Dr. Hanan Luay
PhD. Physiology
Physiology
The muscle
The muscles are excitable cells; they are machines to convert the chemical
energy to mechanical energy.
The muscle can be excited electrically, mechanically, chemically → action
potential (A.p.).
It differs from the nervous system by the fact that it has a contractile
mechanism which is activated by A.p.
Types of muscle:
1- Skeletal muscles: These are voluntary muscles attach to bones.
Skeletal muscles
Smooth muscles
Cardiac muscles
2- Smooth muscles: Involuntary muscle. It is Muscle of the viscera
(e.g., in walls of blood vessels, intestine, & other 'hollow' structures
and organs in the body).
3- Cardiac muscles: Muscle of the heart. Involuntary.
40% of the body is skeletal muscles and 10% are smooth and cardiac
muscles.
Characteristics of muscle:




excitability - responds to stimuli (e.g., nervous impulses)
contractility - able to shorten in length
extensibility - stretches when pulled
elasticity - tends to return to original shape & length after contraction
or extension
Functions of muscle:
1-motion. 2-maintenance of posture. 3-heat production.
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The skeletal muscle:
It is that type of the muscles that is attached to bones & moves skeleton,
also called striated muscle (because of its appearance under the microscope),
it lacks anatomical and functional connection between individual muscle
fibers, and it is voluntary muscle (under voluntary control).
Morphology:
It is composed of numerous fibers (building units of the muscular system),
which is made up of smaller subunits.
Each muscle fiber extends along the length of the muscle, and each is
innervated by one nerve fiber near the middle of the fiber.
The muscle fibers are arranged in parallel between the two tendon ends, so
that the force of contraction is additive.
The muscle fiber is a cylindrical single cell containing:
-multiple nuclei.
-Cell membrane (sarcolemma) fuses with the tendons at the muscle ends.
-Sarcoplasm (intracellular fluid fills the spaces between the myofibrils {K+,
Phosphate, protein enzymes and mitochondria, sarcoplasmic reticulum which
controls the contraction(rapid contracting muscles means extensive reticula)}
-Other organ cells
-Small muscle fibrils, which consist of filaments that are made up of
contractile proteins (actin and myosin).
Actin and myosin are large polymerized protein molecules, responsible for
actual muscle contraction.
2
The striations:
The myosin and actin filaments interdigitate and cause the myofibrils to
have alternate light and dark bands.
The light bands are only Actin filaments called I bands, they are isotropic to
polarized lights.
The dark bands contain Myosin (twice molecular weight of Actin) called A
bands; they are anisotropic to polarized lights, overlapping with Actin
filaments. (It does not change in contraction), each thick filament is
surrounded by 6 thin filaments in a regular hexagonal pattern.
So the striations are due to difference in the refractive index of the parts of
the muscle fibers.
The I band is divided in the middle by darker Z line (the actin filaments are
attached to the Z disc from which the filaments extend in both directions to
interdigitate with the myosin).
The A band is divided by the lighter H band, in the middle of it a transverse
line called M line.
On the ends of the myosin filaments are small projections called the cross
bridges, which interact with the actin filaments to cause contraction.
The portion of the myofibrils (or the whole muscle fiber) that is between 2
successive Z discs is called Sarcomere.
On contraction, the length of it is about 2 micrometer (the actin completely
overlap the myosin, the tips of actin are just beginning to overlap one
another.
The sarcomere is the smallest functional unit of the muscle; it is the area
between 2 Z lines. It increases in relaxation and decreases in contraction.
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It is composed of 6 polypeptide chains, a/ 2 heavy (wrap spirally around
each other to form double helix called tail, one end of these chains is folded
bilaterally into a globular polypeptide structure called head (2 heads) with 2N
terminals, they contain actin binding sites and a catalytic site that hydrolyse
ATP and, b/ 4 light chains (are parts of the head (help control the function of
the head during contraction).
The tails are bundled together to form the body of the filaments, while many
heads hang outwards from the body.
Part of the body with the head extends to form arms (called the cross
bridges). There are no cross bridges in the middle of myosin filaments
because the hinged arms extends away from the center.
The cross bridges are flexible at 2 points one where the arm leaves the body,
the other where the head attaches to the arm, these called hinges.
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The thin filament is made of actin ,torponin and tropomyosin.
Actin molecules:
Actin filament is made up of 2 chains of globular unit that form a long
double helix and contain binding sites for myosin. It is composed of double
stranded F actin protein molecule made in a helix, each strand is composed
of polymerized G actin molecule ,attached to each one molecule of ADP ,
these are the active sites with which the cross bridges of myosin interact.
lrueitua o iu Mro e
They are located in the groove between the two chains forming long
filaments overlying the binding sits of myosin. So in the resting state they lie
on the top of the active sites of the actin strands so no attraction between
actin and myosin.
Troponin
It is a protein attached intermittently at regular intervals along the sides of
tropomyosin molecules. It is a complex of 3 loosely bound protein subunits:
Troponin I has a strong affinity for actin inhibits the interaction between
myosin to actin.
Troponin T binds troponin to tropomyosin.
Tropomyosin C contains binding sites for calcium ions that initiate
contraction.
The troponin- tropomyosin complex is called the relaxating protein, because
it prevents the binding of actin to the heads of myosin and leads to muscle
relaxation.
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The sarcotubular system:
Because the skeletal muscle fiber is so large, the action potential cannot
flow deep within the muscle fiber to cause maximum muscle contraction,
current must penetrate deeply into the muscle fiber, and this is by:
The T system (transverse tubules): it is a system of transverse tubules in the
form of letter T which is continuous with the membrane of the muscle fiber,
it starts from one side of the cell membrane to the opposite side, so it is
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continuous with the extracellular space, and they contain extracellular fluid
inside ; they are present along the whole length of the muscle fiber and is
responsible for spreading of action potential from the cell membrane to the
interior of the muscle fiber, the electrical currents around them create the
muscle contraction.
The sarcoplasmic reticulum : it forms an irregular system of tubules
surrounding the myofibrils it has an enlarging ends or chambers called
terminal cisterns in close contact with the T system at the junction between
A and I bands.
The arrangement of the T system with the ciatern of the endoplasmic
reticulum at either side called Traid.
The sarcoplasmic reticulum contains excess amounts of calcium ions (in the
cistern) in high concentration which are released when the action potential
occurs in the adjacent tubules. After the contraction has been occurred
,active calcium pump located in the walls of sarcoplasmic reticulum pumps
calcium back to the sarcoplasmic tubules (inside the reticulum there is a
protein called calsequestrin which can concentrate and binds up to 40 times
more calcium ions). In addition to that the terminal cisterns help in muscle
metabolism.
Electrical characteristics of skeletal muscles:
1- The resting membrane potential is – 80 to – 90 mill volt in skeletal muscle
fiber (same as in large mylinated nerve fiber).
2- The electrical changes of the ion fluxes are similar to those of the nerve
fiber during action potential.
3- Duration of the action potential is 1 to 5 milliseconds (5 times longer than
that in mylinated nerve fiber).
4- The conduction velocity is 3 to 5 m/ second (less than that in large
mylinated nerve fiber).
5-Due to the slight difference in the threshold between muscle fibers of the
same muscle and the difference in the distance between the stimulation site
and different muscle fibers, the action potential recorded from the whole
muscle after direct stimulation is proportional to the intensity of the stimulus
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between threshold and maximum intensity (do not obey all or none law for
the whole muscle but not for a single muscle fiber which obey this law).
6- Each single contraction is followed by a single relaxation in response to a
single action potential (simple muscle twitch).
Simple muscle twitch:
Is a single contraction followed by single relaxation in response to action
potential .It is measured usually by a device called Myogram.
The shape is consisted of contraction phase which is preceded by latent
period (lag phase), then there is the relaxation phase.
The shape of the single muscle twitch is:
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Excitation contraction coupling
1- Sliding filament theory:
The process by which depolarization of the muscle fiber initiates contraction
is called excitation- contraction coupling. It occurs in the following steps:
1 – The discharge of motor neuron.
2- An action potential travels along the motor nerve to its ending in the
muscle fiber.
3- Secretion of small amounts of neurotransmitter substance Acetylcholine
(Ach) at the motor end plate.
4-Ach binds to nicotinic receptors on muscle fiber membrane to open Ach
gated channels.
5- Increase in Na and K ions conductance (Na ions diffuse to the interior of
the muscle fiber membrane) and this will initiate a local end plate potential,
and when firing level is reached, action potential is generated and spread
along the whole muscle fiber.
6- The inwards spread of the action potential by the T system of tubules.
7- Release of calcium ions from the terminal cisterns of the sarcoplasmic
reticulum.
8-Calcium will bind to Troponin C molecule this will lead to conformational
changes:
The binding of Troponin I to actin will be weakened.
This allows Tropomyosin to move laterally outside the groove and uncover
the binding sites for the myosin heads.
So Ca ions will act as an inhibitory factor on troponin –tropomyosin
attachment to actin.
ATP molecule will split to produce energy (degenerated to ADP) for the
contraction. 7 Myosin heads are uncovered for each molecule of Troponin
that binds to single Ca ion.
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The formation of cross bridges between actin and myosin heads → sliding of
thin on thick filaments producing shortening (the sarcomere will be
shortened).
The width of A band is constant, whereas Z lines move closer when the
muscle contracted and apart when the muscle stretched.
So during muscle contraction 1- the Z lines move closer to each other,2- the
I band becomes shorter and 3- the A band stays at the same length.
2- The walk- along or Rachet theory of contraction:
This theory suggests that the sliding during muscle contraction is produced
by attaching, breaking and reforming of the cross linkages between actin and
myosin heads, the intensity of the interaction depends on the number of
cross linkages .
After uncovering of the active sites of the actin ,myosin head link to actin at
90 degrees angle(then decreasing the angle because energy liberated)
producing movement by swiveling(pulling) and then disconnect and
reconnect at the next linking site repeating the process in a serial fashion(i.e.
after the head attaches to the active site, it produces profound changes in
the intramolecular forces between the head and the arm , the new alignment
of forces causes the head to tilt towards the arm to drag the actin filament
along with it, automatically after tilting the head breaks away from the active
site, then the head returns to its extended direction , then it combines with a
new active site farther down along the actin filament , the head tilts again to
form another power stroke and then the actin filament moves another step
Each single cycle of attaching, swiveling and detaching shortens the muscle
fiber by 1%of its length.
Each thick filament has about 500 myosin heads, and each of these cycle 5
times /second during rapid contraction. The pulling of the heads of myosin to
actin or the tilt of the myosin head is called the power stroke.
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Power stroke of myosin in skeletal muscle. The myosin
head detaches from actin (top), moves several nm
along the actin strand, and reattaches (middle). The
head then flexes on the neck of the myosin molecule
(bottom), moving the myosin along the actin strand.
Steps in relaxation:
1- After a fraction of a second, the calcium ions are pumped actively back
into the sarcoplasmic reticulum by a Calcium membrane pump (active
transport, needs ATP i.e. both contraction and relaxation need energy) they
are going to diffuse into the terminal cisterns to be released by the next
action potential.
2- The release of calcium ions from Troponin C,
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3- Then cessation of binding between actin and myosin (i.e. tropomyosin
returns to its site) this removal of calcium ions causes the muscle contraction
to stop.
If Ca ions stay in high concentration outside the SR, or if the Ca ions
transport to the SR is inhibited, there will be persistent contraction and no
relaxation even though there are no more action potentials and this will
result in what is called contracture (sustained contraction).
Characteristics of whole muscle contraction:
Types of contraction:
1- Isomertic contraction: is when the muscle does not shorten during
contraction i.e. no change in muscle length, but the tension will increase.
The muscle contracts against a force transducer without decreasing the
muscle length. e.g. trying to lift a heavy object. The work done here is zero,
because no movement.
The isometric contraction records the changes in force of the muscle
contraction itself, it is used to compare the functional characteristics of
different muscle types.
2- Isotonic contraction:
It is the contraction that causes shortening of the muscle length and the
muscle has the same tension. e.g. lifting an object by contracting the biceps
muscle.
Here there is work done because there is movement.
The muscle shortens against a fixed load, and its characteristics depends on
the load against which the muscle contracts and on the inertia of the load.
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The summation of contraction:
It means the adding together of individual twitch contractions to increase
the intensity of overall contraction. Because the contractile mechanism has
no refractory period, repeated stimulation (i.e. increase the frequency)
before relaxation can produce additional activation of the contractile
elements and a response will be added to that already present, this is called
"summation of contraction". It depends on the frequency of stimulation it
occurs in 2 ways:
1 – Multiple fiber summation (increasing the number of motor units
contracting at the same time). When the central nervous system sends a weak
signal to contract a muscle, the smaller motor units of the muscle may be
stimulated in preference to the larger motor units. Then, as the strength of the
signal increases, larger and larger motor units begin to be excited as well.
2- Frequency summation and tetanization, with rapid repeated stimulation,
activation of the contractile mechanism occurs repeatedly before any
relaxation occurs and the response fuses into one continuous contraction
and the whole contraction appears to be smooth called Tetanus (by
increasing the frequency of contraction).
During tetanus the tension developed is 4 times than the individual
contraction.
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At slightly higher frequencies, the strength of the muscle contraction
reaches maximum, so any additional increase in frequency beyond that point
has no further effect in increasing the force of contraction, this is because
enough Ca ions are maintained in the sarcoplasm ,even between action
potentials so will not allow relaxation to happen.
But if a lower frequency is used, there will be a period of incomplete
relaxation between the summated stimuli; this condition is called incomplete
tetanization or clonus.
Treppe(staircase effect):
It is another type of graded response occurs when a muscle begins to contract
after a long period of rest. When a series of maximal stimuli is delivered to
skeletal muscle at a low frequency (just below the tetanizing frequency),
there is an increase in the tension developed during each twitch (the second
more than the first and the third more than the second etc.) until, after
several contractions, a uniform tension per contraction is reached. It is
believed to be due to increased availability of Ca2+ for binding to troponin C.
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Effect of muscle length on the force of contraction:
When the length of the unstimulated muscle fiber is changed (the muscle
stretched but not stimulated) this is called passive tension. It exists because
the muscle and its connective tissues have some elasticity.
Passive tension curve is the curve plotted to include the changes in tension
against the changes in the muscle length. It shows that, as the length
increases, it rises sharply.
The total tension curve shows the total tension against the passive tension,
we will see a sharp increase up to a maximum value, then the curve declines.
If we measure the distance between the two curves we will see the active
tension curve which is similar in shape with the total tension curve but has a
lower peak. So the active tension recorded when the muscle contracts.
From these curves we will see that the maximum tension occurs when the
muscle length is at its resting length i.e. the sarcomere length is about 2
micrometer (relaxed state). Shortening or contraction of the muscle will
reduce this tension. This is because the maximum number of interaction
between actin and myosin occurs at the resting length .Stretching of muscle
fiber (increase in its length) will cause less actin to myosin interaction i.e.
bigger sarcomere with a large gap in the middle .Shortening of the muscle
fiber, causes smaller sarcomere and actin filament overlap, so less actin to
myosin interaction sites.
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Energy sources and metabolism:
Contraction of the muscle depends on energy supplied by ATP.
In general the source of energy is the metabolism of carbohydrates and
lipids.
Most of the energy required for Physical activity (contraction, relaxation) or
walk along mechanism, and small amounts are required for:
1- Pumping of Ca ions from the sarcoplasm to the sarcoplasmic reticulum
after the contraction is over.
2- Regeneration of ATP.
ATP split to ADP, then ADP rephosphorlated to ATP.
3- Removal of lactic acid.
4- Heat production.
Sources of energy for the re phosphorlation:
1- Substance called phosphocreatine (high energy phosphate bond)
ADP+P→ATP
This compound synthesized during resting conditions .During exercise this
compound hydrolyse at the junction between actin and myosin releasing
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energy ,this reaction is catalyzed by the enzyme phosphorylcreatinine at the
mitochondria and myosin heads.
ADP+Phosphocreatinin→ creatinine + ATP
2- Glucose: it is supplied by the blood and undergoes series of reactions
forming finally Co2, H2o and Energy.
3- Glycolysis of glycogen stored in the muscle cells: enzymatic break down of
glycogen to pyruvic which has 2 pathways in the presence of O2, it enters
citric acid cycle (crips cycle), then the respiratory chain to form co2, H2O and
large amount of energy, (aerobic Glycolysis). But in the absence of O2(like in
prolong contraction), pyruvate is reduced to lactate and lactic acid and small
amount of energy.
4- The free fatty acids(FFA) (gives double the energy that glucose gives)
skeletal muscles take the FFA in the blood and oxidized to give Co2, H2o and
ATP (the use of FFA mainly at rest and during recovery after contraction).
The oxygen debt mechanism:
During exercise the blood vessels dilates to provide enough O 2 for the
muscle, the energy is supplied by aerobic glycolysis ,but if the exercise is
sever or continues for longer periods, the anaerobic glycolysis contribute also
to provide energy ,but it is self limiting ,because lactic acid will diffuse to the
blood it will lower the PH ,accumulate in the muscle causing muscle
exhaustion .So after the exercise there will be a period of hyperventilation to
produce the extra amount of O2 in order to remove the lactic acid and to
rebuild the storage of ATP and phosphorylcreatinin . This extra amount of O2
taken to replace the demand required more than that supplied by the
aerobic glycolysis during exercise is called the oxygen debt mechanism.
Trained persons need less period of hyperventilation because they have
smaller oxygen debt mechanism (i.e. he has endurance, he can use the
muscle to perform the job better).
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Heat production in the muscle:
This is produced as:
1- Resting heat: liberated during resting stage.
2- Initial heat which is produced during activity and it is divided into:
a- Activation heat: produced during contraction, from the actin –myosin
interaction.
b - Shortening heat: produced during shortening (isotonic contraction), due
to the changes in muscle fiber structure during shortening.
In isotonic contraction there are both activation and shortening heat but in
isometric there is only activation heat.
3- Recovery heat: liberated by the metabolic processes that restore the
muscle fiber to its precontraction state and it is rather equal to the initial
heat.
4- Relaxation heat: liberated because work should be done to return the
muscle to its original length (after isotonic contraction) in addition to the
recovery heat.
Types of muscle fibers:
3 types according to the differences in enzyme activity, metabolism and
contractile properties:
1- Type I fibers: these are darker than other muscles called Red muscles or
the slow fibers, they response slowly and have longer duration of
action(resist fatigue). They are specialized for long slow sustained
contraction, supplied by slow conducting fibers. e.g. muscles in the back and
in the lower limbs which are used to maintain posture. They are small fibers,
have more extensive blood supply to supply high oxygen, and high number of
mitochondria and large number of myoglobulin.
2- Type II b: called the white muscles or the fast fibers, they are innervated
by large mylinated fibers, they have short duration of action (fatigue quickly)
.so they are specialized for fine skilled movement e.g. muscles of the hand
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and the extra-ocular muscles. They are large fibers and have extensive
sarcoplasmic reticulum for rapid release of Ca ions, large amounts of
glycolytic enzymes for rapid release of energy, they have less extensive blood
supply and fewer mitochondria and less myoglobulin.
3- Type II a: this is rare type in human, has properties similar to type I, and
other properties to type II.
The motor units:
The motor unit means all the muscle fibers innervated by a single nerve fiber
.i.e. the axon of a single motor neuron divides to supply many muscle fibers.
There are 2 types of motor units:
1- Small motor units: contain 3-6 muscle fibers, concerned with fine graded,
precise movement, like movements of the hand. They are Small muscles that
react rapidly and whose control must be exact have more nerve fibers for
fewer muscle fibers (2-3 muscle fibers for each motor unit, e.g. laryngeal
muscles).
2- large motor units :contain usually 120-165 muscle fibers ,like muscles of
the back ,for the sustained form of activity. These are large muscles that do
not need fine control (e.g. soleus muscle), may have several hundreds of
muscle fibers in the motor unit.
Each motor unit is of one type i.e. innervates one type of muscle, but when
a nerve to slow muscle is cut and replaced by a nerve to fast muscle ,the slow
muscle after a period of time becomes fast.
The muscle fibers in each motor unit overlap other motor units in
microbundles of 3-15 fibers. This interdigitation allows the separate motor
units o contract in support of one another rather than as individual segment.
Denervation :
Means the deprivation of muscles from the nerve supply, the following
effects will happen:
1- Immediate loss of muscular activity called flaccid paralysis.
2- Abnormal excitability of muscle fiber with increase sensitivity to circulate
Ach (deneravation hypersensitivity), this result in fine irregular contraction of
individual muscle fiber (fibrillation).
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Up to these 2 points, if the nerve fiber regenerates these 2 effects will
disappear.
3- Atrophy of the muscle: prolong denervation results in degeneration of the
muscle fibers and replacement by fibrous tissue, this result in reduction of
muscle size called wasting (because of decay of contractile proteins). If after
2 months the nerve supply back, full return of function .but after 3 months
the return back of muscle function is less, and after 1-2 years, no return of
muscle function.
All these features are of lower motor neuron lesions which is the effect from
the spinal cord to the muscle. Above that is called upper motor neuron
lesion.
Contracture:
This is persistent sustained contraction of the muscle without an action
potential, causing no relaxation. It occurs due to the increase level of
extracellular calcium.
Rigor:
When the muscle fiber is completely depleted of ATP and phosphoryl
creatinin, they develop a state of complete contraction causing increase
rigidity after death because no ATP available for relaxation ,in this state Rigor
mortis ,almost all the myosin heads attached to the actin in an abnormal
fixed and resistant way.(it occurs more rapidly in high temperature).
Muscle fatigue:
Prolonged and strong muscle contraction lead to muscle fatigue. This results
from:
-Depletion of glycogen stores in the muscle (inability of the contractile and
metabolic processes to continue supplying the same work).
-Diminished transmission in the NMJ.
- Interruption of blood supply or flow results in nutrient and O2 deficiency.
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Physiology
Smooth muscles
Dr. Hanan Luay
Contraction and excitation of smooth muscles:
Morphology:
1- Lack visible cross striations.
2- Actin and myosin are present.
3- There are dense bodies instead of Z lines.
4- Contain tropomyosin but toponin absent.
5- Poorly developed sarcoplasmic reticulum
6- Few mitochondria so depend on glycolysis in their metabolism.
Types:
1- Visceral smooth muscle (unitary or single unit).
2- Multi-unit smooth muscle.
Unitary or visceral smooth muscles (or syncytial smooth muscles):
It occurs in large sheets, has low-resistance bridges between
individual muscle cells, and functions in a syncytial fashion, they
contract together as a single unit. It is found primarily in the walls of
hollow viscera.
The cell membranes are joined by gap junctions through whom ions
can flow freely from one muscle cell to another.
Multi-unit smooth muscle:
It is made up of individual units without interconnecting bridges. It is
found in structures such as the iris of the eye, in which fine, graded
contractions occur. It is not under voluntary control.
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Electrical & Mechanical Activity:
Visceral smooth muscle:
It is characterized by the instability of its membrane potential and by the
fact that it shows continuous, irregular contractions that are independent of
its nerve supply.
This maintained state of partial contraction is called tonus or tone.
There is no true "resting" value for the membrane potential, but it averages
about -50 mV, when the muscle active it becomes low and high during
inhibition.
Superimposed on the membrane potential are waves of various types:
These are:
-Slow sine wave-like.
-Sharp spikes.
-Pacemaker potentials.
Thus, the excitation-contraction coupling in visceral smooth muscle is a very
slow process compared with that in skeletal and cardiac muscle, in which the
time from initial depolarization to initiation of contraction is less than 10 ms.
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Molecular Basis of Contraction;
1-Binding of Ach to Muscarinic reseptors.
2-Ca2+ influx from the ECF via Ca2+ channels.
3-Ca2+ binds to calmodulin, and the resulting complex activates calmodulindependent myosin light chain kinase. This enzyme catalyzes the
phosphorylation of the myosin light chain.
4-The phosphorylation allows the myosin ATPase to be activated, and actin
slides on myosin, producing contraction.
5-Myosin is dephosphorylated by myosin light chain phosphatase in the cell.
6-Relaxation of the smooth muscle.
7- Dephosphorylation of myosin light chain kinase does not necessarily lead
to relaxation of the smooth muscle. a latch bridge mechanism by which
myosin cross-bridges remain attached to actin for some time after the
cytoplasmic Ca2+ concentration falls. This produces sustained contraction
with little expenditure of energy, which is especially important in vascular
smooth muscle.
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Stimulation of the smooth muscles:
1-Stretch:
It contracts when stretched in the absence of any extrinsic innervations.
Stretch is followed by a decline in membrane potential, an increase in the
frequency of spikes and a general increase in tone.
2-Chemical mediators:
Epinephrine or norepinephrine :
The membrane potential usually becomes larger, the spikes decrease in
frequency, and the muscle relaxes.
Norepinephrine exerts both α and β actions on the muscle.
The β action, reduced muscle tension in response to excitation, is mediated
via cyclic AMP and is due to increased intracellular binding of Ca2+.
The α action, which is also inhibition of contraction, is associated with
increased Ca2+ efflux from the muscle cells.
Acetylcholin:
Has an effect opposite to that of norepinephrine on the membrane potential
acetylcholine causes the membrane potential to decrease and the spikes
become more frequent , with an increase in tonic tension and the number of
rhythmic contractions.
Released by stimulation of cholinergic nerves (similar to cold and stretch in
vitro).
3- Other chemicals: like progesterone which decreases the activity and
estrogen which increase it (in uterine smooth muscles).
4-Thermal stimuli: like cold which causes spasm.
Function of the Nerve Supply to Smooth Muscle:
It has two important properties: (1) its spontaneous activity in the absence
of nervous stimulation, and
(2) Its sensitivity to chemical agents released from nerves locally or brought
to it in the circulation.
The function of the nerve supply is not to initiate activity in the muscle but
rather to modify it (control).
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It has dual nerve supply from 2 divisions of the autonomic nervous system.
Stimulation of one division usually increases smooth muscle activity, whereas
stimulation of the other decreases it.
(i.e if noradrenergic increase ,the Acetylcholine decrease and visa
versa).
Relation of Length to Tension; Plasticity:
It is the variability of the tension it exerts at any given length. If a piece of
visceral smooth muscle is stretched, it first exerts increased tension, if the
muscle is held at the greater length after stretching, the tension gradually
decreases. It is consequently impossible to correlate length and developed
tension accurately.
In intact humans, For example, the tension exerted by the smooth muscle
walls of the bladder can be measured at different degrees of distention as
fluid is infused into the bladder via a catheter Initially there is relatively little
increase in tension as volume is increased, because of the plasticity of the
bladder wall. However, a point is eventually reached at which the bladder
contracts forcefully. This phenomenon is called stressrelaxation and reverse
stress-relaxation. Its importance is that its ability to return to nearly its
original force of contraction seconds or minutes after it has
been elongated or shortened
MULTI-UNIT SMOOTH MUSCLE:
-It is nonsyncytial .
-Contractions do not spread widely through it (discrete, fine and more
localized).
- Very sensitive to circulating chemical substances and is normally activated
by chemical mediators (acetylcholine and norepinephrine).
- Norepinephrine tends to persist in the muscle and to cause repeated firing
of the muscle after a single stimulus rather than a single action potential.
Therefore, the contractile response produced is usually an irregular tetanus
rather than a single twitch.
The simple muscle twitch resembles the twitch contraction of skeletal muscle
except that its duration is ten times longer.
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The differences between the three types of the muscles:
Skeletal
muscles
Smooth
muscles
Cardiac
muscles
voluntary
in voluntary
in voluntary
Site of action
Attached to bones
In the walls of viscera
In the heart
Morphology
striated
Not striated
striated
The Control
Spindle shaped
cell shape
Long cylindrical
Speed of
contraction
Fast -slow
Very slow(cross-bridge
heads have less
ATPase activity than in
skeletal muscle).
Yes for some
smooth muscles
No
Capable of
spontaneous
contraction
Effect of nerve
stimulation
Excitation(control of
Excitation or
contraction)
inhibition(modulation
of contraction)
Membrane
refractory period
Nuclei in each cell
Connection
between cells
Cylindrical and
branched
Short
slow
yes
Excitation or
inhibition
long
many
No anatomical or
functional connections
26
single
single
Connected by gap
junctions and bridges
Connected by
intercalated discs
Dr. Hanan Luay
PHYSIOLOGY
Physiology of nerve
PhD Physiology
Muscle and nerve are the excitable tissues that we are going to talk
about; they are excitable because they have electrical phenomenon i.e. they
are polarized.
The nervous system in general is divided into:
The central nervous system (CNS) which means the brain and the spinal cord.
The peripheral nervous system (PNS) which include the somatic and the
autonomic nervous system.
The neurons are excitable cells specialized for reception, integration and
transmission of nerve impulses.
The neurons in general are composed of 3 major parts:
1- The soma, which is the main body of the neuron, contains specialized
cytoplasm, single nucleus and other granules.
2- Dendrites (2-7) which are great number of branching projections from the
soma that conduct towards the cell body.
The soma and the dendrites form a large area which is specialized for
reception, and the processes of other neurons terminate at this area to form
what is called synapses by which the neurons communicate with each other.
3- Single axon, which extends from the soma membrane to the periphery, it
conducts away from the cell body. It starts from a thick area called the axon
hillock, after that the part of the axon is called the initial segment (thinner),
then the axon remains the same diameter until its termination (axon
knob),where the chemical substance (neurotransmitter ) is released in
response to nerve impulse.
27
Each axon in the peripheral nervous system after a short distance from its
origin is covered by a series of schwann cells which are the supporting cells of
the peripheral nervous system; they form the myline sheath of the nerve.
The myline is a lipoprotein complex formed of many layers, and it is not
continuous, it is interrupted by a small exposed area of 1 microne in length
which is called "Node of Ranvier" that forms the myline sheath between 2
adjacent nodes.
The process of myline sheath forming (mylination) involves the following:
1- The Schwann cell membrane first envelop the axon 2-then the cell
rotates around the axon many times laying down multiple layers of Schwann
cell membrane containing the lipid substance sphingomyline which is an
electrical insulator decreasing the ion flow through the membrane, this
sheath has a main role in conduction because, it increases the velocity of
conduction 5- 50 times, so diseases like multiple sclerosis causes
demylination and sever nerve defect which block conduction.
At the junction of 2 successive Schwann cells along the axon there is an area
that is not insulated where ions can flow called the Node of Ranvier.
Not all the nerve fibers are mylinated, some are not mylinated but
surrounded by Schwann cells without the deposition of myline (axons more
28
than 1 micrometer in diameter is mylinated, but less than 0.5 micrometer in
diameter are not mylinated).
In the CNS the mylination is done by other cells which are called the
oligodendrocytes which send multiple processes to the number of adjacent
nerve fibers forming the myline sheath of many axons (by one cell).
In addition to the neurons, the nervous system contain glial cells (neuroglia),
there are 10- 50 times as many glial cells as neurons.
In the CNS there is microglia, oligodendrocytes and astrocyte. The
astrocytes support the CNS and transport substances between the neurons
and the blood vessels and contribute in making blood brain barrier(BBB).
Oligodendrocytes produce the myline sheath. Microglia, provide support and
phagocyte bacteria.
TYPES OF NEURONS:
Structurally divided into;
1- Bipolar neurons: the cell body has only 2 processes, one is the axon and the other
is the dendrite e.g in nose, eye, and ears.
2- unipolar neurons: has a single process extending from the cell body then after a
short distance it will divide into 2 branches.
3- 3- multipolar has many processes arising from the cell body, only one is the axon
,the rest are the dendrites.
29
Functionally they are divided in to:
1- Sensory 2- motor and 3- interneuron.
Functional organization of the neuron:
1 - The receptor zone or dendritic zone: it represents the site for the
reception of nerve signals, and much local potential are going to be formed in
this area.
2- The initial segment zone: it is the site and origin of the conducting
impulses; it is the site where the nerve impulses are generated.
3- The axonal zone: or called the transmitting zone where the nerve impulses
are propagated and transmitted.
4- The nerve ending zone: the site where the nerve impulses causes the
release of the neurotransmitter to affect other neuron or muscle fiber.
The neurons are secretory .There is synthesis of proteins which are
transmitted by the axoplasmic transport from the cell body to the axon
terminal and it is of 3 types:
1- Fast one (400mm/day) it is type moves cell organelles from the soma to
the axon terminals.
2- Slower axoplasmic flow (6-10 mm/day), this type moves the cytoskeletal
elements and soluble proteins.
3- Slowest axoplasmic flow (3-5mm/day): this type moves the neurofibrllar
proteins and tubules.
30
There is another type of transport in the neuron, which is called retrograde
transport: this type is for the transport of substances which are taken by the
nerve ending, and nerve growth factor and some viruses from the endings to
the soma (200mm/day).
Neural communication:
The neurons communicate with each other by 2 types of communication:
1- The electronic potential (generator potential): Local, nonpropagated
potentials called, synaptic, generator, or electrotonic potentials
2- The action potential (nerve impulse).
Both types are physiochemical disturbances due to change in conduction
across the cell membrane. The first type is a local non-propagated potential
used for communication between neurons which are very close to each other
e.g. the brain and the eye, where large number of information are sent or
received by adjacent cells.
The second type is a propagated disturbance used to send information for
long distances without any loss of energy.
The electrical phenomena of the nerve cells:
There are electrical changes, these changes can be recorded using 2
microelectrodes which pick up the electrical energy, connected to an
amplifier and then to cathode ray oscilloscope. Which is a type of meter used
to respond rapidly to rapid membrane potential change to measure the
electrical events in living tissue.
31
As long as the electrodes are outside the nerve membrane, the recorded
potential is zero, which is the potential of the extracellular fluid, as the
electrode passes inside, the voltage decreases (to -70mv for the nerve and 90 mv for skeletal muscle and -50mv for the smooth m.) when it passes to
the other side the potential returns to zero.
The ionic basis of the resting membrane potential:
The resting membrane potential of a large nerve fiber when not
transmitting nerve signal is about -90 mv i.e. the potential inside the fiber is
90 mv ,more negative than the outside (actually it is -70 mv in small nerve
fibers, but -90 mv in large nerves).
So the origin of the resting membrane potential is due to the contribution of
the following factors:
1- The contribution of the K ion diffusion potential.
2 - The contribution of the Na ion diffusion potential through the nerve
membrane.
3- The contribution of the Na_ K ion pump.
Regarding the leakage of K and Na ions through the nerve membrane It is
because of the concentration gradient across the cell membrane, Na ions try
to pass inside the cell down their concentration gradient .K ions try to pass
outside the cell down the concentration gradient, but the channels in the cell
membrane are more permeable to K ions than to Na ions about 100 times.
Equilibrium potential of an ion is the value of transmembrane voltage at
which the electric force generated by diffusional movement of the ion down
its concentration gradient becomes equal to the molecular force of that
32
diffusion. The equilibrium potential for any ion can be calculated using the
Nernst equation. For example, for potassium ions will be as follows
E (K+) =_ (2.3 RT) log [K +] o
ZF
[K+] i
Or Nernst potential for any univalent ion at normal body temperature of
98.6°F (37°C):
E=- 61 log Concentration inside
Concentration outside
Where:
E K+ is the equilibrium potential for potassium, measured in volts
R is the universal gas constant.
T is the temperature
Z is the number of charges of the ion.
F is the Faraday constant
[K+] o is the extracellular concentration of potassium.
[K+] i is the intracellular concentration of potassium
So this equation is to calculate the membrane potential, if only one type of
ion is penetrating the membrane.
Goldman equation is used in cell membrane physiology to determine
the equilibrium potential across a cell's membrane taking into account all of
the ions that are permeable through that membrane .
The Na-K ion pump:
It pumps Na ions to the outside of the cell and K ions to the inside, this is an
electrogenic pump (also it requires energy), because more positive charges
are pumped to the outside than inside (3 Na ions to the outside for each 2 K
ions to the inside) i.e. Na ions accumulate outside the cell while K
accumulates inside the cell, leaving a net deficit of positive ions inside leading
to a negative potential across the membrane. It also causes large
concentration gradient for Na and K ions across the resting membrane
potential, these gradients are:
Na ions (outside) 142 meq/L
Na ions (inside) 14 meq /L
SO THE RATIO OF THIS ION FROM INSIDE TO OUTSIDE IS 0.1
K ions (outside) 4 meq/L
K ions (inside) 140 meq/ L
33
SO THE RATIO OF THIS ION FROM INSIDE TO OUTSIDE IS 35.0
In addition to the Na –K pump and ion fluxes there are proteins with
negative charges inside the cell; all of these give the membrane a negative
charge inside. The net result polarization is negative inside and positive
outside.
Nerve action potential:
Nerve signals (are coded information) transmitted by action potentials
which are rapid changes in the membrane potential in response to stimulus
that spread rapidly along the nerve fiber membrane. The stimulus could be
electrical, chemical and thermal.
So if we apply a stimulus and record the changes in the membrane potential
we will notice the following.
34
Sudden change from the normal resting negative membrane potential (-70
mv) to a positive potential, then return back to the negative potential. The
action potential moves along the nerve fiber until it comes to the fiber end.
The successive stages in action potential are as follows:
1-The resting stage: this is the resting membrane potential ,before the action
potential begins i.e. the membrane is polarized, due to the presence of
negative potential (-90 mv).
When the stimulus is applied, there is a brief irregular deflection of the
baseline, the stimulus artifact. This artifact is due to current leakage from the
stimulating electrodes to the recording electrodes.
2- The latent period (latency): is also an isoptential state, the membrane
here is still polarized. It is the interval starting from the beginning of
stimulation to the beginning of potential changes. This period corresponds to
the time taken by the stimulus to pass along the nerve fiber to the recording
site so it is proportional to 1-The distance between the stimulus site and the
recording site 2- Inversely to the conduction speed of the axon.
3- The depolarization stage: the membrane suddenly becomes very
permeable to Na ions, because of opening of Na ion channels, allowing large
amounts of Na ions to diffuse to the interior of the axon. The potential
increases rapidly in the positive direction (it rises about 15 mv) called
depolarization. Then there will be overshooting beyond the zero level
(especially in large nerves but in the small ones it merely reaches zero),
sometimes it reaches a value of + 35 mv. So the permeability to Na ions
rapidly increase called firing level.
35
the overshooting not exceeds 35mv because the driving forces that
causes Na ions influx during depolarization after opening of the channels
(concentration gradient) will be reduced due to the increase in Na ion
electrical gradient from inside to the outside, and when the Na ions
equilibrium potential is reached, the Na influx stops (equilibrium potential is
when influx =efflux, so the net movement is zero).
The equilibrium potential for Na ions is +60 mv .(according to Nernest
equation)Na try to reach it but because the increase in its conductance is
short so its channels close or inactivated rapidly ,also the direction of the
electrical gradient will be reversed ,so the action potential will stop at +35mv.
So three reasons responsible for the fact that Na will not reach to its
equilibrium potential.
4- The repolarization stage:
After 10,000ths of a second, the Na ion channels begin to close and the K
ion channels open(i.e. K ion channels delayed after that of Na ), then rapid
diffusion of K ions to the exterior which reestablish the normal negative
resting membrane potential which is called repolarization.
The repolarization is rapid until 70%, after that it becomes slower until
reaching the resting membrane potential.
36
The sharp rise and the rapid fall of the action potential is called the spike
potential (lasts for 1-2 m seconds), and the last 30% of repolarization which
is slow is called after depolarization (lasts for 4ms). During this period the
membrane potential will not stop at the resting membrane potential (-70
mv), but reduces further 1-2 mv below it, then return to the resting potential
after a period of 40 ms, this period called after hyperpolarization. It occurs
because K ion try to reach its equilibrium point which is -90 mv, also the slow
closure of the K ion channels contributes to this period.
Decreasing the external Na+ concentration decreases the size of the action potential
but has little effect on the resting membrane potential, since the permeability of the
membrane to Na+ at rest is relatively low. Conversely, increasing the external K+
concentration decreases the resting membrane potential (becomes less negative) so the
threshold is reached with less intense stimulus than usual (convulsions may happen).
A decrease in extracellular Ca2+ concentration increases the excitability of nerve and
muscle cells, because Ca ions are necessary to close the Na ion channels ,so if Ca ions are
deficient ,Na ion channels remain open (spasm in the muscle or tetany). Conversely, an
increase in extracellular Ca2+ concentration "stabilizes the membrane" by decreasing
excitability.
Among the most important stabilizers are the local anesthetics, including procaine and
tetracaine. Most of these act directly on the activation gates of the sodium channels,
making it much more difficult for these gates to open, thereby reducing membrane
excitability.
Orthodromic & Antidromic Conduction:
An axon can conduct in either direction. When an action potential is
initiated in the middle of it, two impulses traveling in opposite directions are
set up by electrotonic depolarization on either side of the initial current sink.
In a living animal, impulses normally pass in one direction only, i.e, from
synaptic junctions or receptors along axons to their termination. Such
37
conduction is called orthodromic. Conduction in the opposite direction is
called antidromic. Since synapses, unlike axons, permit conduction in one
direction only, any antidromic impulses that are set up fail to pass the first
synapse they encounter and die out at that point.
Biphasic Action Potentials
If both recording electrodes are placed on the surface of the axon, there is no potential
difference between them at rest. When the nerve is stimulated and an impulse is
conducted past the two electrodes, a characteristic sequence of potential changes
results. As the wave of depolarization reaches the electrode nearest the stimulator, this
electrode becomes negative relative to the other electrode .When the impulse passes to
the portion of the nerve between the two electrodes, the potential returns to zero, and
then, as it passes the second electrode, the first electrode becomes positive relative to
the second.
Therefore, the record shows an upward deflection followed by an
isoelectric interval and then a downward deflection. This sequence is called a biphasic
action potential.
Properties of the action potential:
1 – Threshold: is the minimal intensity of the stimulus required to excite the
nerve and to produce action potential, if we apply subthreshold stimulus,
there is no action potential .The threshold of axon depends on:
1 -Type of the axon.
38
2- Temperature.
If the stimulus is weak, it will disturb the membrane locally and called
acute local potential. So even weak stimulus causes a local potential change
at the membrane, but the intensity of the local potential must rise to the
threshold level before the action potential is set off.
2- Self –reinforcement (regeneration): the action potential serves to conduct
nerve impulse with the same strain along the full length of axon, i.e. the
action potential has the same size and shape without any energy loss.
3- The all or none law: the action potential occurs at constant size and shape,
regardless of the strength of the stimulus, if the stimulus at or above the
threshold, and there will be action potential. Once threshold intensity is
reached, action potential is produced. Further increases in the intensity of a
stimulus produce no increment in the action potential. The action potential
fails to occur if the stimulus is subthreshold in magnitude (the none part),
and it occurs if the stimulus is at or above threshold intensity. So for the
nerve impulse to continue propagated, the ratio of the action potential to the
threshold of excitation must be more than 1, this great than 1 requirement is
called safety factor.
4- The refractory period (RP): it is the time or interval during which the axon
or nerve fiber is incapable of firing a second action potential when a second
stimulus is applied.
During the period from the firing level up to the end of the first third of
repolarization, the membrane is completely refractory to further stimulation.
This is called the absolute refractory period, and no stimulus no matter how
strong can excite the membrane and initiate an action potential. The reason
for that is that almost all Na channels are inactivated and no stimulus can
reopen them, until the membrane is repolarized .From the end of the
absolute refractory period, up to the start of after hyperpolarization, the
membrane is able to fire second action potential but with stronger stimulus
than normally is required, this is called the relative refractory period which
occurs because:
a- Some Na channels during this period are opened and others are closed, so
a stronger stimulus than normal is needed to open these channels required
to trigger an action potential.
b- During the relative RP, the conductance to K is increased which opposite
the depolarization of the membrane and so stronger stimulus is needed.
The refractory period controls the rate at which a membrane can fire i.e
frequency (long refractory period means slow firing).
5- Propagation of action potential:
39
The nerve cell is polarized at rest, when a point on the membrane is
stimulated and action potential is initiated, the polarity of the membrane is
abolished and reversed .The action potential at one point will excite the
adjacent portions of the membrane which leads to propagation of action
potential. So the propagation of action potential occurs in all directions away
from the stimulus until the whole membrane depolarized.
If the nerve excited in the middle → increase permeability to Na→local
circuit of current flow from the depolarizing area to the adjacent area, so the
positive charges from the area in front and behind the action potential will
flow into the area of negativity represented by the action potential(current
sink),this will decrease the polarity of the membrane and when the firing
level is reached ,a propagated action potential occurs ,this sequence of
events moves regularly along the unmylinated axon to reach its end ,thus the
propagation of nerve impulse is due to circular current flow and successive
depolarization to the firing level .Once the action potential moves it does not
depolarize the area behind it because this area is refracted .
40
In mylinated nerve fiber, conduction also depends on similar pattern of a
circular current flow, but since myline is an effective isolator, the current
flow through it is negligible, and instant depolarization jump from one node
to the other (i.e. the electrical currents flow from through the surrounding
extracellular fluid, outside the myline sheath, as well as through the
axoplasm inside the axon from node to node). The Voltage-gated Na+
channels are highly concentrated in the nodes of Ranvier and the initial
segment in myelinated neurons. this type of conduction is called salutatory
conduction. It has 2 advantages: first it causes depolarization process to
jump long intervals along the axis of the nerve which increase the velocity of
transmission in mylinated fibers as much as 5-50 folds. Second this
conduction conserves energy for the axon because the node depolarization
allowing 100 times less loss of ions than otherwise be necessary (so less
metabolism for re-establishing Na and K ions concentration difference across
the membrane.
41
6- Accommodation to slow depolarization (failure to fire despite high
voltage):
When the nerve cell depolarized slowly the firing level may pass without
an action potential being fired, this process called accommodation (Slowly
rising currents fail to fire the nerve because the nerve adapts to the applied
stimulus). During slow depolarization, some of the Na channels which are
opened will have enough time to close before the threshold potential being
reached, in addition K ion channels will have enough time to open during
slow depolarization, this tends to repolarize the membrane and the
threshold will not be reached.
Electrotonic Potentials, Local Response, & Firing Level
Although subthreshold stimuli do not produce an action potential (none
propagated); they do have an effect on the membrane potential. It is a
localized depolarizing potential change that rises sharply and decays
exponentially with time. It is proportional to the magnatitude of the stimulus.
So it loses intensity as it spreads, and its spread is graded. It is important to
contrast this with the all-or-none propagation of the action potential down
the axon of the neuron.
It could be cathodal (produced at the cathode) which are positive
depolarizing potentials causing excitation, while the anodal inhibit the
impulse formation causing hyperpolarization. The importance of this
potential is that in the CNS, the information is exchanged between adjacent
cells by this type. The algebraic summation of inhibitory and stimulatory
potentials determines the state of excitability of the neurons.
42
Energy source and production in the nerve fiber:
The major part of the energy requirement of nerve—about 70%—is the
portion used to maintain polarization of the membrane by the action of Na+K+ ATPase. During maximal activity, the metabolic rate of the nerve doubles
the normal. The heat produced by the nerve is resting heat (during
inactivation), and the recovery heat (follows activity) which is about 30 times
more than the initial heat (during action potential).
43
The mixed nerve:
Peripheral nerves in mammals are made up of many axons bound together
in a fibrous envelope called the epineurium. (The peripheral nerves are
called mixed because they contain both motor and sensory nerves or
histologically speaking mylinated and unmylinated). The thresholds of the
individual axons in the nerve and their distance from the stimulating
electrodes vary. With subthreshold stimuli, none of the axons are stimulated
and no response occurs. When the stimuli are of threshold intensity, axons
with low thresholds fire and a small potential change is observed. As the
intensity of the stimulating current is increased, the axons with higher
thresholds are also discharged. The electrical response increases
proportionately until the stimulus is strong enough to excite all of the axons
in the nerve. (So it does not obey the all or none law). The stimulus that
produces excitation of all the axons is the maximal stimulus, and application
of greater, supramaximal stimuli produces no further increase in the size of
the observed potential.
Compound Action Potentials
Another property of mixed nerves, as opposed to single axons, is the
appearance of multiple peaks in the action potential. The multiple peaked
action potential is called a compound action potential. It has a unique shape
because a mixed nerve is made up of families of fibers with various speeds of
conduction. Therefore, when all the fibers are stimulated, the activity in fastconducting fibers arrives at the recording electrodes sooner than the activity
in slower fibers; and the farther away from the stimulating electrodes the
action potential is recorded, the greater is the separation between the fast
and slow fiber peaks. The number and size of the peaks vary with the types of
fibers in the particular nerve being studied.
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NERVE FIBER TYPES & FUNCTION:
In general the nerve fibers differ in their conduction speed of the impulse,
and this difference is due to:
1 -The difference in diameter: the greater the diameter of a given nerve
fiber, the greater its speed of conduction.
2- Presence of myline sheath.
So the nerve fibers are classified into different types by 2 systems of
classifications:
A –General system: 3 types according to the peaks produced during
compound action potential:
A, B, and C groups, further subdividing the A group into α(the fastest), β, γ,
and δ(the slowest) fibers.
B- Numerical system (Ia, Ib, II, III, IV).
Fiber Type
A
α
β
γ
δ
B
Function
Fiber
Diameter
(μm)
Proprioception;
12-20
somatic motor
Touch, pressure
5-12
Motor to muscle 3-6
spindles
Pain, cold, touch
2-5
Preganglionic
<3
autonomic
Conduction
Velocity
(m/s)
Spike
Duration
(ms)
Absolute
Refractory
Period (ms)
0.4-0.5
0.4-1
1.2
1.2
2
2
2
2
70-120
30-70
15-30
12-30
3-15
C
Dorsal root
Pain,
temperature, 0.4-1.2
0.5-2
some
mechanoreception,
reflex
responses
Sympathetic
Postganglionic
0.3-1.3
0.7-2.3
sympathetics
A and B fibers are myelinated; C fibers are unmyelinated.
45
Number
Ia
Ib
II
III
IV
Origin
Fiber Type
Muscle spindle, annulospinal A α
ending.
Golgi tendon organ.
Aα
Muscle spindle, flower-spray A β
ending; touch, pressure.
Pain and cold receptors; some A δ
touch receptors.
Pain, temperature, and other Dorsal root C
receptors.
Susceptibility to: Most
Susceptible
Hypoxia
B
Pressure
A
Local anesthetics C
Intermediate
A
B
B
Least
Susceptible
C
C
A
So when sleeping with the arms under the head for long period there will be
pressure on the nerve in the arm causing loss of motor activity while the
sensation is preserved this is called Sunday morning or Saturday night
syndrome, and when we give anesthesia, there will be loss of sensation first.
During hypoxia there will be loss of autonomic function first then motor
actions, then sensation.
46
Synaptic & Junctional Transmission:
Junction is the connection between a nerve cell and another (muscle fiber or
gland).
Synapse is the connection between 2 nerve cells.
The skeletal muscle fibers are innervated by large, myelinated nerve fibers
that originate from large motor neurons in the anterior horns of the spinal
cord. Each nerve fiber, after entering the muscle belly, normally branches
(and loses its myline sheath) and stimulates from three to several hundred
skeletal muscle fibers. Each nerve ending makes a junction with the muscle
fiber near its midpoint, called the neuromuscular junction. The action
potential initiated in the muscle fiber by the nerve signal travels in both
directions toward the muscle fiber ends.
The nerve fiber with its branching plus the thickened muscle surface is
called the motor end plate. It is covered by one or more Schwann cells that
insulate it from the surrounding fluids. The invaginated membrane is called
the synaptic gutter or synaptic trough, and the space between the nerve
terminal and the fiber membrane is called the synaptic space or synaptic
cleft. At the bottom of the gutter are numerous smaller folds of the muscle
membrane called subneural clefts, which greatly increase the surface area at
which the synaptic transmitter can act, and there are also large numbers of
Acetylecholine (Ach) receptors.
In the axon terminal (the enlarged part of the nerve ends) are many
mitochondria that supply adenosine triphosphate (ATP), the energy source
that is used for synthesis of an excitatory transmitter acetylcholine. The
acetylcholine in turn excites the muscle fiber membrane. It is synthesized in
the cytoplasm of the terminal, and it is absorbed rapidly into many small
synaptic vesicles, about 300,000 of which are normally in a single terminal. In
the synaptic space are large quantities of the enzyme acetylcholinesterase,
which destroys acetylcholine a few milliseconds after it has been released
from the synaptic vesicles. On the inside surface of the neural membrane are
linear dense bars. To each side of each dense bar are protein particles that
penetrate the neural membrane; these are voltage gated calcium channels.
47
48
Secretion of Acetylcholine and sequence of events during
neuromuscular transmission:
Small amounts (quanta or packets) of acetylcholine are released randomly
from the nerve cell membrane at rest, each producing a minute depolarizing
spike called a miniature end plate potential.
1-When an action potential spreads over the terminal; these channels open
and allow calcium ions to diffuse from the synaptic space to the interior of
the nerve terminal.
2- The calcium ions in turn, exert an attractive influence on the acetylcholine
vesicles, drawing them to the neural membrane adjacent to the dense bars.
3-The vesicles then fuse with the neural membrane and empty their
acetylcholine into the synaptic space by the process of exocytosis (Botulinum
and Tetanus toxins block the transmitter release).
4- Ach will diffuse to the synaptic cleft and binds with the nicotinic receptors,
causing activation of the Na and K ionic channels. This leads to a rapid Na ion
influx resulting in local depolarization and firing level is reached ,and action
potential is initiated ,this local depolarization occur at this point is called end
plate potential which is an electronic potential.
The resting membrane potential of the muscle fiber is -90 mv which is equal
to the equilibrium potential of K ions, so there will be no driving forces for K
channels and Na ions has the major role in the end plate potential.
When the action potential is fired, it will propagate through all of the muscle
membrane. Each nerve impulse release about 60 vesicles, each one contains
10000 molecules of Ach. This amount is enough to activate 10 times the
number of receptors required to produce a full end plate potential triggering
an action potential.
Curary is an arrow poisoning used by the American Indians to paralyze their
victims .The poison binds to the Ach receptors reducing the number of
receptors for the binding with Ach and so they reduce the reaction of the
released Ach ,this is called competitive inhibition.
Acetylcholine Receptors
Historically, acetylcholine receptors have been divided into two main types
on the basis of their pharmacologic properties.1- Muscarinic and 2- nicotinic
receptors.
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Destruction of the Released Acetylcholine by Acetyl
cholinesterase:
Once released into the synaptic space, continues to activate the
acetylcholine receptors as long as the acetylcholine persists in the space.
However, it is removed rapidly by two means:
1-Most of the acetylcholine is destroyed by the enzyme acetylcholinesterase,
into choline and acetate (nerve gases and physostigmine inhibit the enzyme),
the acetate enters the blood, and the choline is recycled into the presynaptic
nerve.
2- A small amount of acetylcholine diffuses out of the synaptic space and is
then no longer available to act on the muscle fiber membrane.
The rapid removal of the acetylcholine prevents continued muscle reexcitation after the muscle fiber has recovered from its initial action
potential.
Mysthemia Gravis:
It is an autoimmune disease in which there is sever voluntary muscle
weakness; the body produces antibodies that destroy the Ach receptors, and
Ach vesicles, so there is no nerve impulse transmitted. Sometimes death
occurs because of respiratory paralysis (Neostigmine is used to allow more
Ach accumulate in the synaptic space).
Another condition that resembles myasthenia gravis is Lambert-Eaton
syndrome. In this condition, muscle weakness is caused by antibodies against
one of the Ca2+ channels in the nerve endings at the neuromuscular junction.
This decreases the normal Ca2+ influx that causes acetylcholine release.
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However, muscle strength increases with prolonged contractions as more
Ca2+ is released.
Some drugs affecting NMJ:
Drugs stimulating the muscle fiber, by Ach like action:
Methacholine,Nicotine(produce a state of muscle spasm ,because not
destroyed by cholinesterase).
Drugs that stimulate the NMJ by inactivating cholinesterase:
Neostigmine,Physostigmine, nerve gas, organophosphate insecticide.
Drugs that blocks transmission of the NMJ: Curariform, blocks the action of
Ach on the receptors and prevents the passage of nerve impulse from the
nerve ending to the muscle.
SYNAPTIC TRANSMISSION:
Synapse is the junction between 2 nerve cells.
Where the axon or some other portion of one cell (the presynaptic cell)
terminates on the dendrites, soma, or axon of another neuron or in some
cases a muscle or gland cell (the postsynaptic cell).So the synapse consists
of:
1-Presynaptic terminal (axon, dendrite).
2-Postsynaptic terminal (axon ,dendrite, soma)
3-Synaptic cleft. Space between 1 and 2.
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The transmission in the synapse is of 3 types:
1- Chemical transmission:
The impulse in the presynaptic axon causes secretion of a
neurotransmitter such as acetylcholine or serotonin. This chemical mediator
binds to receptors on the surface of the postsynaptic cell, and this triggers
events that open or close channels in the membrane of the postsynaptic cell.
2-Electrical transmission:
The membranes of the presynaptic and postsynaptic neurons come close
together, and gap junctions form between the cells and these junctions form
low-resistance bridges through which ions pass with relative ease.
3- Both electrical and chemical transmission.
The summation of all the excitatory and inhibitory effects determines
whether an action potential is generated.
Properties of synaptic transmission:
1- One way conduction:
Synapses generally permit conduction of impulses in one direction only,
from the presynaptic to the post-synaptic neurons. Because the transmitter
is only on one side, the impulse can go in one direction only.
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2- Convergence & Divergence:
When many presynaptic neurons converge on any single postsynaptic
neuron called convergence. Conversely, the axons of most presynaptic
neurons divide into many branches that diverge to end on many postsynaptic
neurons called divergence.
3- The post synaptic potential is an electronic potential.
4- Postsynaptic potential could be excitatory or inhibitory.
If the neurotransmitter (like Ach, epinephrine and norepinephrine) causes
opening of Na ion channels (or Ca ion channels) → Na ion influx and
depolarization occur (excitatory postsynaptic potential (EPSP).
If it opens K ion channels, it will cause hyperpolarization and it will be
inhibitory postsynaptic potential (IPSP), like glycine, GABA (Gamma Amino
Butyric Acid).
If Cl ion channels are opened also it will be inhibitory postsynaptic potential.
The synapse inhibition is of 2 types:
--Direct postsynaptic inhibition: inhibition affecting the neuron directly by
generating IPSP, through interneuron secreting a transmitter that
hyperpolarizes the postsynaptic neuron by increasing Cl ion influx or K
efflux.
--Presynaptic inhibition: mediated by thick interneuron ends on the excitatory
ending of the presynaptic neuron where they form axo-axonal synapse.
5- Summation of the postsynaptic potential:
2 types of summation:
Spatial: When activity is present in more than one synaptic knob at the same
time, spatial summation occurs and activity in one synaptic knob is said to
facilitate activity in another to approach the firing level.
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Temporal: if repeated afferent stimuli cause postsynapyic potential, before
previous one have decayed. This occurs when there is a very short time
interval between the repeated stimuli, so the effect will be added until the
firing level is reached.
The EPSP is therefore not an all-or-none response but is proportionate in size
to the strength of the afferent stimulus.
6- Fatigue of synapses:
In excitatory synapses, repeated stimulation at high rate for long time cause
impairment of the synaptic transmission .this occurs due to:
1-Mainly depression of the stores of the neurotransmitters.
2-Inactivation of the postsynaptic receptors.
3-Slow built up of Ca ions.
7- Synaptic delay:
When an impulse reaches the presynaptic terminals, there is an interval of
at least 0.5 ms, the synaptic delay, before a response is obtained in the
postsynaptic neuron. It is due to the time it takes for the synaptic mediator
to be released and to act on the membrane of the postsynaptic cell,
activation and change in permeability and the ionic fluxes until the firing level
is reached. Because of it, conduction along a chain of neurons is slower if
there are many synapses in the chain than if there are only a few.
Examples of diseases affecting the synapses:
1-Mysthemia Gravis,
2-Eaton- Lambert syndromes (mentioned),
3-Parkinson's disease, cells in substantia nigra of the brain deficient in
Dopamine.
SYNAPTIC PLASTICITY & LEARNING
Short- and long-term changes in synaptic function can occur as a result of
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the history of discharge at a synapse; ie, synaptic conduction can be
strengthened or weakened on the basis of past experience. These changes
are of great interest because they obviously represent forms of learning and
memory .They can be presynaptic or postsynaptic in location.
Here are a few examples of important neurotransmitter actions:
Glutamate is used at the great majority of fast excitatory synapses in the
brain and spinal cord.
GABA is used at the great majority of fast inhibitory synapses in virtually
every part of the brain. Many sedative/tranquilizing drugs act by enhancing
the effects of GABA. Correspondingly glycine is the inhibitory transmitter in
the spinal cord.
Acetylcholine is distinguished as the transmitter at the neuromuscular
junction connecting motor nerves to muscles. The paralytic arrow-poison
curare acts by blocking transmission at these synapses. Acetylcholine also
operates in many regions of the brain, but using different types of receptors.
Dopamine has a number of important functions in the brain. It plays a critical
role in the reward system, but dysfunction of the dopamine system is also
implicated in Parkinson's Disease and schizophrenia.
Serotonin has a number of important functions that are difficult to describe
in a unified way, including regulation of mood, sleep/wake cycles, and body
temperature. It is released during sunny weather, and also when eating
chocolate or taking Ecstasy (MDMA).
Substance P responsible for transmission of pain from certain sensory
neurons to the central nervous system.
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.
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