Lect. 15
Blood Flow
Objectives:
1. List the physiological mechanisms that maintain blood flow in different organs
by adjusting the diameter of their arterioles.
2. List vasoactive hormones together with the organs or cells from which their
release is initiated.
3. Define the term blood flow autoregulation; name two vascular beds that
demonstrate autoregulatory control of blood flow.
A- Regulation of local blood flow to tissues:
Blood flow in different organs is physiologically maintained by adjusting the
diameter of their arterioles. The mechanisms of regulation of regional; local blood
flow can be classified into: Short-term and long term regulation mechanisms.
Short-term regulation mechanisms:
These mechanisms adjust the minute-to-minute flow to the organs according to their
metabolic needs. Four mechanisms are involved:
a- Metabolic autoregulation.
b- Nervous regulation.
c- Humoral regulation.
d- Myogenic autoregulation.
Metabolic autoregulation:
Increased metabolic activity dilates the blood vessels. This effect is
mediated by:
A- Hypoxia, The increased O
2
utilization by the tissues produces local
hypoxia. The degree of vascular dilation is directly proportionate to
the degree of hypoxia in arteriolar blood. In contrast, an increase in
O
2
level (hyperoxia) produce local vasoconstriction and decrease in
blood flow.
B- Vasodilator metabolites, high metabolism with hypoxia produces a
number of vasodilator metabolites, which include:
1. Adenosine; which is the most important vasodilator
substance released from active tissues. An ischemic or
hypoxic heart releases adenosine which dilates the
coronaries and corrects the ischemia or hypoxia. Adenosine
is also released by skeletal muscles and other tissues.
2. ADP and AMP which are produced by hydrolysis of ATP.
3. CO
2
and H
+
ions which act directly on the vascular smooth
muscles and relax them. CO
2
is a very powerful dilator of
the cerebral blood vessels.
4. Lactic acid which is produced by anaerobic glycolysis. It has
no direct vasodilator effect, but acts through elevation of H
+
ion concentration.
5. K
+
released from active cells. It relaxes the vascular smooth
muscles.
C- The endothelium produces several molecules that promote smooth
muscle relaxation (vasodilators), including nitric oxide (NO),
bradykinin, and prostacyclin.
D- The Endothelium-Derived Relaxing Factor (EDRF): This is a
powerful vasodilator substance secreted by the vascular
endothelium. This substance chemically was found to be nitric
oxide. It is released from the arterial endothelium when stimulated
by bradykinin, VIP or ACH (acetylcholine), i.e. these vasodilator
substances act through releasing EDRF and it is the EDRF which
mediates the vasodilator effect of these substances. In the absence
of EDRF, bradykinins and VIP are ineffective and ACH produces
vasoconstriction not dilation. EDRF is also produced when the
blood flow to a tissue is increased as a result of arteriolar dilatation,
thus further increasing the blood flow to that tissue.
Nervous regulation:
All blood vessels except the capillaries are innervated. Regional
vasodilator fibers supply the vessels of some organs. Vasodilation in
specific organs occurs by the following mechanisms:
Activation of the parasympathetic vasodilator nerves produces
vasodilation in their specific organs, e.g. the salivary glands.
Stimulation of the sympathetic vasodilator system dilates the
skeletal muscle vessels and increases the blood flow in the skeletal
muscles.
Stimulation of sympathetic cholinergic nerve supply to sweat
glands dilates the gland vessels and increases the local blood flow.
Inhibition of the basal sympathetic vasoconstrictor tone to the
vessels. Some organs receive no vasodilator fibers (e.g. the skin).
Constriction or dilation of their vessels occurs by changing the
sympathetic vasomotor tone.
Humoral regulation:
This is regulation by vasoactive substances released from the tissues into
the blood and tissue fluids, examples:
Serotonin: This is a vasoconstrictor substance released from platelets
during the platelet release reaction. It helps to stop bleeding from wounds.
Serotonin is also found in chromaffin cells in the intestine.
Histamine: This is a strong vasodilator substance which is released from
mast cells and basophiles in damaged or inflamed tissues. It is also
released during allergic reactions. In small doses, histamine dilates the
arterioles, but in large doses, it dilates all the vessels.
Prostaglandins (PG): These are hormone-like substances, some of them
(PG F) are constrictors, but most of them (PG A and PG E) are dilators.
Bradykinins: These are strong vasodilator substances formed in tissues
during inflammations or increased activity. The tissues release an activator
substance to activate prekallikrein in tissue fluids into active kallikrein.
Kallikrein acts on
α
2
-globulin in tissue fluids to produce kallidin. Kallidin is
then converted by tissue enzymes into bradykinin. Bradykinin is now
believed to be the mediator of vasodilation in sweat and digestive glands
when they are activated. Prekallikrein, kallikrein and
α
2
-globulin are also
found in plasma.
Myogenic autoregulation:
This is done by constriction when pressure increases and dilation when
pressure decreases. This phenomenon is found in the vascular beds of certain
organs like the kidney, brain, skeletal muscles, mesentery and the liver.
The mechanism of myogenic autoregulation is that when the blood
pressure increases → distention of the arteriole and stretch of its wall →
intrinsic myogenic contraction response → vasoconstriction → decrease in
blood flow back towards normal.
The opposite reaction occurs when the blood pressure falls. This enables an
organ like the kidney to maintain an almost constant blood flow in arterial
blood pressure range of 80-160 mmHg. In the brain, changes in systemic
arterial pressure are compensated by the appropriate responses of
vascular smooth muscle.
A decrease in arterial pressure causes cerebral vessels to dilate, so that
adequate rates of blood low can be maintained despite the decreased
pressure. While, high blood pressure causes cerebral vessels to constrict,
so that finer vessels downstream are protected from the elevated pressure.
These responses are myogenic; they are direct responses by the vascular
smooth muscle to changes in pressure.
Long-term regulation mechanisms:
These mechanisms adjust the basal blood flow over long periods of time.
They take few hours up to few weeks to be fully effective. They correct
any change in basal flow at blood pressure range of 50-250 mmHg.
Three mechanisms are involved:
a- Opening of closed collaterals.
b- Formation of new vessels.
c- Narrowing or closure of some vessels.
Opening of closed collaterals:
When an artery or a vein is blocked, new vascular channels, which bypass
the blocked segment, opens within one to two minutes. Such alternative
vascular channels are normally found, but they are closed, Hypoxia and
the metabolic vasodilators of the ischemic segment lead to their opening.
Formation of new vessels (angiogenesis):
Hypoxic tissues (either due to lack of O
2
supply or high metabolic rate)
produce angiogenic substances called angiogenins. These substances
stimulate the sprouting of new vessels from the wall of venules and
capillaries. Some of these vessels may grow up to form arterioles or even
small arteries. The ability of young tissues to form new blood vessels in
response to hypoxia is very high.
Narrowing or closure of vessels:
Increased blood flow (e.g. by increase in arterial blood pressure) or
breathing air with high O
2
content or depression of tissue metabolism
elevates the local O
2
level (hyperoxia). Blood vessels constrict. If
hyperoxia lasts for a long time, structural changes take place in the
vascular wall leading to permanent narrowing of the vascular lumen (e.g.
arteriosclerotic changes which occur with chronic hypertension) some
vessels might even get completely closed and obliterated.
B-Regulation of Blood Flow:
This is the Regulation of Blood Flow either by the autonomic nervous
system or by the endocrine system. Angiotensin II, for example, directly
stimulates
vascular
smooth
muscle
to
produce
generalized
vasoconstriction. Antidiuretic hormone (ADH) also has a vasoconstrictor
effect at high concentrations; this is why it is also called vasopressin. This
vasopressor effect of ADH is not believed to be significant under
physiological conditions in humans.
Regulation of blood flow by Sympathetic Nerves
Stimulation of the sympathoadrenal system produces an increase in the
cardiac output and an increase in total peripheral resistance through α-
adrenergic stimulation of vascular smooth muscle by norepinephrine and
to a lesser degree, by epinephrine. This produces vasoconstriction of the
arterioles in the viscera and skin.
In resting condition, when a person is calm, the sympathoadrenal system
is active to a certain degree and helps set the tone of vascular smooth
muscles. In this case, adrenergic sympathetic fibers (those that release
norepinephrine) activate α-adrenergic receptors to cause a basal
level of vasoconstriction throughout the body. During the fight-or-flight
reaction, an increase in the activity of adrenergic fibers produces
vasoconstriction in the digestive tract, kidneys and skin, and vasodilation
in the skeletal muscles which receive cholinergic sympathetic fibers, that
release acetylcholine as a neurotransmitter. Vasodilation in skeletal
muscles is also produced by epinephrine secreted by the adrenal medulla,
which stimulates beta-adrenergic receptors. In other words, during the
fight-or-flight reaction, blood flow is decreased to the viscera and skin
because of the α-adrenergic effects of vasoconstriction in these organs,
whereas blood flow to skeletal muscles is increased.
Regulation of blood flow by Parasympathetic Nerves
Parasympathetic endings in arterioles are always cholinergic and always
promote vasodilatation. Parasympathetic innervation of blood vessels,
however, is limited to the digestive tract, external genitalia, and salivary
glands. Because of this limited distribution, the parasympathetic system is
less important than the sympathetic system in the control of total
peripheral resistance.
Types of blood flow:
Laminar flow: The flow of blood in almost all vessels in the body is a
smooth, streamline, laminar flow, i.e. the blood flows in several layers or
laminae around a central layer. The central lamina moves at
maximum velocity, whereas the outer laminae move at lower velocities.
The outermost lamina is practically static and adherent to the vascular
endothelium. The mean velocity of blood flow is the average of the
velocities of all layers in the vessel. The RBCs generally travel in the
central laminae, while the plasma generally travels in the outer laminae. The
laminar flow is silent (i.e. producing no sounds). So, normally no sound is
heard if a stethoscope is applied over a blood vessel. The friction forces on
the vascular endothelium are minimal.
Turbulent Flow: This is disturbed blood flow in the form of eddies in
various directions, in which fluid particles move in forward as well as
side-to-side directions. Turbulence produces sounds (bruits or murmurs)
that can be heard by the stethoscope. The friction forces of the turbulent
flow on vascular endothelium are high. It may lead to excessive shedding
of the lining endothelium (thus predisposing to intravascular clotting and
development atherosclerosis).
Methods for measuring the blood flow rate:
Measuring blood flow through an organ
1-Plethysmography: recording change in volume of an organ after
occluding its venous drainage. Rate of increase in volume of the organ
equals rate of blood flow.
2-Fick's principle.
3-Plasma clearance: e.g., determination of renal blood flow.
Measuring blood flow through a blood vessel
1-Electromagnetic flow meters.
2-The ultrasonic Doppler flow meters.
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Laminar flow explains why the measured circulation times are shorter than
real times. This is because the timing is made on the arrival of the first amount
of the indicator to the end point. This first amount travels at maximum speed
in the central axial stream, not at an average speed.
Total peripheral resistance:
It is the sum of all the vascular resistances within the systemic
circulation.
Vasodilation in a large organ might, however, significantly decrease the
total peripheral resistance and. by this means, might decrease the mean
arterial pressure. In the absence of compensatory mechanisms, the driving
force for blood flow through all organs might be reduced. This situation
is normally prevented by an increase in the cardiac output and by
vasoconstriction in other areas. During exercise of the large muscles, for
example, the arterioles in the exercising muscles are dilated. This would
cause a great fall in mean arterial pressure if there were no
compensations. The blood pressure actually rises during exercise,
however, because the cardiac output is increased and because there is
constriction of arterioles in the viscera and skin.
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Paracrine Regulation of Blood Flow
Paracrine regulators are molecules produced by one tissue that help to
regulate another tissue of the same organ. Blood vessels are particularly
subject to Paracrine regulation. Specifically, the endothelium of the
tunica interna produces a number of Paracrine regulators that cause the
smooth muscle of the tunica media to either relax or contract.
The endothelium produces several molecules that promote smooth muscle
relaxation, including nitric oxide, bradykinin, and prostacyclin. The
endothelium-derived relaxation factor that earlier research had shown to
be required for the vasodilation response to nerve stimulation appears to
be nitric oxide.
The endothelium of arterioles contains an enzyme, endothelial nitric
oxide synthase, which produces nitric oxide (NO) from L-arginine. The
NO diffuses into the smooth muscle cells of the tunica media of arterioles
and activates the enzyme guanylate cyclase, which converts GTP into
cyclic GMP (cGMP) and pyrophosphate (PP,). The cGMP serves as a
second messenger that, through a variety of mechanisms, acts to lower
the cytoplasmic Ca
+2
concentrations. This leads to smooth muscle
relaxation and thus vasodilation. In many arterioles, a baseline level of
NO production helps regulate the resting "tone" (degree of
vasoconstriction/vasodilation) of the arterioles.
In response to ACh released from autonomic axons, however, the
production of NO may be increased. This occurs through the following
sequence of events:
(1) ACh stimulates the opening of Ca
2+
channels in the endothelial cell
membrane.
(2) The Ca
2+
then binds to and activates calmodulin:
(3) Activated calmodulin, in turn, activate nitric oxide synthase and thus
increase the production of NO. It is interesting in this regard that
vasodilator drugs often given to treat angina pectoris—including
nitroglycerin—promote vasodilation indirectly through their conversion
into nitric oxide.
The endothelium also produces Paracrine regulators that promote
vasoconstriction. Notable among these is the polypeptide endothelin-1.
This Paracrine regulator stimulates vasoconstriction of arterioles, thus
raising the total peripheral distance. In normal physiology, this action
may work together /ith those regulators that promote vasodilation to help
regulate blood pressure.
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Intrinsic Regulation of Blood Flow
Intrinsic, or "built-in," mechanisms within individual organs provide a
localized regulation of vascular resistance and blood flow.
Intrinsic mechanisms are classified as myogenic or metabolic. Some
organs, the brain and kidneys in particular, utilize lese intrinsic
mechanisms to maintain relatively constant flow rates despite wide
fluctuations in blood pressure. This ability is termed autoregulation.
Myogenic Control Mechanisms
If the arterial blood pressure and flow through an organ are inadequate—
if the organ is inadequately perfused with blood— the metabolism of the
organ cannot be maintained beyond a limited time period. Excessively
high blood pressure can also be dangerous, particularly in the brain,
because this may result in the rupture of fine blood vessels (causing
cerebrovascular accident—CVA, or stroke).
Changes in systemic arterial pressure are compensated for in the brain
and some other organs by the appropriate responses of vascular smooth
muscle. A decrease in arterial pressure causes cerebral vessels to dilate,
so that adequate rates of blood low can be maintained despite the
decreased pressure. High blood pressure, by contrast, causes cerebral
vessels to constrict, so that finer vessels downstream are protected from
the elevated pressure. These responses are myogenic; they are direct
responses by the vascular smooth muscle to changes in pressure.
Metabolic Control Mechanisms
Local vasodilation within an organ can occur as a result of the chemical
environment created by the organ's metabolism. The localized chemical
conditions that promote vasodilation include
1) Decreased oxygen concentrations that result from increased Metabolic
rate;
(2) Increased carbon dioxide concentrations;
(3) Decreased tissue pH (due to CO
2
, lactic acid, and other metabolic
products); and (4) the release of adenosine or K
+
from the tissue cells.
Through these chemical changes, the organ signals its blood vessels of its
need for increased oxygen delivery.
The vasodilation that occurs in response to tissue metabolism can be
demonstrated by constricting the blood supply to an area for a short time
and then removing the constriction. The constriction allows metabolic
products to accumulate by preventing venous drainage of the area. When
the constriction is removed and blood flow resumes, the metabolic
products that have accumulated cause vasodilation. The tissue thus
appears red. This response is called reactive hyperemia. A similar in-
crease in blood flow occurs in skeletal muscles and other organs as a
result of increased metabolism. This is called reactive hyperemia. The
increased blood flow can wash out the vasodilator metabolites, so that
blood flow can fall to pre-exercise levels a few minutes after exercise
ends.
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(1) Laminar blood flow : This is the normal smooth (streamline) flow of
blood in the blood vessels. It is silent (i.e. producing no sounds) and
laminar i.e. the blood flows in several layers or laminae (figure 62 A).
The outermost layer of blood in contact with the vessel wall is almost
completely static (i.e. not moving) while the other layers move by
velocities that increase gradually from out inwards till becoming maximal
in the central layer of the stream. The mean velocity is the average of
velocities in all blood layers, and beyond a certain critical velocity,
turbulence occurs (see below).
. ■
^ It should be noted that the circulation times measured above reflect the
maximum blood velocity and not the mean velocity. This is because these
times are determined by the first appearance of the indicator substances at
the end points (which depends on the maximal velocity in the centra!
blood layer)- Therefore, the measured circulation times are actually
shorter than the true times between the corresponding points.
(2) Turbulent blood flow: This is disturbed blood flow in the form of
eddies in various directions. It produces sounds (= bruits or murmurs^
which can be heard by the stethoscope. It may lead to excessive shedding
of the lining endothelium (thus predisposing to atherosclerosis). It
specially occurs when the critical velocity is exceeded, in addition to
other factors (see next).
There are several methods for measuring the blood flow rate through
organs or through individual blood vessels.
Several methods could be used. The following are two widely used
methods:
This is done by regulating the diameter of arterioles by constriction or
dilation.
1-Electromagnetic flow meters: This technique depends on the principle
that the flow of blood between two poles of a magnet generates an
electromotive force (EMF) in the blood, because the RBC's cut the
power lines in the magnetic field. The magnitude of the EMF is
proportionate to the flow of blood. This EMF magnitude can be
measured from the surface of the blood vessel.
2-The ultrasonic Doppler flow meters: A piezoelectric piece of crystal
emit a pulse of ultrasonic waves (several million Hz) downstream the
flowing blood. The sound waves that hit the RBC's are reflected back
but at different slower frequency, because RBCs are moving away
from the crystal. The amount and the wave length of the reflected
waves are picked up by the crystal and the data are computed. The
amount of the reflected waves is indicative of the density of RBCs
which is indicative of the diameter of the vessel. The difference in
wave length between the emitted and the reflected waves is indicative
of the velocity of blood flow.
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