Chapter 9

CONTROL OF BLOOD FLOW

Learning Objectives

After reading this chapter you should be able to:

1. Describe the consequences of changing vascular tone on CVS parameters.

2. List the factors that reduce vascular tone.
3. List the factors that increase vascular tone.
4. Explain why the blood flow to the brain would be relatively constant despite fluctuations
in perfusion pressure.
5. Explain the mechanism by which blood flow to exercising muscle is increased.
6. Explain why there is a rebound increase in blood flow to an organ following temporary
occlusion of its arterial supply.
7. Explain how the sympathetic nervous system causes vasoconstriction.
8. Describe the effects of the parasympathetic nervous system on the vasculature.
9. Explain why epinephrine causes vasoconstriction in some organs and vasodilation in
others.

Introduction

Blood Flow α P/R (Bulk Flow Law)

Resistance 1/α r4 (r = radius)

Blood flow to various organs can change depending on which activities the body is
performing. For example, during exercise, blood flow to the heart and skeletal muscles
increases whilst blood flow to the gastrointestinal system decreases. Look at the above
bulk flow relationship and think of how blood flow could possibly change. Well, the
pressure gradient (blood pressure) could increase or the resistance could decrease. If the
blood pressure was changed then this would affect the whole cardiovascular system and
all the organs. This is not practical, and also we know that it is extremely important that
the blood pressure is maintained within a relatively narrow range to ensure that all organs
are adequately perfused at all times. The best way of altering blood flow to individual
organs is to alter the resistance of the vessels supplying that particular organ. How could
the resistance be altered? This is the subject of this chapter and we are going to discuss
the different mechanisms that different organs use.

The resistance to blood flow is largely determined by the diameter of the blood vessel.
Note from the equation above (fourth power of the radius!) that a very small change in
vessel diameter will lead to a large change in resistance and consequently blood flow.
Therefore any factor that causes vasoconstriction will reduce the radius, increase the

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resistance and decrease the blood flow. Conversely, factors that relax vascular smooth
muscle increase blood flow. Which type of blood vessels exert most influence on blood
flow? The arterioles. These have abundant smooth muscle and also at their capillary end
there is a precapillary sphincter made up of smooth muscle. Factors that cause smooth
muscle contraction then constrict the arterioles, close the precapillary sphincter and result
in a reduced flow of blood to the organ.

In a resting individual the arterioles of all organs are generally under a degree of tone i.e.
they are partially constricted. This tone results from the interplay between various locally
produced vasoconstrictors and vasodilators and from tonic activity of the sympathetic
nervous system. In terms of control, what is the advantage of an arteriole being partially
constricted? Well, this allows the arteriole to become either more constricted or dilated so
that blood flow can be made to increase or decrease. If the arterioles had no resting tone,
the only thing that could happen would be to make them constrict, reducing blood flow.
With a resting tone, they can be made to constrict or dilate.

In this chapter we will consider the various substances and mechanisms that alter tone in
blood vessels. In the next chapter we will see which of these mechanisms come into play
in regulating blood flow to various individual organs.

What controls vascular tone?

Intrinsic mechanisms.

These are local factors or mechanisms found entirely within the organ or tissue. They
play a role in regulating blood flow to individual organs. They include:

The Myogenic Response: “mechanical” response of the blood vessel to BP

changes.

Endothelial secretions: NO, prostacyclin, endothelin

Metabolic vasodilators: generated by active tissues e.g. adenosine, lactic acid

Autacoids: paracrines such as histamine, bradykinin (mainly during

inflammation)

Temperature: important in the cutaneous circulation

Intrinsic mechanisms mediate :

Autoregulation

Active (functional) Hyperemia and Reactive Hyperemia

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The intrinsic mechanisms ensure that each individual organ has adequate blood flow to
meet its metabolic demands, at all times.

Extrinsic Mechanisms

These are mediated by factors outside the individual organ, and include:

Autonomic Nervous System: Sympathetic and parasympathetic

Circulating hormones: Epinephrine, angiotensin, vasopressin

Extrinsic mechanisms meet the needs of the whole organism. They play an important role
in regulating mean arterial blood pressure rather than regulating blood flow to individual
organs.

Intrinsic Mechanisms and the Local Control of Blood Flow

The Myogenic Response

When blood pressure is raised in a blood vessel, the blood vessel is distended and it
responds by contracting. This contraction is termed the myogenic response. This response
stabilizes local blood flow and thus capillary filtration pressure when arterial blood
pressure changes. This response is particularly important in maintaining blood flow to the
brain and kidney and is described more fully under autoregulation.

Endothelial Secretions:

Nitric Oxide (NO): Vasodilator

NO is synthesized from L-arginine by NO synthase (NOS). Low levels of NO are

produced continuously. Ach and some cytokines induce NOS and ↑ NO production.
NO stimulates guanylyl cyclase in vascular smooth muscle, to ↑ cGMP which relaxes
smooth muscle, causing vasodilation and increased blood flow.

Functions: Continually modulates basal tone

Mediates flow-induce vasodilation during exercise
Mediates the vasodilation of erection (see box)
Mediates vasodilation during inflammation
Mediates the vasodilation associated with endotoxic shock

Pregnancy: High estrogen levels ↑ NO production, leading to a generalized ↓ vascular

tone and a ↓ in BP (despite a 50% ↑ in CO).

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Sexual Erection and NO

Vasodilation of the arterioles of the corpus cavernosum is brought about by NO released

from parasympathetic nerves. The NO acts on G proteins to ↑ cGMP levels. Sildenafil
(Viagra) mimics the action of NO because it indirectly increases cGMP by inhibiting
phosphodiesterase – the enzyme that breaks down cGMP. Sildenafil is used for erectile
dysfunction.

Nitrate Drugs: Glyceryl trinitrate, sodium nitroprusside, isosorbide dinitrate

Used as vasodilators to treat angina. Act by mimicking NO. They cause venodilation and
arteriolar dilation. The venodilation → ↓ CVP → ↓ preload → ↓ stroke volume and↓the O2
demand of the heart. The venodilation is more pronounced than the arteriolar dilation.

NO inhibits platelet aggregation, thus protecting vessels against thrombosis.

Role of NO in atheroma (atherosclerosis)

NO has been implicated in atherosclerosis: a disease characterized by a patchy deposition

of lipids (plaques) in the subendothelial space of large arteries resulting in their lumen being
reduced. The overall effects are tissue ischemia and thrombosis. When the coronary
circulation is involved, atherosclerosis causes angina and heart attacks; in the brain,
transient ischemic attacks and strokes, and in the legs, intermittent claudication and
gangrenous necrosis. The chief predisposing factor are high plasma levels of LDL and
fibrinogen, smoking, diabetes and hypertension.
NO has several anti-atherogenic actions. Low levels of NO may contribute to plaque
formation. NO levels are low in smokers and diabetics.

Prostacyclin: Vasodilator
Inhibits platelet aggregation

It is one of the prostaglandins (PGI2) and is generated from arachidonic acid by COX
enzyme. It is produced in response to thrombin.

Both NO and prostacyclin limit the spread of platelet aggregation and prevent
uncontrolled vascular thrombosis.

Endothelin: Vasoconstrictor

Contributes to basal vascular tone.

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Endothelin levels are ↑ed in:

Hypoxia: endothelin is partly responsible for pulmonary hypertension seen at

high altitudes.

Pre-eclampsia (acute hypertension of pregnancy).

Cardiac failure: endothelin may contribute to the characteristic renal and

peripheral vasoconstriction.

Strokes: endothelin levels are increased in the CSF following subarachnoid

hemorrhages, brain injury. Contributes to cerebral vasospasm.

Metabolic Vasodilators

When the metabolic rate of the heart, skeletal muscles or regions of the brain increase,
the blood flow to the active region also increases. O2 delivery thus meets O2 demands.
This phenomenon is called metabolic, functional or active hyperemia. The hyperemia is
brought about by vasodilator substances released from the metabolically-active tissues.
These include adenosine, K+, phosphate. Other factors that cause vasodilation are
hypoxia, acidosis (↑ PCO2 and H+) and hypersomolarity.

H+
Cerebral blood vessels are very sensitive to PaCO2 (excess of which leads to
acidosis). Arterial pCO2 is an important regulator of cerebral blood flow.

Low PaO2 (Hypoxia)

PaO2 is normally ~100 mm Hg. If PaO2 < 40 mm Hg systemic blood vessels
dilate; and the resulting increase in blood flow helps to restore the oxygen supply
to the tissue. In the lungs however, hypoxia constricts pulmonary vessels.

Adenosine
It is formed in the interstitial fluid of skeletal and cardiac muscle from AMP. A
good correlation exists between metabolic rate in cardiac muscle, adenosine
content and coronary blood flow.

Interstitial K+
Increasing activity in skeletal muscle and brain causes an ↑ in [K+]o due to ↑ in
action potentials. In skeletal muscle [K+]o can increase from 4 mM to 9 mM. The
increased K+ causes relaxation of vascular smooth muscle.

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Autacoids

Some cause vasodilation and others vasoconstriction. They do not normally play a major role
in the local control of blood flow in healthy individuals, but they do alter local blood flow
significantly in pathological conditions which involve the inflammatory response.

Histamine: Vasodilator
Released from mast cells during the inflammatory response.
Dilates arterioles and constricts veins and ↑ venular permeability.
Largely responsible for redness and edema of inflammation.

Bradykinin: Vasodilator
Stimulates nociceptors and is a potent algogen.

Serotonin: Vasoconstrictor
(5-HT) Released from platelets during clotting –vasoconstriction stops the
bleeding.
In atheromatous coronary arteries the platelets are activated
inappropriately and the 5-HT released can cause coronary vasospasm.
In the brain, 5-HT is partly responsible for the cerebral vasospasm
that occurs in migraine and following a subarachnoid hemorrhage.

Prostaglandins: Synthesized from arachidonic acid by COX enzyme.

PGFs are mainly vasoconstrictors.
PGEs and prostacyclin are vasodilators – contribute to inflammatory
vasodilation and reactive hyperemia.

Thromboxane: Vasoconstrictor.
Synthesized in platelets from arachidonic acid via COX.
Released during clotting and helps to stop bleeding.
Released inappropriately by atheroma-activated platelets and
contributes to the vasospasm.

Leukotrienes: Vasoconstriction
Play a major role in inflammation.

Thrombosis

Formation of a clot within a blood vessel. The 1st stage is aggregation of platelets,
mediated by release of thromboxane. Aspirin (in low doses) inhibits the formation of
thromboxane in platelets which is why it is used to prevent thrombosis in patients with
coronary atheroma.

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Autoregulation of Blood Flow

One would expect, from the bulk flow law, that as perfusion pressure (BP) increases,
flow increases. However when we look at the graph in the figure, we see that despite
changes increases in BP there is hardly any change in blood flow (between ~60 to ~160
mm Hg). How can this be? The only parameter that must be changing must be the
resistance. As the perfusion pressure is increasing the resistance must also be increasing,
thereby keeping the flow constant. This is what is happening. This increase in resistance
is brought about by the myogenic response, described earlier. It is a local response of
blood vessels to an increased pressure.

Range of blood pressure over

which organs such as the brain
and heart maintain a constant
flow
Autoregulatory
Range
Blood Flow

Normal

50 100 150 200 250

Mean Arterial Pressure

Figure 1 Effects of increasing MAP on Blood Flow

The increased BP stretches the blood vessel wall. The resulting stretch of the smooth
muscle causes the muscle to respond by contracting, thus reducing the diameter of the
blood vessel and increasing its resistance. This would return the blood flow back towards
normal. Conversely, a fall in blood pressure would lessen the stretch on the vessel wall,
reduce the contraction of the arteriolar smooth muscle and restore the flow. This
phenomenon whereby changes in blood pressure over a wide range have no effect on
local blood flow is called autoregulation. It means that the blood vessels to the organ
itself, is regulating its own blood flow. The advantage of this system is that blood flow to
an organ is maintained despite large fluctuations in blood pressure. It operates in most
organs but is particularly important in maintaining cerebral and renal blood flow should
the mean arterial pressure fall – as may occur following hemorrhage.
Autoregulation also stabilizes the capillary pressure and filtration rate and prevents
edema formation should blood pressure rise. However, autoregulation does function
within limits. In severe hypotension blood flow will be compromised. Another important
point to realize is that, autoregulation does not mean that blood flow cannot be altered.
Vasodilators and sympathetic activity can still change blood flow but what they do is,
they reset the level at which autoregulation operates.

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Metabolic (Functional, Active) Hyperemia

When the metabolic rate of organs (or tissues) increase - the rate of production of
various metabolites increase and these accumulate in the ECF. Several metabolites (e.g.
adenosine, K+, lactic acid, phosphate) cause vasodilation by relaxing the precapillary
sphincters. This results in an increased blood flow to the active tissue. This phenomenon
of increased blood flow in response to metabolites is called metabolic, functional or
active hyperemia.

METABOLIC
HYPEREMIA
Organ
Blood
Flow

Period of increased metabolic rate

Figure 2 Metabolic Hyperemia

Metabolic hyperemia is mainly responsible for the increased blood flow to exercising
muscle. Metabolic hyperemia can operate together with autoregulation. What it means is
that autoregulation just operates at higher levels of blood flow. Another example of the
cooperation between the two mechanisms: in the cerebral circulation, autoregulation
ensures that the blood flow to the brain, as a whole, is constant, whereas metabolic
hyperemia increases blood flow to regions of the brain that happen to be more active at
that particular time.

Reactive (post-ischemic) Hyperemia

REACTIVE
HYPEREMIA
Organ
Blood
Flow

Period of arrested blood flow

Figure 3 Reactive Hyperemia

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When an artery is compressed to such a point that the supply of oxygen to a tissue is
seriously impaired, an O2 debt is incurred and the blood flow upon releasing the
compression is several times higher than normal. This is the phenomenon of reactive or
post-ischemic hyperemia. Again, the hyperemia is mainly due to the accumulation of
vasoactive metabolites which, in this case, were not being washed away.

Extrinsic Mechanisms and the control of TPR and MAP

The intrinsic mechanisms ensure that each individual organ gets an adequate blood flow
to match its metabolic needs. The extrinsic mechanisms ensure that blood flow
throughout the body is adequate and this is done by controlling total peripheral resistance
and mean arterial pressure. The regulation of MAP is discussed in chapter 10. In this
chapter we will discuss actual mechanisms involved.

Extrinsic Mechanisms:

Autonomic Nervous System: Sympathetic and Parasympathetic

Sympathetic activity → Vasoconstriction

Parasympathetic activity → Vasodilation

The sympathetic nervous system is tonically active on blood vessels (mainly arterioles,
and to a lesser extent arteries and veins). An ↑ in sympathetic activity leads to an
increased vasoconstriction; and a ↓ in sympathetic tone leads to vasodilation. Note that
the sympathetic nervous system does not behave as a single entity. The tone in one tissue
can be regulated independently of other tissues. This is because each organ is represented
on the brain stem (just like the body is represented on the motor and sensory cortex).

Anatomy of the Sympathetic NS

Descending (bulbospinal) fibres from the vasomotor centres in the medulla act upon
sympathetic preganglionic neurons (cell bodies) found in spinal segments T1 to L3.
Preganglionic fibres exit the spinal cord and synapse with sympathetic postganglionic
fibres in the sympathetic ganglia. The preganglionic fibres release ACh as transmitter
which acts on nicotinic receptors on postganglionic cell bodies. (Smoking stimulates
postganglionic nicotinic receptors resulting in vasoconstriction and ↑ BP).

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 Medullary
Vasomotor
Centres

Bulbospinal Pathway

Vascular Smooth Muscle

ACh Nicotinic NE
α1
Pre- Post-
Ganglionic Fibres

Figure 4 The Sympathetic Nervous System

Some preganglionic fibres innervate the adrenal medulla directly. The adrenal medulla is
a modified postganglionic fibre. It releases into the bloodstream both epinephrine and NE
(in a ratio of 3 : 1).
The postganglionic neurons innervate mainly small arteries and arterioles, and to a lesser
extent, veins. The neurotransmitter is NE and the vascular receptors are α1.

Effects of activating α1 receptors on vascular smooth muscle

Norepinephrine

activates α1 receptors

Induces conformational change in Gq protein

Activates phospholipase C

Diacylglycerol IP3

↑ Protein Kinase C ↑ Release of Ca from SR

Contraction of Smooth muscle Vasoconstriction

Drugs which block α receptors are widely used in the treatment of hypertension.

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Vasoconstriction (↑ vascular tone) results in:

↓ Blood Flow (Flow = ∆P/R, R = 1/r4

A small ↓ in vessel diameter will ↓↓ blood flow)

↑ Arterial Pressure (MAP = CO x TPR)

↓ Capillary Pressure Capillary blood flow is ↓

Net Filtration Rate is ↓

↑ Venous Pressure ↑ Venomotor tone. This displaces blood from the

peripheral veins into the central veins → ↑ CVP.
Peripheral veins are more affected by sympathetic
vasoconstrictor nerves than central veins.
↑ CVP → ↑ Stroke Volume

Changes in vascular tone not only affects the blood flow to individual organs but can also
affect the whole organism – by affecting TPR, MAP, CVP and SV.

Effects of Parasympathetic Activity

Sympathetic nerves have a widespread distribution in the vasculature, in contrast to

parasympathetic fibres which innervate blood vessels of only the erectile tissue, salivary
glands and some GIT glands. The transmitter released is acetylcholine and the receptors
are muscarinic.

ACh causes vasodilation of blood vessels and this response is partly mediated by NO.
Muscarinic activation leads to increase production of NO which in itself is a vasodilator.
(Remember that the major effect of parasympathetic activity on the cardiovascular
system is its negative chronotropic effect on the heart).

Hormonal Control of Blood Flow

Hormones are generally less important than the ANS in regulating vascular tone;
although they become important in many pathological states (e.g. hemorrhage) and in
individuals with transplanted hearts.

Hormones include: Epinephrine

Angiotensin II
Vasopressin

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Both angiotensin and vasopressin cause vasoconstriction. However, they tend to operate
as parts of homeostatic mechanisms designed to maintain fluid balance and their roles
will be discussed in more detail in renal physiology.

Epinephrine

Synthesized and released from the adrenal medulla in response to sympathetic activity.
Release is increased during exercise, the alerting response (fear - fight – flight reaction),
hypotension and hypoglycemia.

Epinephrine acts on both α and β receptors, but has a greater affinity for β receptors.

Activation of α receptors by epinephrine obviously causes the same response as when

these receptors are activated by norepinephrine i.e. vasoconstriction.
Activation of β2 receptors on blood vessels causes a vasodilation. (Note that blood
vessels have β2 whereas the heart has β1 receptors!)

How the ANS regulates blood pressure will be discussed in detail in Chapter 11.

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