Local and Humoral Control of Blood Flow by the Tissues pdf - The Circulation

more than required to maintain full tissue oxygenation but no more than this.

delivery of oxygen, the blood flow is always controlled at a level only slightly

no less. For instance, in tissues for which the most important requirement is

lated at the minimal level that will supply the tissue’s requirements— no more,

require many times more blood flow than the heart can pump.

ity of the tissue is little or great? The answer is equally simple: To do this would

tissue of the body, always enough to supply the tissue’s needs whether the activ-

tion: Why not simply allow a very large blood flow all the time through every

Importance of Blood Flow Control by the Local Tissues.

min/100 g of muscle).

as high as 16,000 ml/min in the body’s total muscle vascular bed (or 80 ml/

increase more than 60-fold and the blood flow as much as 20-fold, increasing to

4 ml/min/100 g. Yet, during heavy exercise, muscle metabolic activity can

bolic activity of the muscles is very low, and so also is the blood flow, only

between 30 and 40 per cent of the total body mass. In the resting state, the meta-

of the body, only a total of 750 ml/min, even though the muscles constitute

Conversely, most surprising is the low blood flow to all the

tion of cleansing the blood of waste products.

This extreme amount of flow is required for the kidneys to perform their func-

of 1350 ml/min in the liver, which is 95 ml/min/100 g of liver tissue.

large blood flows in some organs—for example, several hundred milliliters per

Note in Table 17–1 the very

Variations in Blood Flow in Different Tissues and Organs.

We shall see that most of these factors exert extreme degrees of local blood

allows the kidneys to excrete the waste products of the body.

perature. Also, delivery of adequate quantities of blood plasma to the kidneys

Certain organs have special requirements. For instance, blood flow to the skin

6. Transport of various hormones and other substances to the different tissues

5. Maintenance of proper concentrations of other ions in the tissues

4. Removal of hydrogen ions from the tissues

3. Removal of carbon dioxide from the tissues

2. Delivery of other nutrients, such as glucose, amino acids, and fatty acids

1. Delivery of oxygen to the tissues

to this is manyfold, including the following:

What are some of the specific needs of the tissues for blood flow? The answer

bolic needs.

Local Control of Blood

Blood Flow by the Tissues

195

Local and Humoral Control of

Flow in Response to
Tissue Needs

One of the most fundamental principles of circula-
tory function is the ability of each tissue to control
its own local blood flow in proportion to its meta-

determines heat loss from the body and in this way helps to control body tem-

flow control.

minute per 100 grams of thyroid or adrenal gland tissue and a total blood flow

Also note the extremely large blood flow through the kidneys—1100 ml/min.

inactive muscles

One might ask the simple ques-

Experiments have shown that the blood flow to each tissue usually is regu-

mainly in response to oxygen deficiency. For instance,

, and

histamine, potassium ions

carbon dioxide

suggested are

metarterioles, and arterioles to cause dilation. Some of

through the tissues to the precapillary sphincters,

The

nutrients to a tissue, the greater the rate of formation

ing to this theory, the greater the rate of metabolism

lation—Possible Special Role of Adenosine.

Vasodilator Theory for Acute Local Blood Flow Regu-

lack theory

oxygen

They are (1) the

olism changes or the availability of oxygen changes.

There are two basic theories for the regulation of

effect of oxygen deficiency to increase blood flow.

much as sevenfold, thus demonstrating the extreme

Total cyanide poisoning of oxygen usage by a local

supply of oxygen to the tissues.

blood, thus almost maintaining an exact constant

increases almost enough, but not quite enough, to

leg increases about threefold; that is, the blood flow

per cent of normal, the blood flow through an isolated

tissues increases markedly. Figure 17–2 shows that as

tissues to use oxygen), the blood flow through the

cyanide poisoning (which poisons the ability of the

ability of hemoglobin to transport oxygen), or (4) in

tude at the top of a high mountain, (2) in pneumonia,

oxygen to the tissues decreases, such as (1) at high alti-

nutrients is oxygen. Whenever the availability of

Acute Local Blood Flow Regulation When Oxygen Availability

a local tissue, such as in a skeletal muscle. Note that an

Figure

Effect of Tissue Metabolism on Local Blood Flow.

Acute Control of Local Blood Flow

tissues.

needs of the tissues. These changes come about as a

months. In general, these long-term changes provide

changes in flow over a period of days, weeks, or even

however, means slow, controlled

tenance of appropriate local tissue blood flow.

metarterioles, and precapillary sphincters, occurring

vasodilation or vasoconstriction of the arterioles,

phases: (1) acute control and (2) long-term control.

Flow Control

deficiency, and yet the workload on the heart is kept

By controlling local blood flow in such an exact way,

196

Unit IV

The Circulation

the tissues almost never suffer from oxygen nutritional

at a minimum.

Mechanisms of Blood

Local blood flow control can be divided into two

Acute control is achieved by rapid changes in local

within seconds to minutes to provide very rapid main-

Long-term control,

even better control of the flow in proportion to the

result of an increase or decrease in the physical sizes
and numbers of actual blood vessels supplying the

17–1 shows the approximate quantitative acute effect
on blood flow of increasing the rate of metabolism in

increase in metabolism up to eight times normal
increases the blood flow acutely about fourfold.

Changes.

One of the most necessary of the metabolic

(3) in carbon monoxide poisoning (which poisons the

the arterial oxygen saturation decreases to about 25

make up for the decreased amount of oxygen in the

tissue area can cause local blood flow to increase as

local blood flow when either the rate of tissue metab-

vasodilator theory and (2) the

Accord-

or the less the availability of oxygen or some other

of vasodilator substances in the tissue cells.
vasodilator substances then are believed to diffuse

the different vasodilator substances that have been

adenosine,

, adenosine

phosphate compounds,
hydrogen tons.

Most of the vasodilator theories assume that the

vasodilator substance is released from the tissue

Blood Flow to Different Organs and Tissues Under Basal

Table 17–1

Total

100.0

5000

Other tissues

3.5

175

1.3

Adrenal glands

0.5

300

Thyroid gland

160

Skin (cool weather)

300

Bone

250

Muscle (inactive state)

750

Arterial

(6)

300

Portal

(21)

1050

Liver

1350

Kidneys

1100

360

Bronchi

100

Heart

200

Brain

700

Per cent

ml/min

ml/min/100 g

Conditions

Based mainly on data compiled by Dr. L. A. Sapirstein.

Blood flow (x normal)

Rate of metabolism (x normal)

Normal level

Effect of increasing rate of metabolism on tissue blood flow.

Figure 17–1

The cyclical opening and closing is called

oles open and close cyclically several times per minute,

nutrition. The precapillary sphincters and metarteri-

open or completely closed. The number of precapillary

scope—for example, in a bat’s wing—one sees that the

muscle fibers. Observing such a tissue under a micro-

single sidearm capillary and its surrounding tissue. At

shows a tissue unit, consisting of a metarteriole with a

could operate is shown in Figure 17–3. This figure

local blood vessels, and this, too, would cause local

and therefore naturally dilate. Also, increased utiliza-

absence of adequate oxygen, it is reasonable to

to cause vascular muscle contraction. Therefore, in the

oxygen are involved). Oxygen (and other nutrients

nutrient lack theory

the oxygen lack theory or, more accurately, the

favor still another theory, which can be called either

Oxygen Lack Theory for Local Blood Flow Control.

tors could increase the blood flow sufficiently.

flow. But a combination of several different vasodila-

has been the following: It has been difficult to prove

well as in the heart. The problem with the different

Although research evidence is less clear, many phys-

heart muscle cells to cause coronary vasodilation, pro-

(ATP), which (3) increases the release of adenosine. It

utilization of oxygen, followed by (1) decreased

increases an extra amount, this, too, causes increased

more active than normal and the heart’s metabolism

back to normal. Also, whenever the heart becomes

becomes too little, and this causes enough local vasodi-

example, minute quantities of adenosine are released

vasodilators for controlling local blood flow. For

sible, or partially responsible, for the local blood flow

between the tissue cells; these substances then cause

Local and Humoral Control of Blood Flow by the Tissues

Chapter 17

197

experiments have shown that decreased availability of
oxygen can cause both adenosine and lactic acid (con-
taining hydrogen ions) to be released into the spaces

intense acute vasodilation and therefore are respon-

regulation.

Many physiologists have suggested that the sub-

stance adenosine is the most important of the local

from heart muscle cells when coronary blood flow

lation in the heart to return coronary blood flow

oxygen concentration in the heart muscle cells with (2)
consequent degradation of adenosine triphosphate

is believed that much of this adenosine leaks out of the

viding increased coronary blood flow to supply the
increased nutrient demands of the active heart.

iologists also have suggested that the same adenosine
mechanism is the most important controller of blood
flow in skeletal muscle and many other tissues as

vasodilator theories of local blood flow regulation

that sufficient quantities of any single vasodilator sub-
stance (including adenosine) are indeed formed in the
tissues to cause all the measured increase in blood

Although the vasodilator theory is widely accepted,

several critical facts have made other physiologists

(because other nutrients besides

as well) is required as one of the metabolic nutrients

believe that the blood vessels simply would relax

tion of oxygen in the tissues as a result of increased
metabolism theoretically could decrease the availabil-
ity of oxygen to the smooth muscle fibers in the

vasodilation.

A mechanism by which the oxygen lack theory

the origin of the capillary is a precapillary sphincter,
and around the metarteriole are several other smooth

precapillary sphincters are normally either completely

sphincters that are open at any given time is roughly
proportional to the requirements of the tissue for

with the duration of the open phases being propor-
tional to the metabolic needs of the tissues for oxygen.

vasomotion.

Let us explain how oxygen concentration in the

local tissue could regulate blood flow through the area.
Because smooth muscle requires oxygen to remain

Blood flow (x normal)

100

Arterial oxygen saturation (per cent)

through an isolated dog leg.

Effect of decreasing arterial oxygen saturation on blood flow

Figure 17–2

Precapillary sphincter

Metarteriole

Sidearm capillary

for controlling capillary blood flow.

precapillary sphincter

sidearm capillary

passing through

metarteriole

back control of blood flow, showing a

Diagram of a tissue unit area for explanation of acute local feed-

Figure 17–3

the tissue and a

with its

“acute” curve in Figure 17–4. Note that between an

flow.” After autoregulation has occurred, the local

flow toward normal is called “

the arterial pressure is kept elevated. This return of

tissues returns almost to the normal level, even though

within less than a minute, the blood flow in most

pressure causes immediate rise in blood flow. But,

In any tissue of the body, an acute increase in arterial

Arterial Pressure Changes from Normal—

“Autoregulation” of Blood Flow When the

as 20-fold during intense exercise.

pointed out earlier, active hyperemia in skeletal

required to sustain its new level of function. As

and, therefore, to increase local blood flow. In this way,

stances. The result is to dilate the local blood vessels

The increase in local metabolism causes the cells

control, one can easily understand this

flow through the tissue increases. Here again, by

brain during rapid mental activity, the rate of blood

gland during a hypersecretory period, or even the

active, such as an exercising muscle, a gastrointestinal

When any tissue becomes highly

ents to the tissues.

during the period of occlusion. This mechanism

lar occlusion, the extra blood flow during the reactive

that cause vasodilation. After short periods of vascu-

that is, lack of flow sets into motion all of those factors

local “metabolic” blood flow regulation mechanism;

blood flow has been stopped for an hour or more. This

normal; this increased flow will continue for a few

and then is unblocked, blood flow through the tissue

When the blood supply to a tissue

examples of metabolic control of local blood flow are

metabolic needs of the tissues. Two additional special

nisms” because all of them function in response to the

local blood flow control are called “metabolic mecha-

The mechanisms that we have described thus far for

Control of Local Blood Flow

deficiency of these vitamins might lead to diminished

ATP in the tissue cells, one can well understand how

disease, the peripheral vascular blood flow everywhere

. In this

, and

lation occurs in the vitamin deficiency disease

has not been studied adequately. In addition, vasodi-

amino acids or fatty acids, are deficient, although this

this same effect occurs when other nutrients, such as

cause local tissue vasodilation. Also, it is possible that

Under special conditions, it has been

Local Blood Flow.

mechanisms.

response to the metabolic needs of the tissues.

oxygen lack theory

or an

Thus, on the basis of available data, either a

the cycle again.

enough, the sphincters would open once more to begin

cells consume the excess oxygen. But when the excess

a certain level, the precapillary and metarteriole

increase in oxygen concentration. Consequently, when

contracted, one might assume that the strength of con-

198

Unit IV

The Circulation

traction of the sphincters would increase with an

the oxygen concentration in the tissue rises above

sphincters presumably would close until the tissue

oxygen is gone and the oxygen concentration falls low

vasodilator substance theory
could explain acute local blood flow regulation in

Probably the truth lies in a combination of the two

Possible Role of Other Nutrients Besides Oxygen in Control of

shown that lack of glucose in the perfusing blood can

beriberi,

in which the patient has deficiencies of the vitamin B
substances thiamine, niacin

riboflavin

in the body often increases twofold to threefold.
Because these vitamins all are needed for oxygen-
induced phosphorylation that is required to produce

smooth muscle contractile ability and therefore also
local vasodilation.

Special Examples of Acute “Metabolic”

reactive hyperemia and active hyperemia.

Reactive Hyperemia.

is blocked for a few seconds to as long an hour or more

usually increases immediately to four to seven times

seconds if the block has lasted only a few seconds but
sometimes continues for as long as many hours if the

phenomenon is called reactive hyperemia.

Reactive hyperemia is another manifestation of the

hyperemia phase lasts long enough to repay almost
exactly the tissue oxygen deficit that has accrued

emphasizes the close connection between local blood
flow regulation and delivery of oxygen and other nutri-

Active Hyperemia.

simply applying the basic principles of local blood flow

active hyper-

emia.
to devour tissue fluid nutrients extremely rapidly and
also to release large quantities of vasodilator sub-

the active tissue receives the additional nutrients

muscle can increase local muscle blood flow as much

“Metabolic” and “Myogenic” Mechanisms

autoregulation of blood

blood flow in most body tissues will be related to arte-
rial pressure approximately in accord with the solid

Blood flow (x normal)

100

0.5

1.0

1.5

2.0

2.5

150

200

250

Arterial pressure (mm Hg)

Acute

Long-term

curve shows the effect if the arterial pressure is raised extremely

sure is raised over a period of a few minutes. The dashed green

a muscle. The solid red curve shows the effect if the arterial pres-

Effect of different levels of arterial pressure on blood flow through

Figure 17–4

slowly over a period of many weeks.

response, the effectiveness of local blood flow control

lar blood flow increases downstream. Without such a

nitric oxide then relaxes the blood vessels. This is for-

nificant increase in the release of nitric oxide. The

against the vascular walls. This stress contorts the

blood of only 6 seconds. Rapid flow of blood through

, which has a half-life in the

nitric oxide

, which is composed

traction of the arterial wall. The most important of

released, can affect the degree of relaxation or con-

arteries synthesize several substances that, when

The endothelial cells lining the arterioles and small

the larger arteries as well. This mechanism is the

vascular portion of the circulation increases, this sec-

upstream. Yet, when blood flow through a micro-

vessels, not the intermediate and larger arteries back

or tissue cell oxygen deficiency can reach only these

The local mechanisms for controlling tissue blood flow

When Microvascular Blood Flow Increases—

Mechanism for Dilating Upstream Arteries

. This special mechanism for cerebral

dioxide concentration and hydrogen ion

ions from the brain tissues. This is important

prominent roles. An increase of either or both of

tissue oxygen concentration, the concentrations of

, in addition to control of blood flow by

2. In the

filtration rate back to or near to normal. The

constriction of the afferent arterioles, in this way

glomerulus into the tubular system, appropriate

When too

juxtaglomerular apparatus.

This is located where the distal tubule lies adjacent

tubuloglomerular feedback,

, blood flow control is vested mainly

1. In the

throughout this text in relation to specific organs, but

operate in a few special areas. They all are discussed

tissues of the body, distinctly different mechanisms

Control in Specific Tissues

blood flow.

increased, such as during vigorous muscle exercise,

tissue. Indeed metabolic factors appear to override

pressure is increased. However, the importance of

The myogenic mechanism may be important in pre-

vascular wall or to the ion channels themselves.

teins that are tethered to cytoskeleton elements of the

cular ion channels are still uncertain, but likely involve

lar contraction. The precise mechanisms by which

to contract. Changes in vascular pressure may also

from the extracellular fluid into the cells, causing them

ization, which then rapidly increases calcium ion entry

veins, and even lymphatic vessels. Myogenic contrac-

rioles but can also be observed in arteries, venules,

or hormonal influences. It is most pronounced in arte-

The myogenic response is inherent to vascular

relaxes and allows increased flow.

stretch of the vessel is less, so that the smooth muscle

normal. Conversely, at low pressures, the degree of

stretches the vessel, this in turn causes reactive vascu-

vessel wall to contract for a few seconds. Therefore, it

explains the phenomenon of autoregulation. This

, however, suggests that still

The

pressure.

ents to the tissues. These nutrients (especially oxygen)

arterial pressure becomes too great, the excess flow

lation discussed in previous sections. Thus, when the

The

myogenic theory.

to explain this acute autoregulation mechanism. They

For almost a century, two views have been proposed

arterial pressure of about 70 mm Hg and 175 mm Hg,

Local and Humoral Control of Blood Flow by the Tissues

Chapter 17

199

the blood flow increases only 30 per cent even though
the arterial pressure increases 150 per cent.

have been called (1) the metabolic theory and (2) the

metabolic theory can be understood easily by

applying the basic principles of local blood flow regu-

provides too much oxygen and too many other nutri-

then cause the blood vessels to constrict and the flow
to return nearly to normal despite the increased

myogenic theory

another mechanism not related to tissue metabolism

theory is based on the observation that sudden stretch
of small blood vessels causes the smooth muscle of the

has been proposed that when high arterial pressure

lar constriction that reduces blood flow nearly back to

smooth muscle and can occur in the absence of neural

tion is initiated by stretch-induced vascular depolar-

open or close other ion channels that influence vascu-

changes in pressure cause opening or closing of vas-

mechanical effects of pressure on extracellular pro-

venting excessive stretch of blood vessel when blood

the myogenic mechanism in blood flow regulation
is unclear because this pressure sensing mechanism
cannot directly detect changes in blood flow in the

the myogenic mechanism in circumstances where the
metabolic demands of the tissues are significantly

which can cause dramatic increases in skeletal muscle

Special Mechanisms for Acute Blood Flow

Although the general mechanisms for local blood flow
control discussed thus far are present in almost all

two notable ones are as follows:

kidneys

in a mechanism called
in which the composition of the fluid in the early
distal tubule is detected by an epithelial structure
of the distal tubule itself called the macula densa.

to the afferent and efferent arterioles at the
nephron
much fluid filters from the blood through the

feedback signals from the macula densa cause

reducing both renal blood flow and glomerular

details of this mechanism are discussed in
Chapter 26.

brain

carbon dioxide and hydrogen ions play very

these dilates the cerebral vessels and allows rapid
washout of the excess carbon dioxide or hydrogen

because the level of excitability of the brain itself is
highly dependent on exact control of both carbon

concentration
blood flow control is presented in Chapter 61.

The Endothelium-Derived Relaxing Factor
(Nitric Oxide)

can dilate only the very small arteries and arterioles in
each tissue because tissue cell vasodilator substances

ondarily entrains another mechanism that does dilate

following:

these is a vasodilator substance called endothelium-
derived relaxing factor (EDRF)
principally of

the arteries and arterioles causes shear stress on the
endothelial cells because of viscous drag of the blood

endothelial cells in the direction of flow and causes sig-

tunate because it increases the diameters of the
upstream arterial blood vessels whenever microvascu-

growth of new vessels.

larger vessels. Thus, angiogenesis explains the manner

the wall, so that some of the new vessels eventually

great enough, smooth muscle cells eventually invade

loop through which blood begins to flow. If the flow is

fold over into a tube. Next, the tube connects with

The cells in each cord continue to divide and rapidly

directed toward the source of the angiogenic factor.

cells at the point of sprouting. This is followed by rapid

to sprout from other small vessels. The first step is dis-

vessel growth in the same way. They cause new vessels

tissue oxygen or other nutrients, or both, that leads to

equate blood supply. Presumably, it is deficiency of

, each

, and

(VEGF), fibroblast growth factor

vascular endothelial growth factor

small peptides. Three of those that have been best

blood vessels have been found, almost all of which are

Factor in Formation of New Blood Vessels

Importance of Vascular Endothelial Growth

and this eventually causes blindness. (This condition is

grow out from the retina into the eye’s vitreous humor;

the sudden decrease in available oxygen; indeed, there

the infant is taken out of the oxygen tent, there is

the small vessels that already have formed. Then when

baby’s eyes and even causes degeneration of some of

The excess oxygen causes almost immediate cessation

babies put into oxygen tents for therapeutic purposes.

conductivity as is normally true.This same effect is also

high altitudes, where the atmospheric oxygen is low. A

also for long-term control. One example of this is

Role of Oxygen in Long-Term Regulation.

quently lags far behind the needs of the tissues.

blood flow, whereas in older tissues, vascularity fre-

older, so that in the neonate, the vascularity will adjust

the elderly person. Furthermore, the final degree of

well-established tissues. Therefore, the time required

tissue; however, it occurs much more slowly in old,

growth tissue, such as in scar tissue and cancerous

extremely young animals. It also occurs rapidly in new

This reconstruction occurs rapidly (within days) in

the tissue vasculature to meet the needs of the tissues.

Thus, there is actual physical reconstruction of

vascularity decreases.

vascularity increases; if the metabolism is decreased,

of the tissues. For instance, if the metabolism in a

The mechanism of long-term local blood flow regula-

Change in “Tissue Vascularity”

Mechanism of Long-Term Regulation—

increased quantities of oxygen and other nutrients, the

of a tissue change. Thus, if a tissue becomes chroni-

effect on the rate of local blood flow.

rial pressure between 50 and 250 mm Hg have little

tion has had time to occur, long-term changes in arte-

flow regulation. Note that once the long-term regula-

Figure 17–4 shows by the dashed green curve the

rial pressure remains at 150 mm Hg indefinitely, within

instance, in the aforementioned example, if the arte-

regulation gives far more complete regulation. For

in addition to the acute regulation. This long-term

However, over a period of hours, days, and weeks, a

cent increase in blood flow.

at the same time, it demonstrates that the regulation is

acute mechanisms for local blood flow regulation, but

nal control value. This illustrates the rapidity of the

Then, within 30 seconds to 2 minutes, the flow

increased from 100 to 150 mm Hg, the blood flow

For instance, when the arterial pressure suddenly is

the exact additional requirements of the tissues.

of these acute mechanisms, the blood flow usually

tions have changed. Yet, even after full activation

Thus far, most of the mechanisms for local blood flow

Long-Term Blood Flow Regulation

small arteries.

200

Unit IV

The Circulation

would be significantly decreased because a significant
part of the resistance to blood flow is in the upstream

regulation that we have discussed act within a few
seconds to a few minutes after the local tissue condi-

is adjusted only about three quarters of the way to

increases almost instantaneously about 100 per cent.

decreases back to about 15 per cent above the origi-

still incomplete because there remains an excess 15 per

long-term type of local blood flow regulation develops

a few weeks the blood flow through the tissues gradu-
ally reapproaches almost exactly the normal flow level.

extreme effectiveness of this long-term local blood

Long-term regulation of blood flow is especially

important when the long-term metabolic demands

cally overactive and therefore requires chronically

arterioles and capillary vessels usually increase both in
number and size within a few weeks to match the
needs of the tissue—unless the circulatory system has
become pathological or too old to respond.

tion is principally to change the amount of vascularity

given tissue is increased for a prolonged period,

for long-term regulation to take place may be only
a few days in the neonate or as long as months in

response is much better in younger tissues than in

to match almost exactly the needs of the tissue for

Oxygen is impor-

tant not only for acute control of local blood flow but

increased vascularity in tissues of animals that live at

second example is that fetal chicks hatched in low
oxygen have up to twice as much tissue blood vessel

dramatically demonstrated in premature human

of new vascular growth in the retina of the premature

explosive overgrowth of new vessels to make up for

is often so much overgrowth that the retinal vessels

called retrolental fibroplasia.)

A dozen or more factors that increase growth of new

characterized are

angiogenin

of which has been isolated from tissues that have inad-

formation of the vascular growth factors (also called
“angiogenic factors”).

Essentially all the angiogenic factors promote new

solution of the basement membrane of the endothelial

reproduction of new endothelial cells that stream
outward through the vessel wall in extended cords

another tube budding from another donor vessel
(another arteriole or venule) and forms a capillary

grow to be new arterioles or venules or perhaps even

in which metabolic factors in local tissues can cause

severely depressed. However, the real importance of

tissue area, the blood flow to that area can be

the small arterioles. If this occurs in an isolated

The effect of angiotensin II is to constrict powerfully

being 50 mm Hg or more.

constrictor substance. As little as

lation, thus providing a dual system of control: (1)

nephrine into the blood. These hormones then circu-

and contracts the veins and arterioles. In addition,

tissues release norepinephrine, which excites the heart

cise, the sympathetic nerve endings in the individual

When the sympathetic nervous system is stimulated

arteries during increased heart activity.)

vasodilation. (A special example of vasodilation

Vasoconstrictor Agents

following.

culatory effects. Among the most important of the

the blood throughout the entire body. Others are

such as hormones and ions. Some of these substances

Circulation

Humoral Control of the

als to develop that serious heart attacks occur.

ciency occurs too rapidly or too severely for collater-

oped rapidly enough to prevent myocardial damage. It

coronary vessels close. Yet most people do not know

of the coronary arteries. Almost all people by the age

The most important example of the development of

of weeks and months.

metabolic dilation, followed chronically by manifold

control, the acute control being rapid neurogenic and

needed during strenuous tissue activity. Thus, the

returns very near to normal, but the new channels

vessel. Under resting conditions, the blood flow usually

months thereafter, almost always forming multiple

The collateral vessels continue to grow for many

within a few days often all the tissue needs.

as much as half the tissue needs may be met, and

occurs within the ensuing hours, so that within 1 day

supply all the tissue needs. However, further opening

initial opening of collateral vessels, the blood flow

muscle fibers of the small vessels involved. After this

first minute or two, indicating that the dilation is

age to the vessel below. This dilation occurs within the

partial resupply of blood to the affected tissue. The

tissue of the body, a new vascular channel usually

When an artery or a vein is blocked in virtually any

Term Local Blood Flow Regulation

A Phenomenon of Long-

Development of Collateral

required extra flow.

vasodilatory stimuli, or other stimuli call forth the

propriate local stimuli such as oxygen lack, nerve

stricted, opening to allow extra flow only when ap-

However, after extra vascularity does develop, the

especially the required oxygen, so that the muscles

muscles would fail to receive the required nutrients,

every time that a person attempted heavy exercise, the

vascularity as required. Were it not for this capability,

ertheless, even this short need can cause enough

required for more than a few minutes each day. Nev-

blood flow. This great excess of flow may not be

flow need rather than by average need. For instance,

by Average Need.

Vascularity Is Determined by Maximum Blood Flow Need, Not

cular cells and disappearance of vessels. Therefore,

vessels, occasionally even causing dissolution of vas-

mones, have exactly the opposite effect on small blood

Certain other substances, such as some steroid hor-

Local and Humoral Control of Blood Flow by the Tissues

Chapter 17

201

blood vessels can also be made to disappear when not
needed.

An especially valuable characteristic

of long-term vascular control is that vascularity is
determined mainly by the maximum level of blood

during heavy exercise the need for whole body blood
flow often increases to six to eight times the resting

VEGF to be formed by the muscles to increase their

simply would fail to contract.

extra blood vessels normally remain mainly vasocon-

Circulation—

develops around the blockage and allows at least

first stage in this process is dilation of small vascular
loops that already connect the vessel above the block-

simply a neurogenic or metabolic relaxation of the

often is still less than one quarter that needed to

small collateral channels rather than one single large

seldom become large enough to supply the blood flow

development of collateral vessels follows the usual
principles of both acute and long-term local blood flow

growth and enlargement of new vessels over a period

collateral blood vessels occurs after thrombosis of one

of 60 years have had at least one of the smaller branch

that this has happened because collaterals have devel-

is in those other instances in which coronary insuffi-

Humoral control of the circulation means control by
substances secreted or absorbed into the body fluids—

are formed by special glands and transported in

formed in local tissue areas and cause only local cir-

humoral factors that affect circulatory function are the

Norepinephrine and Epinephrine.

Norepinephrine is an

especially powerful vasoconstrictor hormone; epi-
nephrine is less so and in some tissues even causes mild

caused by epinephrine occurs to dilate the coronary

in most or all parts of the body during stress or exer-

the sympathetic nerves to the adrenal medullae cause
these glands to secrete both norepinephrine and epi-

late to all areas of the body and cause almost the same
effects on the circulation as direct sympathetic stimu-

direct nerve stimulation and (2) indirect effects of
norepinephrine and/or epinephrine in the circulating
blood.

Angiotensin II.

Angiotensin II is another powerful vaso-

one millionth of a

gram can increase the arterial pressure of a human

angiotensin II is that it normally acts on many of the
arterioles of the body at the same time to increase the

(decrease in pH) causes dilation of the arterioles.

4. An

powerful vasodilation

3. An increase in

. This results from the ability of

2. An increase in

contraction, as discussed in Chapter 8.

. This results from the general

1. An increase in

circulation, but some specific effects are:

overall regulation

either dilate or constrict local blood vessels. Most of

Vascular Control by Ions and Other

edema. The local vasodilatory and edema-producing

to leak out of the circulation into the tissues, inducing

many pathological conditions, the intense arteriolar

of both fluid and plasma protein into the tissues. In

increase greatly capillary porosity, allowing leakage

the arterioles and, like bradykinin, has the ability to

inflamed or is the subject of an allergic reaction. Most

testinal glands.

fluids in inflamed tissues. It also is believed that

There is reason to believe that kinins play special

size.

through the arm as much as sixfold, and even smaller

1 microgram

instance, injection of

. For

also present in the body fluids.

angiotensin, as discussed in Chapter 19. The activated

, the same

or by

carboxypeptidase

. Once formed, bradykinin persists for only

tissues. As kallikrein becomes activated, it acts imme-

tion of the blood, by tissue inflammation, or by other

form. This inactive kallikrein is activated by macera-

, which

plasma or tissue fluids. A proteolytic enzyme of par-

The kinins are small polypeptides that are split away

fluids of some organs.

Vasodilator Agents

injury.

blood vessel damage, release of local endothelin and

tizing chemical into the blood vessel. After severe

release is damage to the endothelium, such as that

of all or most blood vessels. The usual stimulus for

tion. This substance is present in the endothelial cells

, which requires only

Vessels.

Endothelin—A Powerful Vasoconstrictor in Damaged Blood

to help control body fluid volume. That is why this

the blood (discussed in Chapter 28), and therefore

Vasopressin has a major function to increase greatly

60 mm Hg. In many instances, this can, by itself, bring

little role in vascular control. However, experiments

minute amounts of vasopressin are secreted, so that

effects on circulatory function. Yet, normally, only

nerve axons to the posterior pituitary gland, where it

most potent vascular constrictor substances. It is

a vasoconstrictor, thus making it one of the body’s

, is even more powerful than angiotensin II as

also called

Vasopressin

Vasopressin.

in the regulation of arterial pressure, as is discussed in

rial pressure. Thus, this hormone plays an integral role

, thereby increasing the arte-

total peripheral resistance

202

Unit IV

The Circulation

detail in Chapter 19.

antidiuretic

hormone

formed in nerve cells in the hypothalamus of the brain
(see Chapter 75) but is then transported downward by

is finally secreted into the blood.

It is clear that vasopressin could have enormous

most physiologists have thought that vasopressin plays

have shown that the concentration of circulating blood
vasopressin after severe hemorrhage can rise high
enough to increase the arterial pressure as much as

the arterial pressure almost back up to normal.

water reabsorption from the renal tubules back into

hormone is also called antidiuretic hormone.

Still another vasoconstrictor substance that

ranks along with angiotensin and vasopressin in its
vasoconstrictor capability is a large 21 amino acid
peptide called endothelin
nanogram quantities to cause powerful vasoconstric-

caused by crushing the tissues or injecting a trauma-

subsequent vasoconstriction helps to prevent exten-
sive bleeding from arteries as large as 5 millimeters in
diameter that might have been torn open by crushing

Bradykinin.

Several substances called kinins cause pow-

erful vasodilation when formed in the blood and tissue

by proteolytic enzymes from alpha2-globulins in the

ticular importance for this purpose is kallikrein
is present in the blood and tissue fluids in an inactive

similar chemical or physical effects on the blood or

diately on alpha2-globulin to release a kinin called

kallidin that then is converted by tissue enzymes into
bradykinin
a few minutes because it is inactivated by the enzyme

converting enzyme

enzyme that also plays an essential role in activating

kallikrein enzyme is destroyed by a kallikrein inhibitor

Bradykinin causes both powerful arteriolar

dilation and increased capillary permeability

of bradykinin into

the brachial artery of a person increases blood flow

amounts injected locally into tissues can cause marked
local edema resulting from increase in capillary pore

roles in regulating blood flow and capillary leakage of

bradykinin plays a normal role to help regulate blood
flow in the skin as well as in the salivary and gastroin-

Histamine.

Histamine is released in essentially every

tissue of the body if the tissue becomes damaged or

of the histamine is derived from mast cells in the
damaged tissues and from basophils in the blood.

Histamine has a powerful vasodilator effect on

dilation and increased capillary porosity produced
by histamine cause tremendous quantities of fluid

effects of histamine are especially prominent
during allergic reactions and are discussed in
Chapter 34.

Chemical Factors

Many different ions and other chemical factors can

them have little function in

of the

calcium ion concentration causes

vasoconstriction
effect of calcium to stimulate smooth muscle

potassium ion concentration causes

vasodilation
potassium ions to inhibit smooth muscle
contraction.

magnesium ion concentration

causes

because magnesium

ions inhibit smooth muscle contraction.

increase in hydrogen ion concentration

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sympathetic nervous vasoconstrictor system, to

indirect effect, transmitted through the

vasomotor center, has an extremely powerful

dioxide in the blood, acting on the brain

marked vasodilation in the brain. Also, carbon

causes moderate vasodilation in most tissues, but

increase in carbon dioxide concentration

6. An

, both of which cause

slight decrease in hydrogen ion

Conversely,

Local and Humoral Control of Blood Flow by the Tissues

Chapter 17

203

concentration causes arteriolar constriction.

5. Anions that have significant effects on blood

vessels are acetate and citrate
mild degrees of vasodilation.

cause widespread vasoconstriction throughout the

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