NROSCI-BIOSC 1070
MSNBIO 2070
September 28, 2015
Cardiovascular 5
Control of Blood Flow
• Neural control of blood
pressure
• Local control of blood
pressure
• Hormonal control of blood
pressure
The Baroreceptor Reflex
• Baroreceptors innervate the carotid sinus and aortic arch
• Carotid sinus baroreceptors course in cranial nerve IX
• Aortic arch baroreceptors course in a branch of cranial
nerve X
The Baroreceptor Reflex
• When blood pressure
increases, the
baroreceptor terminals are
stretched and the
afferents fire more.
• As with other types of
stretch receptors, the
responses of these
afferents adapt to
prolonged stretch. In the
case of baroreceptors, this
adaptation (resetting)
begins within a few
minutes.
The Baroreceptor Reflex
• Increases or
decreases in blood
pressure induce
baroreceptor-mediated
changes in
sympathetic and
parasympathetic
activity
• Baroreceptor activity
displays “ceiling” and
“floor” effects
Brain Regions Mediating the
Baroreceptor Reflex
RVLM
Rostral
Ventrolateral
Medulla
Brain Regions Mediating the
Baroreceptor Reflex
CVLM
Caudal
Ventrolatera
l
Medulla
Neural Basis of the Baroreceptor Reflex
Some
NTS neurons
Baroreceptor
afferents
project
directly
to
terminate
in nucleus
parasympathetic
tractus solitarius
preganglionic
(NTS) in the neurons
caudal
in nucleus
ambiguus
medulla.
(a region of the caudal
medullary lateral
reticular formation)
Neural Basis of the Baroreceptor Reflex
The
RVLM
is theare
major
NTS
neurons
also
CVLM
neurons
region
projectof
tothe
an
area
of the
inhibitory,
andbrainstem
inhibit
involved
inventrolateral
cardiothecaudal
activity
of neurons
vascular
control.
The
medullary
reticular
in the
rostral
ventroRVLM
projects
to
formation
(CVLM).
lateral
medulla
(RVLM)
sympathetic preganglionic neurons in
the intermediolateral
cell column (IML) of
the thoracic spinal
cord.
Baroreceptor Reflex
Response of RVLM Neuron to
Carotid Artery Stretch
mm Hg
90
µV
100
200
100
0
-100
-200
Blood Pressure
80
Neural Activity
0
2
4
6
8
10 12 14 16 18 20 22 24
Time (sec)
What Happens if
the Baroreceptor
Reflex is
Dysfunctional?
RVLM Neurons Integrate a
Variety of Inputs
 The baroreceptor reflex provides a powerful
mechanism to prevent sudden increases or
decreases in blood pressure.
 However, additional mechanisms are
needed to adjust blood pressure in the
absence of perturbations.
 RVLM neurons integrate inputs from many
regions of the nervous system, all of which
contribute to altering blood pressure.
Changes in Regional Perfusion
During Exercise






Blood flow to different organs changes appreciably during
exercise
Factors Adjusting Blood Flow to
Different Vascular Beds
 Neural control (results in some patterning)
 Myogenic autoregulation (the ability of vascular
smooth muscle to regulate its own activity)
 Response to paracrines from surrounding tissues
(major factor producing increases in blood flow to
metabolically active tissues)
 Hormonal control (epinephrine, vasopressin,
angiotensin 2, aldosterone, atrial natriuretic
factor)
Myogenic Autoregulation
 Blood vessels automatically adjust their diameter in
response to alterations in blood pressure, so that flow
through the vascular bed remains constant.
 Ohm’s law (Q = ΔP/R) indicates that flow and perfusion
pressure are directly proportional.
 As such, vascular resistance must increase in proportion to
the increase in pressure to achieve autoregulation.
Myogenic Autoregulation
 A rise in pressure stretches
the wall of vascular smooth
muscle cells, opening stretchsensitive Na+ channels,
thereby resulting in a
depolarization of the cell.
 This depolarization elicits an
opening of voltage-gated Ca2+
channels on the surface,
increasing Ca2+ and triggering
vasoconstriction.
 Consequently, vessel diameter will become smaller as
perfusion pressure rises.
 Autoregulation provides for a constant rate of O2 delivery
regardless of perfusion pressure.
Paracrine Control of Local Blood Flow
 Local control of vascular resistance is mainly
controlled by the release of metabolites from tissues.
 H+ from acids (e.g. lactic acid), K+, and CO2 release
promotes vasodilation.
 Low oxygen levels can also induce vasodilation, likely
mediated by the release of adenosine from muscle
cells during hypoxia.
 Each factor is additive, and the accumulation of all of
these chemicals during exercise promotes the
extensive increases in skeletal muscle perfusion that
occur.
Paracrine Control of Local Blood Flow
 Adenosine triggers an increase in cAMP, which
activates protein kinase A (PKA).
 PKA phosphorylates and opens K-ATP channels,
resulting in K+ efflux and hyperpolarization.
 Conductance through another K+ channel, the K-IR channel,
increases when extracellular K+ rises, causing
hyperpolarization of the cell.
 Increases in extracellular K+ due to metabolism of surrounding
tissues also opens and increases K+ conductance through KIR channels.
 Hyperpolarization of smooth muscle causes a closing of
voltage-gated Ca2+ channels, thereby resulting in relaxation of
the smooth muscle.
 Through these mechanisms, there is profound vasodilation of
vascular smooth muscle during exercise.
Other Paracrine Factors that Regulate Blood Flow
 A large number of additional paracrine factors help to
precisely regulate blood flow to particular vascular
beds.
 One example is endothelin, which is released from
damaged endothelial cells. Endothelin produces
powerful vasoconstriction, which serves to reduce
bleeding from damaged arteries.
 Release of serotonin from activated platelets induces
vasoconstriction to prevent blood loss.
 In contrast, histamine release from healing tissues or
mast cells promotes vasodilation.
Endothelium-Derived Relaxing Factor
 Vasodilation is also produced by a chemical first called
“endothelium-derived relaxing factor,” which is now know to be
nitric oxide (NO).
 Sheer stress produced by the flowing of blood across the
surface of endothelial cells opens mechanically-gated channels
on the surface, including Ca2+ channels.
Endothelium-Derived Relaxing Factor
 Ca2+ entering the endothelial cell through open channels
combines with calmodulin (CM); the resulting Ca2+—CM
complex activates NO synthase.
 An additional mechanotransduction mechanism initiates a
kinase cascade, ultimately leading to phosphorylation of NO
synthase and increased production of NO.
Endothelium-Derived Relaxing Factor
 NO diffuses from endothelial cells to adjacent smooth muscle
cells.
 NO produces smooth muscle relaxation by activating the
enzyme guanylate cyclase, which results in increased levels of
cyclic guanosine monophosphate (cGMP).
Endothelium-Derived Relaxing Factor
 cGMP activates an ATPase that pumps calcium out of
the smooth muscle cell, thereby inhibiting interactions
between actin and myosin.
 Other factors besides sheer stress can also lead to NO
production by endothelial cells:
 Bradykinin, an agent that is released during cellular
damage.
 A number of products of metabolism
 Parasympathetic activity acting on vessels that receive
this innervation (e.g., genitalia)
Endothelium-Derived Relaxing Factor
 cGMP is rapidly broken down in vascular smooth muscle cells.
 In male genitalia, the degredation of cGMP is the result of the
actions of phosphodiesterase type 5 (PDE5). cGMP can be
degraded via other routes in other tissues.
 Drugs such as Viagra are phosphodiesterase type 5 inhibitors.
 Sexual stimulation in males results in parasympatheticallymediated vasodilation in the penis, via the local release of NO
from endothelial cells in the corpus cavernosum. This NO
release results in an increase in cGMP in smooth muscle cells
of the corpus cavernosum, which generates vasodilation, an
influx of blood, and an erection.
 Viagra prevents the cGMP from being rapidly degrated, so the
vasodilation persists much longer than usual.
Sheer Stress vs. Pressure Effects on Vessels
 Remember that sheer stress is tangential (parallel) to the vessel
wall, while pressure is perpendicular to the wall. Sheer stress
mainly affects the endothelial cells, while pressure affects the
deeper layers of the vessel including the smooth muscle.
 Sheer stress and pressure can trigger different autoregulatory
processes that oppose each other:
o Acute increases in perfusion pressure can trigger smooth
muscle cells to contract, reducing vessel diameter.
o Reduced vessel diameter can raise the drag of blood along
the vessel wall, leading to more sheer stress (and release of
NO from endothelial cells).
 Thus, sheer stress can act as a negative modulator of
myogeneic responses: sheer stress and blood pressure can
induce opposing responses that keep each other in check.
Sheer Stress vs. Pressure Effects on Vessels
 However, sheer stress responses can also have other
roles. Vasodilation of muscle arterioles during exercise
increases blood flow in the arterioles. The increased blood
flow leads to sheer stress, and release of NO from endothelial
cells in the arterioles. This leads to even more vasodilation.
Hormonal Control of Blood Pressure
•
•
•
•
Atrial Natriuretic Factor (Peptide)
Vasopressin (Antidiuretic Hormone)
Angiotensin II
Aldosterone
Atrial Natriuretic Factor (Peptide)
• Atrial natriuretic factor is released from the
atria when venous pressure (atrial stretch) is
high.
• This hormone tends to produce vasodilation.
This will diminish cardiac return, and will
thus decrease the workload of the heart
which is overloaded with blood.
• In addition, atrial natriuretic factor promotes
secretion of water and salt by the kidney, to
reduce blood volume.
Atrial Natriuretic Factor (Peptide)
Atrial Stretch Receptors
• Both the atria and the pulmonary arteries
contain stretch receptors, which are called
low-pressure receptors.
• These low-pressure receptors are much like
arterial baroreceptors in structure, but
because of their location do not sense
pressure in the systemic circulation. Instead,
they detect increases in pressure in the lowpressure parts of the circulation that are
generated by increases in blood volume.
Atrial Stretch Receptors
• The axons of atrial stretch receptors project
to the brainstem via the vagus nerve, and
synapse in nucleus tractus solitarius (NTS).
• Activation of atrial stretch receptors elicits a
brainstem-mediated reflex that tends to an
increase heart rate and probably
contractility.
Vasopressin
• Signals from atrial stretch receptors are also
transmitted to the hypothalamus, and affect the
release of vasopressin. Signals from atrial stretch
receptors can elicit a decrease in vasopressin
release, which will in turn act on the kidney to
result in lowered volume in the cardiovascular
system.
• Vasopressin is additionally released when the
hypothalamus detects an increase in blood
osmolarity, which occurs when blood volume
decreases or the concentration of solutes
increases.
Vasopressin
• A large decrease in blood pressure sensed by
arterial baroreceptors triggers vasopressin
release.
• Increased blood levels of angiotensin II induce
vasopressin release.
Vasopressin
• Increases in vasopressin result in kidney
reabsorbing more water. As a
consequence, blood volume increases and
urine production decreases.
• Drastic reductions in blood volume and
blood pressure result in massive elevations
in vasopressin levels, which induces
vasoconstriction in some vascular beds.
Vasopressin
Posterior Pituitary Hormones
• Posterior pituitary
hormones are
synthesized by neurons in
the paraventricular and
supraoptic nuclei of the
hypothalamus
• These hormones are
released like
neurotransmitters when
the neurons fire
• The release of the
hormones is dependent
on the number of neurons
that fire and the rate and
duration of their firing
What Happens if Baroreceptors
are Removed?
• Following baroreceptor
denervation, blood
pressure is highly
unstable.
• However, mean blood
pressure remains near
100 mmHg.
• A mechanism other than
the baroreceptor reflex
must establish the blood
pressure set-point.
Renin-Angiotensin System
•• Renin
converts
an
inactive
plasma
protein made
by the liver,
Angiotensin
II
is
a
very
potent
vasoconstrictor
substance.
• angiotensinogen,
When blood pressure
is low, special
into angiotensin
I. cells in the kidney called
juxtaglomerular
cells (JG cells)
detect the
condition
and
• Angiotensin
I is converted
by an enzyme
located
on the
release a peptide
called
renin.called angiotensin converting
endothelium
of blood
vessels,
• enzyme
The sympathetic
nervous
system
can
also act toII.induce
renin
(ACE), into
the active
form,
angiotensin
This enzyme
isrelease.
concentrated in blood vessels of the lung.
Other Functions of Angiotensin II
•
•
It affects
causes the
the parts
adrenal
cortex
to release
the
of
the
medulla
that
control
potentiates
the
release
of
NE
from
sympathetic
It stimulates thirst,
the release
and the
of antidiuretic
addition of water
hormone
to the
hormone
aldosterone,
which
causes
the
kidney
to
sympathetic
outflow,
to
increase
heart
rate
and
terminals.
(vasopressin) from the pituitary, which stimulates
body
reabsorb
salt and water into the blood. The net
vasoconstriction.
water retention and an increase in plasma volume.
result is that blood volume is increased.
Summary of Angiotensin 2 Actions
Summary of Angiotensin 2 Actions
Not all Triggers of Ang Secretion are Equal!
Clinical Note
Widely-prescribed anti-hypertensive
mechanisms include Angiotensin
Converting Enzyme (ACE) inhibitors
and Angiotensin II receptor
antagonists
Advantage of Angiotensin II Receptor
Blockers Over ACE Inhibitors
 AT1 receptors mediate
most of the effects of
Ang-II on blood
pressure.
 AT2 receptors are found in
many tissues, including
the uterus, ovary and
several brain regions, but
they are not known to be
directly related to
cardiovascular
homeostasis.
ACE-2 and Alternate Ang Pathways
Red — Inhibitory
Green — Excitatory
Summary:
Control of Blood
Pressure
Questions for
Discussion
What is a quadriplegic’s resting
blood pressure, and how is it
maintained? What happens when
he/she is lifted out of bed?
Question for Discussion
How do anti-hypertensive medications work?
1.
2.
3.
4.
5.
6.
7.
8.
Peripherally-acting alpha-receptor antagonist
Centrally-acting alpha receptor agonist
Beta-1 receptor antagonist
Diuretic
ACE inhibitor
Angiotensin-2 receptor antagonist
Calcium channel blocker
Direct vasodilator
MAP = (HR * (EDV-ESV)) * TPR