing
increase in blood pressure.
↑BP causes Baroreceptor reflex to shut off the SNS
and to cause PSNS reflexes to go to the heart.
↓BP causes the Baroreceptor reflex to shut off,
making the SNS to predominate and therefore cause
↑BP.
2. CHEMORECEPTOR MECHANISM
This mechanism is similar with the Baroreceptor Reflex. The
receptors are located in the Aortic Arch and Carotid Sinus as
well. They also have the same nerve fibers involved. The only
difference is that these receptors do not respond to pressure
changes, but rather to chemical changes such as oxygen
saturation. This means that when the Blood Pressure
decreases, the pO2 (Oxygen Saturation of blood) also
decreases. This change in saturation triggers the receptors,
stimulating the vasomotor center, then causing the increase
in heart rate of the heart, and thus bringing the blood
pressure higher to increase Blood pressure.
↓BP - ↓pO2 – Stimulate Receptors – Afferent Neurons
– Vasomotor Center –sympathetic impulse is sent to
the heart - efferent neurons – ↑BP
3. CENTRAL NERVOUS SYSTEM ISCHEMIC MECHANISM
This mechanism only occurs when the blood flow to the brain
is very low. When your blood volume decreases (Bleeding),
your blood pressure is decreased. The priority organ that
needs blood supply will be the brain. So for the brain to
actually have decreased blood supply, the patient would have
to be severely hypovolemic (Severely low amount of blood).
Korotkoff sounds cannot be heard on auscultation due to the
severely low blood levels, and must be taken palpatory.
When the blood oxygen is decreased, there is ischemia to the
brain. This causes carbon dioxide to accumulate, causing
strong stimulation of the vasomotor center. This causes an
excessively strong impulse from the vasomotor center to the
heart which can elevate the blood pressure to 200/120’s or
higher, but only for a short time.
*Palpatory blood pressure is done using the sphygmomanometer
only. Instead of using a stethoscope to hear the Korotkoff sounds,
you will palpate the vein and feel for the BP.
Page 5
↓↓ BF to the brain – Ischemia - ↑pCO2 –
↑↑Vasomotor Stimulation - ↑↑Sympathetic
Stimulation to Heart - ↑↑BP
Cushing’s Reaction
Occurs when the Intracerebral pressure (ICP) is more than the
arterial Blood Pressure. This occurs when there is an
accumulation of cerebrospinal fluid in the Cranium. When the
ICP increases, the cerebral arteries are compressed,
preventing flow of oxygen into the brain. This is then
followed by the same events of the CNS Ischemic Response
ACTING AFTER MANY MINUTES OR HOURS
1. STRESS-RELAXATION MECHANISM
To better understand this concept, we must first recall MCSFP
On the other hand, if the blood pressure is decreased, the
capillary hydrostatic pressure is decreased and the oncotic
pressure is greater than the hydrostatic pressure.
Reabsorption is favored and fluid enters the intravascular
space, increasing blood volume, increasing blood pressure.
↓BP - ↑OP – Reabsorption - ↑BV - ↑BP
Brief Orientation about Renal Physiology
Kidneys function to filter blood, and the filtrate becomes the
urine. The kidneys are bilaterally located on each side of the
aorta. The renal artery is a major branch of the Aorta that
supplies the kidneys.
VR = MCSFP – CVP
R
MCSFP - Mean Circulatory or Systemic Filling Pressure
*If you stop the heart from pumping, it will give off a value of
70mmHg. This is the MCSFP.
CVP - Central Venous Pressure
*CVP is normally 0; this is the pressure in the right atrium
R - Resistance to Venous Return (Compliance)
↑Blood Flow = ↑ MCFSP
↑MCFSP = ↑Venous Return
↑ Blood Flow = ↑Venous Return
↑Compliance = ↓ MCFSP
↑Compliance = ↓Venous Return
This occurs when a decrease in Arterial Blood Pressure (ABP)
no longer distends the arteries. Therefore, their compliance is
decreased. If the compliance is decreased, the Mean
Circulatory Systemic Filling Pressure (MCSFP) increases. If
the MCSFP is increased, Venous Return (VR) is also increased.
So if the pressure is decreased, the vessel failed to distend
and the compliance is decreased, then the MCSFP increases,
causing also an increase in venous return. The increase in
venous return causes an increase in End Diastolic Volume
(EDV). According to Frank Starling’s Law, when EDV is
increased within physiologic limits, the force of ventricular
contraction will also be great. This causes the cardiac output
to increase, and ultimately the blood pressure is also
increased.
These arteries divide into several small arterioles until they
become the afferent arterioles, the smallest branch of the
renal artery. These terminate into the renal glomerulus which
is where filtration occurs. When filtration has undergone in
the glomerulus, the filtrate is then called glomerular filtrate.
The filtrate then travels to the nephron until it reaches the
ureter to become the urine.
↓ABP - ↓Distending Pressure - ↓Vascular
Capacity - ↑MCSFP - ↑VR - ↑ CO - ↑ABP
2. CAPILLARY FLUID SHIFT
When blood pressure is increased, the hydrostatic pressure
increases. This favors filtration and fluid goes to the
interstitial spaces. The blood volume therefore decreases,
causing the blood pressure to decrease.
Also take note that the distal tubule of the nephron abuts the
afferent arteriole.
↑BP - ↑HP – Filtration - ↓BV - ↓BP
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Page 6
3. RENAL FLUID SHIFT
When the arterial blood pressure is decreased, the blood flow
to renal artery will also be decreased. This means that there
will be decreased blood flowing to the afferent arteriole
causing a decreased in glomerular filtrates, or urine. This
means that you are preserving your blood volume which
increases venous return, thus also increasing cardiac output
and overall blood pressure.
This is evident in patients with decreased blood volume
(Bleeders). An initial symptom in them is decreased or absent
urine. This is because the afferent arterioles are closed. This
serves the function to maintain blood volume so that blood
can reach the more important organs. When the volume has
already been corrected and the pressure has risen back to
normal, the first sign to assess for will be urination. This will
signify the start of improvement in the circulation of the
patient. The afferent arterioles have already dilated, and
blood is being filtered.
-Can stimulate the hypothalamus to release Vasopressin
(ADH). It is a potent vasoconstrictor and can also promote
water reabsorption in the distal tubule of the kidney. The
overall effect is to increase blood volume, therefore
increasing venous return. This also means increase in cardiac
output and finally leading to an increase in blood pressure.
AII – Hypothalamus – ADH - ↑H2O reabsorption in DCT & CD
- ↑BV - ↑MCSFP - ↑VR & CO - ↑BP
In some adults with Chronic Hypertension, there is an
increase in angiotensin II. We manage this by giving Ace
Inhibitors which prevent conversion of angiotensin I to
angiotensin II.
Finally, a summary of RAAS…
↓BP - ↓Renal Blood Flow – Glomerular Capillary HP ↓Filtration - ↓Urine Formation – Preserved Blood
Volume – Improve VR and CO - ↑BP
This also explains why the more you drink fluids, the more
you urinate. Increased fluid intake causes increased blood
volume, thus increasing blood pressure. This causing
increased renal blood flow, causing increased filtration.
Therefore, urine production is increased.
ACTING AFTER SEVERAL HOURS
1. RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM (RAAS)
This is the most important control of long term regulation of
blood pressure. Remember that the distal tubule of the
nephron abuts the afferent arteriole. This is important
because a special structure called Macula Densa found in the
distal tubule. This structure can detect the Sodium content of
the filtrate. If the amount of filtrate is low (↓BP), the amount
of sodium delivered in the Macula Densa is also low and this
causes the JG cells found at the afferent arterioles to secrete
Renin. Renin functions by converting the protein
Angiotensinogen to Angiotensin I. Angiotensin I is converted
to Angiotensin II (potent vasoconstrictor) in the lungs by the
enzyme Angiotensin Converting Enyzme (ACE).
↓BP - ↓NA in Renal Blood Flow - Alert JG Cells Release Renin - Converts Angiotensinogen to
Angiotensin I - ACE - Converted to Angiotensin II
Functions of Angiotensin II
-Increases total peripheral resistance, bringing the BP up back
to normal
AII - ↑TPR - ↑BP
-Can stimulate the Adrenal Cortex to release Aldosterone, a
steroid hormone that promotes sodium absorption in the
tubules of the kidney. Where sodium goes, water goes.
Therefore the blood pressure goes back to normal.
AII-↑Aldosterone - ↑Sodium Reabsortion in DCT & CD -↑BP
JOSE ALFONSO A. ROQUE, 1E-MD 2014
God Bless Us All 
Page 7
PHYSIOLOGY A – Vascular Physiology Pt.2
Dr. Olivar
Adenosine
INTRODUCTION
Regulations in the Vascular System
-Under Basal conditions, the blood flow to the different
organs is different.
Organ
Brain
Heart
Bronchi
Kidneys
Liver
Muscle(Inactive)
Bone
Skin(Cool Weather)
Thyroid Gland
Adrenal Gland
Other Tissues
TOTAL
%cardiac output
14
4
2
22
27
15
5
6
1
0.5
3.3
100
ml/min
700
200
100
1100
1350
1050
300
750
50
25
175
5000
ml/min/g
50
70
25
360
95
4
3
3
160
300
1.3
b. Oxygen Theory/Nutrient Lack Theory – Oxygen and
nutrients are required for the smooth muscles to contract.
Therefore, the absence of oxygen would cause the smooth
muscle to relax and dilate the vessel. We must then recall
that dilation of blood vessels will cause an increase in blood
th
flow to the 4 power (Poiseuille’s Law)
-Take note of the large amount of blood flow to the
Kidneys (360ml/min/g),
Adrenal Gland (300ml/min/g), and
Thyroid Gland (160ml/min/g)
-Take note of the very little blood flow to the
Inactive Muscle (4ml/min/g)
Question: Why is blood flow not always increased in every
organ, in such a way that it would always be enough to meet
the needs of the tissue whether the activity of it is less or
great?
Answer: It is simply because the heart is unable to handle
that much more blood flow than normal. Studies have also
shown that if blood is regulated in such a way (as presented
in the table above), almost all tissue will not suffer from
oxygen deprivation or nutrient deficiency, with the heart also
kept at minimal workload.
LECTURE OUTLINE
I. Local and Humoral Control of Blood Flow
II. Nervous Regulation of the Circulation and Arterial Pressure
I.LOCAL AND HUMORAL CONTROL OF BLOOD FLOW
A. LOCAL
1. Acute Control (Happens in seconds to minutes)
a. Vasodilator Theory - If the rate of metabolism is increase,
it is accompanied by an immediate increase in blood flow.
This is because when a tissue is highly metabolic, it is
excreting a lot of metabolites and by-products which cause
the vessels to dilate. The most commonly associated byproduct is adenosine.
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Examples of Situations
-this theory presents in people high altitude. Due to the low
supply of oxygen, vessels are dilated and blood flow is
increased to the organs. (People from Baguio with fair
complexion have reddish cheeks)
-In Carbon Monoxide Poisoning, the hemoglobin is more
attached with carbon monoxide rather than CO2 and oxygen.
Patients with this poisoning have severely low oxygen in
blood vessels, which trigger massive vasodilation. These
patients will therefore present with reddish skin all over the
body.
-Cyanide Poisoning is another condition which prevents o2
utilization (ETC). The ultimate effect is that oxygen perfusion
to organs will decrease, and the vessels will dilate causing the
reddish discoloration.
Page 1
c.1 Reactive Hyperemia is appreciable when applying
tourniquet. Blocking the blood for a prolonged period of time
will cause a momentary hypoxia to the tissues initiating vessel
dilation. Release of the tourniquet would then cause blood to
flow back to the dilated vessels at a more rapid rate because
of its dilation. This is a compensation of the blood
oxygenation lost during the time of blockage.
c.2 Active Hyperemia is similar to vasodilator theory. It states
that when a muscle is at rest, the blood vessels are
constricted, and when the muscle or tissue is active, the
blood vessels will dilate. This is because of the metabolites
that cause vasodilation. This explains why you are flushed
whenever you are exercising.
The same theory applies when the blood pressure is
decreased. It causes the blood flow to decrease, and there
will be less oxygen reaching the cells. The blood vessel then
dilates and the blood flow returns to normal.
↓BP - ↓BF - ↓O2perfusion- Smooth Muscles
Relaxation – Dilate Vessel – Regulate Blood Flow
Autoregulation according to the Myogenic Theory is based on
the observation that sudden stretch of small blood vessels
causes the smooth muscle of the vessel wall to contract for a
few seconds.
Therefore, it has been proposed that when high blood
pressure stretches the vessel, this in turn causes the wall to
react by constricting. This reduces blood flow nearly back to
normal.
↑BP – Momentary ↑BF - Sudden Stretch – Smooth
Muscle Contraction – Regulate Blood Flow
Conversely, at low pressures, the degree of stretch of the
vessel is less, so that the smooth muscle relaxes and allows
increased flow.
↓BP - ↓BF – Less Degree of Stretch - Smooth Muscle
Relax – Regulate Blood Flow
The importance of Autoregulation is evident in cases when
the blood pressure is increased. When there is increased
blood pressure, the capillaries will increase Hydrostatic
Pressure causing increased filtration. GFR will also increase
because it is triggered by the increase in blood pressure.
Therefore whenever there is a rise in blood pressure, you will
urinate.
d. Autoregulation
Autoregulation is defined as the Capability of the blood
vessels to maintain normal blood flow despite fluctuations in
the blood pressure.
In any tissue of the body, an acute increase in arterial
pressure causes immediate rise in blood flow. But, within less
than a minute, the blood flow in most tissues returns almost
to the normal level, even though the arterial pressure is kept
elevated. This return of flow toward normal is called
autoregulation of blood flow.
When the blood pressure increases, the blood vessel will
dilate. Therefore, the blood flow increases as well. The
oxygen delivered to the tissue will increase and this will cause
the smooth muscles to contract. The blood flow ultimately
returns to normal. This is termed as Autoregulatiion
according to the Metabolic Theory.
↑BP - ↑BF - ↑O2perfusion – Smooth Muscle
contraction – Contract Vessel – Regulate Blood Flow
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Between 75-175mmHg, the blood flow is regulated
2. Long Term Control(Days to Months,but more complete)
a. Increased Tissue Vascularity
When requirement of oxygenation is high for a prolonged
period of time, the number of blood vessels in the tissue will
actually increase. On the other hand, if oxygenation
requirement is low, some blood vessels will disappear, or will
not form any more.
Page 2
When there is bacterial infection in the bone, this will require
longer time for healing. This also requires prolonged
metabolic process and therefore requires more oxygen
perfusion. Blood vessels will therefore start to increase in the
sites of the bone that are infected. This continues until the
bone is healed, at which point we notice that the blood
vessels will also disappear from the previous sites of
infection.
Recap:
A. Local
1. Acute Control (Happens in seconds to minutes)
a. Vasodilator Theory
b. Oxygen Theory/ Nutrient Lack Theory
c. Reactive and Active Hyperemia
d. Autoregulation (Metabolic & Myogenic)
2. Long Term Control (Days to Months, but more complete)
a. Increased Tissue Vascularity
b. Formation of Collateral Circulation
B. Humoral
1. Vasoconstrictors
Long term control is also seen in babies born prematurely.
These babies lack surfactant which is essential for proper
ventilation. An immediate management is to give high dose
oxygen. This can act on the retina of the babies’ eyes,
preventing blood vessels from forming, or even degenerating
formed blood vessels. Upon cessation of the high dose O2
(When the baby can now ventilate on its own), there will be
an overcompensated perfusion of blood in the retina which
can reach up to the vitreous humor of the eye (Retrolental
Fibroplasia, or in this case Retinopathy of Prematurity).
Ultimately, this can cause blindness.
Agent
Norepinephrine
(more potent) and
Epinephrine
Angiotensin ll
Where Produced
-from the Sympathetic Nerve Endings
or Adrenal Medulla)
Vasopressin (ADH;
potent
vasoconstrictor)
Endothelin
produced by the hypothalamus, and
stored in the posterior pituitary
-component in the RAAS (renin
angiotensin aldosterone system)
-Produced in the endothelial cells of
blood vessels
Serotonin
2. Vasodilators
Agent
Bradykinin
Histamine
b. Formation of collateral circulation
When an artery or a vein is blocked in virtually any tissue of
the body, a new vascular channel usually develops around the
blockage and allows at least partial resupply of blood to the
affected tissue.
The most important example of the development of collateral
blood vessels occurs after thrombosis of one of the coronary
arteries. Almost all people by the age of 60 years have had at
least one of the smaller branch coronary vessels close. Yet
most people do not know that this has happened because
collaterals have developed rapidly enough to prevent
myocardial damage.
Where Produced
released by mast cells, basophils
Effect of Ions & Other Chemical Factors
Ion
Effect
Calcium
Vasoconstriction
Potassium
Vasodilatation
Mmagnesium
Vasodilatation
H+
Vasodilatation
Carbon Dioxide
Vasodilatation
* no need for a recap.. 
II. NERVOUS REGULATION OF THE CIRCULATION AND
ARTERIAL PRESSURE
-Regulation that is confined in the autonomic nervous system,
specifically
the
sympathetic
nervous
system
(Vasoconstriction).
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Page 3
Sympathetic
Vasoconstriction
Sympathetic vasomotor nerve fibers that leave the spinal
cord immediately pass through the sympathetic chain, and
the sympathetic nerves pass to supply the heart as well as the
peripheral vessels. The sympathetic nerves supply all vessels
except the capillaries and the metaarterioles.
The effect of sympathetic stimulation on the arteries and
arterioles is constriction, thus regulating blood flow to the
capillaries.
The effect of sympathetic stimulation on the veins and
venules is increase in vasomotor tone, also constricting veins.
Remember that the veins are more compliant than the
arteries. They propel blood when the smooth muscles
contract. Therefore when the venous tone increases, the
veins will cause the blood to flow back to the right side of the
heart.
Vasomotor Center
It is located bilaterally in the reticular substance of the
medulla in the lower third of the pons. These centers send
sympathetic impulses to the heart and to the blood vessels.
They also send parasympathetic impulses but only to the
heart, not the blood vessels.
Sympathetic
Heart - ↑Heart Rate (Pulse Rate)
Blood Vessels – Vasoconstriction
Parasympathetic
Heart - ↑ Heart Rate
Blood Vessels – there is no parasympathetic supply to the BV
The reason why there is no parasympathetic vasodilation in
the blood vessels is because the main mechanism of causing
vasodilation is when the Sympathetic impulse is shut off. A
blood vessel at rest is dilated, and the only reason why it is
constricted is because of the effect of the sympathetic
impulse.
JOSE ALFONSO A. ROQUE, 1E-MD 2014
The Vasoconstrictor Area once again is responsible for
sending impulses that cause vasoconstriction to the blood
vessels and increase the heart rate of the heart.
The Vasodilator Area inhibits the vasoconstrictor area thus
causing vasodilation.
A sensory area (The third center) located bilaterally in the
tractus solitarius in the posterolateral portions of the
medulla and lower pons. The neurons of this area receive
sensory nerve signals from the circulatory system mainly
through the vagus and glossopharyngeal nerves, and output
signals from this sensory area then help to control activities
of both the vasoconstrictor and vasodilator areas of the
vasomotor center, thus providing “reflex” control of many
circulatory functions. An example is the baroreceptor reflex
for controlling arterial pressure.
To clarify, the impulse received by the sensory area in the
tractus solitarius will affect the activity of either the
vasoconstrictor area or the vasomotor area.
ARTERIAL PRESSURE (BP) CONTROL MECHANISMS
Acting within seconds or minutes or days
1. Baroreceptor feedback mechanism
2. Chemoreceptor mechanism
3. Central nervous system ischemic mechanism
4. Low pressure receptor mechanism
Acting after many minutes or hours
1. Stress- relaxation mechanism
2. Capillary fluid shift
3. Renal fluid shift
Acting after several hours
1. Renin –angiotensin –aldosterone system (RAAS)
ACTING WITHIN SECONDS OR MINUTES OR DAYS
1. BARORECEPTOR REFLEX
To understand the BR, we must first recall the parts of the
reflex arc:
Receptor (Baroreceptor) – the area that receives the stimulus
Sensory Neuron – sends signal from the receptor to the
center
Center (in the Tractus Solitaries) – analyzes the impulse and
gives it off towards the motor neuron
Motor Neuron – receives impulse from the Center
Effector – where impulse
Page 4
This can also happen the other way around…
The Baroreceptors are located in the Aortic Arch or Carotid
Sinuses. They are stretched receptors, meaning that they are
stimulated when they are stretched. The increase in blood
pressure causes this stretch. The sensory neurons can either
be the Glossopharyngeal Nerve for the Carrotid Sinus or the
Vagus Nerve for the Aortic Arch. The Center is the Tractus
Solitarius at the Vasomotor Center, and the efferent neurons
could either be the parasympathetic fibers or the
sympathetic fibers. The effectors could either be the heart of
the blood vessels.
Baroreceptors ( Carotid
sinus & Aortic Arch)
↓
Glossopharyngeal and
Vagus Nerve
↓
Vasomotor Center
↓
Sympa/Parasympathetic
Fibers
↓
Heart and Blood Vessels
Among the two receptors, the Carotid Baroreceptors have
the wider range of response. This means that the Aortic Arch
only responds to high pressure, whereas the Carotid
Baroreceptors can be stimulated even if the pressure is not
that high.
Scenario 1:
Your Physiology Professor suddenly enters the room to
announce that there will be an examination in a few minutes.
This caused you to have a sudden increase in blood pressure.
This causes the stretch of the Baroreceptor. This stretch
initiates them to send impulse towards the Center. Aortic
Arch sends through the Vagus and the Carotid Sinuses
through the Glossopharyngeal Nerve. Your Tractus Solitarius
recognizes the sudden increase in blood pressure and acts by
shutting of your sympathetic nervous system. This
parasympathetic impulse is sent off using the efferent
neurons towards the Heart. This causes the heart rate to
decrease. Without any stimulation going to the blood vessels,
they will dilate. So the pressure decreases.
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Scenario 2:
A medical student who had an examination at 7 am woke up
at 7:15 am. Startled, he suddenly stood up from bed. This
caused a sudden pooling of blood in the lower extremities
due to gravity (Orthostatic Hypotension). The abrupt pooling
of blood in the lower extremities doesn’t really stretch any
baroreceptor response because they are located away from
the lower extremities. This then causes the sympathetic
nervous system to predominate. This then causes the heart
rate to increase, and the vessels to constrict, allowing
increase in blood pressure.
↑BP causes Baroreceptor reflex to shut off the SNS
and to cause PSNS reflexes to go to the heart.
↓BP causes the Baroreceptor reflex to shut off,
making the SNS to predominate and therefore cause
↑BP.
2. CHEMORECEPTOR MECHANISM
This mechanism is similar with the Baroreceptor Reflex. The
receptors are located in the Aortic Arch and Carotid Sinus as
well. They also have the same nerve fibers involved. The only
difference is that these receptors do not respond to pressure
changes, but rather to chemical changes such as oxygen
saturation. This means that when the Blood Pressure
decreases, the pO2 (Oxygen Saturation of blood) also
decreases. This change in saturation triggers the receptors,
stimulating the vasomotor center, then causing the increase
in heart rate of the heart, and thus bringing the blood
pressure higher to increase Blood pressure.
↓BP - ↓pO2 – Stimulate Receptors – Afferent Neurons
– Vasomotor Center –sympathetic impulse is sent to
the heart - efferent neurons – ↑BP
3. CENTRAL NERVOUS SYSTEM ISCHEMIC MECHANISM
This mechanism only occurs when the blood flow to the brain
is very low. When your blood volume decreases (Bleeding),
your blood pressure is decreased. The priority organ that
needs blood supply will be the brain. So for the brain to
actually have decreased blood supply, the patient would have
to be severely hypovolemic (Severely low amount of blood).
Korotkoff sounds cannot be heard on auscultation due to the
severely low blood levels, and must be taken palpatory.
When the blood oxygen is decreased, there is ischemia to the
brain. This causes carbon dioxide to accumulate, causing
strong stimulation of the vasomotor center. This causes an
excessively strong impulse from the vasomotor center to the
heart which can elevate the blood pressure to 200/120’s or
higher, but only for a short time.
*Palpatory blood pressure is done using the sphygmomanometer
only. Instead of using a stethoscope to hear the Korotkoff sounds,
you will palpate the vein and feel for the BP.
Page 5
↓↓ BF to the brain – Ischemia - ↑pCO2 –
↑↑Vasomotor Stimulation - ↑↑Sympathetic
Stimulation to Heart - ↑↑BP
Cushing’s Reaction
Occurs when the Intracerebral pressure (ICP) is more than the
arterial Blood Pressure. This occurs when there is an
accumulation of cerebrospinal fluid in the Cranium. When the
ICP increases, the cerebral arteries are compressed,
preventing flow of oxygen into the brain. This is then
followed by the same events of the CNS Ischemic Response
ACTING AFTER MANY MINUTES OR HOURS
1. STRESS-RELAXATION MECHANISM
To better understand this concept, we must first recall MCSFP
On the other hand, if the blood pressure is decreased, the
capillary hydrostatic pressure is decreased and the oncotic
pressure is greater than the hydrostatic pressure.
Reabsorption is favored and fluid enters the intravascular
space, increasing blood volume, increasing blood pressure.
↓BP - ↑OP – Reabsorption - ↑BV - ↑BP
Brief Orientation about Renal Physiology
Kidneys function to filter blood, and the filtrate becomes the
urine. The kidneys are bilaterally located on each side of the
aorta. The renal artery is a major branch of the Aorta that
supplies the kidneys.
VR = MCSFP – CVP
R
MCSFP - Mean Circulatory or Systemic Filling Pressure
*If you stop the heart from pumping, it will give off a value of
70mmHg. This is the MCSFP.
CVP - Central Venous Pressure
*CVP is normally 0; this is the pressure in the right atrium
R - Resistance to Venous Return (Compliance)
↑Blood Flow = ↑ MCFSP
↑MCFSP = ↑Venous Return
↑ Blood Flow = ↑Venous Return
↑Compliance = ↓ MCFSP
↑Compliance = ↓Venous Return
This occurs when a decrease in Arterial Blood Pressure (ABP)
no longer distends the arteries. Therefore, their compliance is
decreased. If the compliance is decreased, the Mean
Circulatory Systemic Filling Pressure (MCSFP) increases. If
the MCSFP is increased, Venous Return (VR) is also increased.
So if the pressure is decreased, the vessel failed to distend
and the compliance is decreased, then the MCSFP increases,
causing also an increase in venous return. The increase in
venous return causes an increase in End Diastolic Volume
(EDV). According to Frank Starling’s Law, when EDV is
increased within physiologic limits, the force of ventricular
contraction will also be great. This causes the cardiac output
to increase, and ultimately the blood pressure is also
increased.
These arteries divide into several small arterioles until they
become the afferent arterioles, the smallest branch of the
renal artery. These terminate into the renal glomerulus which
is where filtration occurs. When filtration has undergone in
the glomerulus, the filtrate is then called glomerular filtrate.
The filtrate then travels to the nephron until it reaches the
ureter to become the urine.
↓ABP - ↓Distending Pressure - ↓Vascular
Capacity - ↑MCSFP - ↑VR - ↑ CO - ↑ABP
2. CAPILLARY FLUID SHIFT
When blood pressure is increased, the hydrostatic pressure
increases. This favors filtration and fluid goes to the
interstitial spaces. The blood volume therefore decreases,
causing the blood pressure to decrease.
Also take note that the distal tubule of the nephron abuts the
afferent arteriole.
↑BP - ↑HP – Filtration - ↓BV - ↓BP
JOSE ALFONSO A. ROQUE, 1E-MD 2014
Page 6
3. RENAL FLUID SHIFT
When the arterial blood pressure is decreased, the blood flow
to renal artery will also be decreased. This means that there
will be decreased blood flowing to the afferent arteriole
causing a decreased in glomerular filtrates, or urine. This
means that you are preserving your blood volume which
increases venous return, thus also increasing cardiac output
and overall blood pressure.
This is evident in patients with decreased blood volume
(Bleeders). An initial symptom in them is decreased or absent
urine. This is because the afferent arterioles are closed. This
serves the function to maintain blood volume so that blood
can reach the more important organs. When the volume has
already been corrected and the pressure has risen back to
normal, the first sign to assess for will be urination. This will
signify the start of improvement in the circulation of the
patient. The afferent arterioles have already dilated, and
blood is being filtered.
-Can stimulate the hypothalamus to release Vasopressin
(ADH). It is a potent vasoconstrictor and can also promote
water reabsorption in the distal tubule of the kidney. The
overall effect is to increase blood volume, therefore
increasing venous return. This also means increase in cardiac
output and finally leading to an increase in blood pressure.
AII – Hypothalamus – ADH - ↑H2O reabsorption in DCT & CD
- ↑BV - ↑MCSFP - ↑VR & CO - ↑BP
In some adults with Chronic Hypertension, there is an
increase in angiotensin II. We manage this by giving Ace
Inhibitors which prevent conversion of angiotensin I to
angiotensin II.
Finally, a summary of RAAS…
↓BP - ↓Renal Blood Flow – Glomerular Capillary HP ↓Filtration - ↓Urine Formation – Preserved Blood
Volume – Improve VR and CO - ↑BP
This also explains why the more you drink fluids, the more
you urinate. Increased fluid intake causes increased blood
volume, thus increasing blood pressure. This causing
increased renal blood flow, causing increased filtration.
Therefore, urine production is increased.
ACTING AFTER SEVERAL HOURS
1. RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM (RAAS)
This is the most important control of long term regulation of
blood pressure. Remember that the distal tubule of the
nephron abuts the afferent arteriole. This is important
because a special structure called Macula Densa found in the
distal tubule. This structure can detect the Sodium content of
the filtrate. If the amount of filtrate is low (↓BP), the amount
of sodium delivered in the Macula Densa is also low and this
causes the JG cells found at the afferent arterioles to secrete
Renin. Renin functions by converting the protein
Angiotensinogen to Angiotensin I. Angiotensin I is converted
to Angiotensin II (potent vasoconstrictor) in the lungs by the
enzyme Angiotensin Converting Enyzme (ACE).
↓BP - ↓NA in Renal Blood Flow - Alert JG Cells Release Renin - Converts Angiotensinogen to
Angiotensin I - ACE - Converted to Angiotensin II
Functions of Angiotensin II
-Increases total peripheral resistance, bringing the BP up back
to normal
AII - ↑TPR - ↑BP
-Can stimulate the Adrenal Cortex to release Aldosterone, a
steroid hormone that promotes sodium absorption in the
tubules of the kidney. Where sodium goes, water goes.
Therefore the blood pressure goes back to normal.
AII-↑Aldosterone - ↑Sodium Reabsortion in DCT & CD -↑BP
JOSE ALFONSO A. ROQUE, 1E-MD 2014
God Bless Us All 
Page 7
RESPIRATORY PHYSIOLOGY I
LUNGS
Functions:
1. Gas exchange
- Transport of gas from the atmosphere towards
the lungs, to the blood, to the different tissues.
- Elimination of CO2
2. Host defense
- It secretes several inflammatory mediators,
immunoglobulins.
3. Metabolic organ
- It secretes several hormones
- Ex. Dopamine, Serotonin, Angiotensin
Volume: 4 Liters
Surface Area: 85 m2
Demonstrates “functional unity” Weight (Adults): approximately 1 kg
- VISCERAL PLEURA: tightly adherent to the lung
itself
- PARIETAL PLEURA: attached inside the chest
wall/ thoracic cavity
NOSE
- Very important because it is where air enters
- Although we can breathe through our mouth, it is
better if we breathe through our nose because:
- it humidifies the air
- entraps of clear particles more than 10μm in size (protective function: it acts as protective barrier)
- sense of smell (olfactory sense)
- 50% of the total resistance of the airway
- Host defense
- Secretes several inflammatory mediators,
immunoglobulins.
PARANASAL SINUSES
- Frontal, Sphenoid, Ethmoid, Maxillary
- It lightens the skull
- For voice resonance
- In SINUSITIS, changes in voice may be evident.
LARYNX
RIGHT LUNG
- Divided into 3 LOBES (upper, middle, lower)
- 2 interlobular fissures: HORIZONTAL FISSURE
and OBLIQUE FISSURE
- Opening from the oropharynx towards the
trachea
- Formed by:
- Epiglottis
- Arytenoids
- Vocal cords
- Also acts as a gate/door towards the airway
- During swallowing, epiglottis closes (covers the
larynx) so that the food will not enter the airway;
LEFT LUNG
- Divided into 2 LOBES (upper, lower)
- Divided by OBLIQUE FISSURE
- It has the LINGULA (part of the lungs where the
heart lies)
1
The lungs are covered by a thin membrane called
PLEURA.
JOHN LERY T. MENIANO I-C
LOWER AIRWAY
- As it goes further down, it becomes the
BRONCHIOLES.
LOWER AIRWAY
- Undergoes dichotomous branching (divides
into two’s) - This tubular structure is composed of cartilage
and muscle
- Bronchi and bronchioles differ in:
- Size
- Cartilage
- Epithelium
- Blood supply
- Any structures found BELOW the LARYNX is
considered LOWER RESIPIRATORY TRACT;
ABOVE
the
LARYXNX
is
UPPER
RESIPIRATORY TRACT.
- The demarcation is the LARYNX.
TRACHEA
- Further down the line, once the bronchioles
attach to the alveoli or the alveolar ducts, it now
forms the respiratory unit.
RESPIRATORY UNIT (“Gas Exchange Unit”) - It is where gas exchange occurs.
Composed of:
- Respiratory bronchioles
- Alveolar ducts
- Alveoli
- Those that are not attached to the alveoli or the
alveolar ducts, is called the conducting unit.
- Ex. trachea, main stem bronchus
CONDUCTING UNIT (“Anatomic Dead Space”) - Only conducts air from the upper airways
towards the alveoli.
- Dead space because there is no gas exchanges
that occurs.
- 150 ml in adults
- Divides into several bronchi.
- RIGHT and LEFT MAINSTEM bronchus → divides into SECONDARY bronchus → TERTIARY bronchus
TRACHEA→ divides 16x After the 16th division, it becomes the
RESPIRATORY UNIT.
It is now attached to the Respiratory Bronchioles
and Alveolar Ducts
JOHN LERY T. MENIANO I-C
2
the trachea down to the respiratory bronchus are
known as the CONDUCTING airways.
ALVEOLI
- It is where gas exchange occurs.
- Polygonal in shape.
- Type 1 and Type 2 cells.
- TYPE1 CELLS
- 96-98% of the surface area
- Thin cytoplasm
- Basement membrane fused with the capillary
endothelium
TYPE2 CELLS
Small and cuboidal
Although they are more numerous that Type1
cells, they only cover around 2-4% of surface
area because they are small and cuboidal.
FUNCTIONS:
Synthesize pulmonary surfactant
Repair of alveolar structures
Gas exchange occurs in the alveoli through a
dense meshlike network of capillaries and alveoli
called ALVEOLAR-CAPILLARY NETWORK
The barrier between gas in the alveoli and the red
blood cell is only 1-2 μm in thickness. - It is like a white polygon provided with several
RBC’s;; basement membrane, septum is not visible because it is very thin.
- LUNG INTERSTITIUM
- Composed of connective tissues, primarily
fibroblast.
- FIBROBLAST
- COLLAGEN- limits lung distensibility
- ELASTIN- for elastic recoil of the lung
- Cartilage
- Neuroendocrine cells
- KULTSCHITZKY CELLS: secretes DOPAMINE
and SEROTONIN
- Responsible for the metabolic function of the
lungs, because it secretes dopamine and
serotonin.
BLOOD SUPPLY
1. PULMONARY CIRCULATION
- Pulmonary Artery: the ONLY artery that carries
UNOXYGENATED blood.
- Pulmonary Vein: carries OXYGENATED blood;
the blood vessel that comes from the lungs.
- Largest vascular bed in the body (70-80 m2)
- Dense capillary network
- At REST: each capillary has a volume is 70 ml
- During EXERCISE: it can span and open up, and
the volume can increase up to 200 ml.
2. BRONCHIAL CIRCULATION
- 2 Bronchial Arteries
- Supplies the bronchi, bronchioles, blood vessels,
nerves, lymph nodes and visceral pleura.
- 1/3 of the blood returns to the atrium
- Rest of the blood to the left atrium via the
pulmonary veins.
INNERVATION
- When we breathe, our breathing is AUTOMATIC
and UNDER CNS CONTROL
- Autonomic Nervous system
Parasympathetic
stimulation:
BRONCHOCONSTRICTION
Sympathetic
BRONCHORELAXATION/DILATION
stimulation:
Non-Adrenergic, Non-cholinergic
BRONCHODILATION
Inhibitory:
Non- Adrenergic, Non-cholinergic Stimulatory:
BRONCHOCONSTRICTION
CENTRAL CONTROL OF RESPIRATION
- Automatic, rhythmic, and centrally regulated
- VOLUNTARY control
- But when you hold your breath, you can just hold
it for a period of time.
- BRAINSTEM: main control center
MUSCLES OF RESPIRATION
1. At INSPIRATION
- Principal Muscles:
A. DIAPHRAGM
JOHN LERY T. MENIANO I-C
3
B. EXTERNAL INTERCOSTALS
- Accessory Muscles:
A. STERNOCLEIDOMASTOID
B. SCALENE MUSCLES
2. At EXPIRATION
- In ordinary quiet respiration, EXPIRATION is
purely PASSIVE. It is accomplished when the
muscles of inspiration relax.
- In forced expiration:
a. Rectus abdominis, oblique and transverse
muscles
b. Internal intercostals
MUCOCILIARY CLEARANCE SYSTEM
1. PERICILIARY FLUID
Secreted by the pseudostratified columnar
epithelium
2. MUCUS GLANDS
- Secreted by mucus and serous cells
Functions:
- To remove particles and particulate in the lungs
(protective function)
PULMONARY SURFACTANT
Secreted by Type2 pneumocytes
80% phospholipids: Dipalmitoyl
Choline (DPPC); ex.Lecithin
8% proteins
8% Neutral Lipids (cholesterol)
Phosphatidyl
4 Surfactant Proteins: SP-A, B, C, D
Function: reduces surface tension inside the
lungs
SP-A



SP-B



Figure 37–1 shows the mechanism by which the
external and internal intercostals act to cause
inspiration and expiration. To the left, the ribs
duringexpiration are angled downward, and the
externalintercostals are elongated forward and
downward. As they contract, they pull the upper
ribs forward in relationto the lower ribs, and this
causes leverage on theribs to raise them upward,
thereby causing inspiration.
The internal intercostals function exactly in the
opposite manner, functioning as expiratory
muscles becausethey angle between the ribs in
the opposite directionand cause opposite
leverage. (Guyton and Hall , 2011)
SP-C



SP-D






hydrophilic collectin,
Type II epithelial cells and clara cells
Required in the formation of tubular myelin
Hydrophobic protein
Protein clipped from Type II cell
Optimize rapid absorption and spreading
of phospholipids
Hydrophobic
Develops Airway during early gestation
Spreading of Pho