REVIEW

The Concept of Autoregulation of Total Blood

Flow and Its Role in Hypertension

ALLEN W. COWLEY, Jr.. M.D.

\&son,

Arterial vascular resistance to blood flow is increased in every

known form of established hypertension. The proposed mechanisms
responsible for these alterations in vascular resistance include humoral factors, the nervous system and local autoregulatory events.
This study focuses on the potential importance of the phenomenon
of tissue autoregulation as a factor in vascular resistance. Nearly all
individual organ systems can locally adjust their vascular resistance
(autoregulate) to maintain appropriate blood flow, so that the sum
of all the tissue resistances determines the total blood flow through
the circulation (cardiac output). The extent to which these Iocal autoregulatory mechanisms can influence hemodynamic events associated with various types of hypertension is evaluated. It is concluded
that even slight fluid retention over periods of weeks and months
enables autoregulatory mechanisms to sustain a 50 per cent increase
in arterial pressure with only a 5 per cent observed increase in cardiac output. In some forms of hypertension, these mechanisms ap
pear to explain the observed hemodynamic changes (i.e., low renin
essential hypertension or primary aldosteronism) In other forms,
there may be no reason for autoregulation to occur, so the mechanism might be of no consequence in determining the vascular resistance. The evidence indicates that regulation of cardiac output
cannot explain the cause of hypertension, but local autoregulation
of flow must be carefully considered if we are to understand fully
the hemodynamic events associated with various forms of hypertension.

Mississippi

From the Department of Physiology and Biophysics, University of Mississippi Medical

Center, Jackson, Mississippi. This study was
supported by NIH Grants HL14306 and HL11678.
Requests for reprints should be addressed to Dr.
Allen W. Cowley, Jr., Department of Physiology
and Biophysics, University of Mississippi Me&
ical Center, Jackson. Mississippi 39218. Manuscript accepted March 7.1980.

Bo6

June 1980

The Am&can

The importance of body fluid volumes in the etiology of hypertension

has been viewed with varying degrees of enthusiasm since the early
20th century when the consequences of an increased arterial blood
pressure were first perceived. In the early part of this century, expansion of body fluid volumes was thought to be responsible for hypertension, but as evidence accumulated it appeared that nearly all
hypertension, including the essential form, was a result of factors that
influence total peripheral resistance, not body fluid volumes. This
belief became firmly entrenched following Goldblatts demonstration
of hypertension resulting from stenosis of the renal artery [1] and the
studies that followed which characterized the release of renin from
the kidney. Furthermore, as methods were developed for measuring
cardiac output and body fluid volumes, it also became apparent that
subjects with established hypertension could exhibit levels of cardiac
output, blood volume and extracellular fluid volume that were normal,

Journal of Medicine Volume 68

AUTOREGULATION

mildly elevated or even below normal limits [2,3]. The

only common feature that hypertensive subjects shared
was an increased total peripheral resistance. From this
it seemed logical to conclude that the volume status and
cardiac output played no direct role in the hypertensive
process.
These types of observations led to a widespread and
continuing search for various neurohumoral factors that
could increase the over-all peripheral vascular resistance to flow. The major share of this research has
centered on the renin-angiotensin system and the
sympathetic nervous system. But, as techniques for renin
measurements became widespread, renin activity has
been found to be increased above normal in only a small
portion of essential hypertensive patients [4,5].
However, more recent studies, using drugs that block the
renin system, have shown that a normal renin level
may contribute to maintenance of the hypertension. The
sympathetic nervous system, which was virtually ignored for many years after observing that complete
sympathectomy could not reverse established hypertension, is now once again under close scrutiny consequent to the development of sensitive new techniques
to determine plasma catecholamines, and because of the
beneficial effects of drugs that block the autonomic
nervous system. However, admitting what appears to
be an important role of renin activity in many patients
and the possibly important role of the catecholamines
in others, it seems likely that neither pressor system can
entirely explain in all patients the increased peripheral
resistance which is the hallmark of established hypertension, especially in those patients without evidence
of significant renin or catecholamine activity.
There is, however, yet another explanation which has
been proposed to account for increased peripheral
vascular resistance in hypertension. This intriguing alternative mechanism is the focus of this paper and has
been termed the autoregulation theory. This concept,
suggested in 1963 by Borst and Borst-de-Geus [6],
and
Ledingham and Cohen [?I,proposes that expansion of
body fluid volumes with consequent increase in cardiac
output results in overperfusion of peripheral arterial
beds, which in turn vasoconstrict to normalize tissue
blood flow. Considerable interest in this hypothesis has
resulted since it can reconcile a number of paradoxic
observations that had earlier led to abandonment of
interest in the role of body fluid volumes and cardiac
output in hypertension [8].
As will be explained, this
theory can explain why the blood volume and cardiac
output are usually found to be nearly normal in established hypertension whereas the total peripheral resistance is consistently increased.
Evidence for the participation of whole-body autoregulation as a determinant of vascular resistance has
been presented by a number of different investigators
utilizing several types of experimentally-induced
hypertension. In these well controlled laboratory models
of hypertension, cardiac output and peripheral resis-

OF BLOOD FLOW AND ITS ROLE IN HYPERTENSION-COWLEY

tance went through a reproducible and revealing sequence of transient changes. Cardiac output was observed to be initially increased, accounting almost entirely for the increase in arterial pressure during the first
week of hypertension. Over the next week, however,
cardiac output and blood volume returned toward
normal levels and the hypertension was increasingly
sustained by the increase in total peripheral resistance.
Although many people believe that these events are best
explained by the mechanism of autoregulation, the
concept has met with increasing criticism for a number
of reasons (discussed herein).
Detailed coverage of this subject is beyond the scope
of this review which is intended to focus on a few basic
principles that will hopefully provide a framework to
apply the concept of autoregulation of blood flow to
clinical problems of hypertension. Autoregulation is
only one of many overlapping, parallel control systems
for the regulation of blood flow, not for the regulation
of arterial blood pressure. Clearly the theory cannot be
used to explain all the hemodynamic changes observed
in hypertension. It is important, however, to understand
those situations in which autoregulation probably does
influence observed hemodynamic changes and how
these changes relate to the etiology of the disease.
Demonstration of Autoregulation in Hypertension.
The concept of autoregulation in hypertension may be
best illustrated by the hemodynamic changes that occur
when an animal with a reduced functional renal mass
is subjected to a sustained excess volume load [9,10].
Figure 1 shows the results obtained in dogs that had
undergone previous surgical reduction of renal mass to
one-third normal and that were then subjected to a daily
sodium and water intake of nearly four times normal.
The sequential changes in cardiac output, total peripheral resistance and mean arterial pressure were
determined by continuous 24 hour per day computerized monitoring. The average hourly changes shown in
this figure indicate that arterial pressure increases soon
after salt and water intake is increased by the intravenous infusion of soline solution. Increases in pressure
corresponded to measured increases in blood volume
and were directly related to the increased cardiac output
during the first 18 hours. The total peripheral resistance
during this initial period was actually reduced below
normal as a result of baroreceptor reflex activity. Following these initial changes, total peripheral resistance
progressively increased and accounted for an increasingly larger portion of the increased arterial pressure,
whereas cardiac output returned toward normal levels.
After less than one week of sustained volume loading,
the hemodynamic pattern became that of only a slightly
increased cardiac output with the arterial pressure now
being associated with a predominant increase of total
peripheral resistance. Blood volume and extracellular
fluid volume increased 25 per cent at the third day of
infusion. But, despite the fact that this is as near to a pure
volume-induced hypertension as has been achieved, by

June 1960

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110

OF BLOOD FLOW AND ITS ROLE IN HYPERTENSION-COWLEY

INTACT

DOGS

1 - I

50

24

STAdT INFUSION

48

72

TIME

96

Ii0

( HOURS 1

gwe 1. Average hourly changes in cardiac output, arterial

pressure, and total peripheral resistance during tt~ first five
days of development of hypertension by satt loading of dogs
with a renal mass reduced to one-third normal.
the end of two weeks of a continuous infusion of saline
solution no statistical increase in either plasma volume
or extracellular volume was observed.
The theory of autoregulation predicts these events in
that the initially increased cardiac output from initial
fluid retention would result in overperfusion of peripheral tissues and initiate a local arteriolar response
to increase peripheral vascular resistance. Subsequently, cardiac output would gradually return towards
normal as a result of an over-all increase in systemic
resistance to flow (which would decrease the venous

909

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The American Journal of Medicine

return] and then a decrease in blood volume (secondary

to renal pressure diuresis). Therefore, arterial pressure
is initially increased by the increase in cardiac output,
which in time decreases, and pressure is sustained
predominately by autoregulatory increases in total peripheral resistance. The autoregulatory increase in resistance enables fluid balance to be achieved with less
than a 10 per cent final expansion of blood volume
during the hypertension. It is evident that neither blood
volume nor cardiac output could theoretically return
completely to normal or the stimulus for increased
vascular resistance to flow would be abolished and body
fluid volumes would once again expand.
Clearly in this type of hypertension the observed sequence of hemodynamic events follows the changes
predicted by autoregulation. Direct proof of autoregulation as the cause for the observed increases in total
peripheral resistance in the intact animal has not yet
been obtained. However, no generalized neurohumoral
mechanism yet described can explain the observed
sequence of events, and all available evidence supports
the concept that the vascular changes are indeed initiated at the local tissue level.
Autoregulation Defined. Before further discussing the
role of autoregulation in hypertension it is appropriate
to define the term as applied to this review. Autoregulation refers to local tissue mechanisms which act intrinsically to control vascular resistance and thereby
flow through a particular tissue [ll].
The underlying
mechanisms in this process are poorly understood but,
by definition, occur independently of the central nervous system or circulating hormones and appear to
differ in different organs. The term autoregulation in its
narrowest sense is used to describe the rapid vascular
responses which occur to return blood flow to normal
within seconds following a step change in tissue perfusion pressure; or the rapid vascular resistance changes
that occur following a step change in tissue blood
flow.
An example of an autoregulatory response is illustrated in Figure 2 by an experiment performed using an
isolated perfused hind limb skeletal muscle in which
blood flow was lowered from 64 to 24 ml/min while
arterial perfusion pressure was recorded. The instantaneous decrease in pressure caused by decreased blood
flow is followed by a slower but progressive further
decline in pressure caused by autoregulatory vasodilation [K]. Similar local adjustments to underperfusion
of blood flow have been observed in nearly every organ
system studied, including kidney, heart, skeletal muscle,
brain, splanchnic and hepatic circulation, bone and
spinal cord.
Conversely, overperfusion of blood to tissues has been
shown to have the opposite effect of increasing vascular
resistance. This response is also illustrated in Figure 2
in which blood flow to isolated skeletal muscle is tripled.
This caused an immediate initial increase in arterial
pressure due to purely physical factors from blood en-

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AUTOREGULATION

OF BLOOD

FLOW AND ITS ROLE IN HYPERTENSION-COWLEY

PRU

JA?

5;s

4;2

3i8

Figure 2. Autoregulation demonstrated by the effect on the arterial perfusion pressure caused
by a forced increase (upper) and a forced decrease (lower) in blood flow through an isolated
skeletal muscle. Observe that the change in flow resulted in a change in pressure followed by
a slower secondary change caused by autoregulation.

tering the muscle. Secondarily, a slow increase is seen

over the next 2 minutes while flow was maintained
constant with the perfusion pump. This slow increase
in pressure with a constant flow was caused by a progressive autoregulatory increase in vascular resistance.
These locally controlled adjustments of skeletal
muscle blood flow also play an important role during
increased tissue metabolic activity initiated either artificially by electrical stimulation or during physical exercise in the intact state. The predominance of local
mechanisms in regulating skeletal muscle blood flow
is demonstrated by the observation that during prolonged exercise blood flow through a totally denervated
hindlimb of a dog is the same as that in the innervated
contralateral limb.
Mechanism of Autoregulation.
Four major hypotheses
have been proposed to explain local tissue regulation
of blood flow [13,14]. The first, the metabolic theory,
evolved from observations that either decreased oxygen
tension or decreased pH of the blood cause vasodilation.
Secondly, the myogenic theory resulted from the observation that vascular smooth muscle relaxes with
decreased vascular transmural pressure. Thirdly, viscosity factors figured in another hypothesis since a de-

crease in capillary hydrostatic pressure is known to

cause influx of tissue fluid which lowers the viscosity
of blood flowing through the veins. The fourth hypothesis, based on tissue pressure, is also linked to a decrease
in capillary hydrostatic pressure since influx of tissue
fluid ultimately decreases the tissue fluid pressure
surrounding the vessels. Unfortunately, it has been
difficult to devise experiments to determine the relative
importance of each of these factors independently of
one another [which also appear to differ from organ to
organ].
Local regulation of blood flow is believed to reside at
the level of the immediate precapillary vessels (20 to 15
ccwide]. Within these small vessels flow is maintained,
in many tissues, within a narrow range despite wide
fluctuations in pressure. In some tissues, however,
control of blood flow is located more proximally in the
microcirculation enabling shifts of flow between entire
capillary networks. The local autoregulatory responses
in most tissues appear to be closely linked to cellular
delivery and utilization of oxygen, but a variety of
metabolic end products have also been suggested as
moderators of vascular tone such as oxygen, per se,
carbon dioxide, hydrogen, potassium, adenosine, adenine nucleotides and Krebs-cycle intermediate me-

June 1990 The American Journal of Medicine

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OF BLOOD FLOW AND ITS ROLE IN HYPERTENSION-COWLEY

Hematocrit

Efii
/min)
(L

53

52

52

:17,
os

~---

I50

Arterial
Pressure 100

3%

+I0

Pressure
@!I(mmlig)
-I0
27

Figure3. Whole body autoregulation demonstrated in a dog following total removal of the
central nervous system. cardiac output was decreased by removal of blood and arterial pressure
was maintained at 55 mm Hg. Note the initial decrease in arterial pressure as cardiac output
decreased. This is followed by a gradual increase in cardiac output as total peripheral resistanoe
(not shown) decreased by autoregulation.

Also, a variety of humoral substances have

been investigated in the local regulation of blood flow,
but as yet there are no definitive results. Local control
of flow has been observed to persist after adrenergic,
cholinergic and histamine@
blockade, and under
conditions which appear to exclude serotonin and
bradykinin. Further, recent data suggest a possible role
for prostaglandins in local regulation of flow, especially
in the kidney and skeletal muscle, but further studies
are required in this area. In brief, the local mechanisms
that regulate tissue blood flow remain to be elucidated.
Since nearly
Autoregulation of the Total Cirdation.
all of the individual organ systems locally adjust their
vascular resistance to some degree to maintain an appropriate flow, it follows that the sum of all the tissue
resistances and the total blood flow through the entire
circulation [cardiac output] is ultimately influenced by
autoregulation. The total peripheral resistance is in this
manner determined by the spectrum of tissue autoregulatory capacities ranging from relatively passive
tissues, such as skin, to highly autoregulated tissue, such
as the skeletal muscle and kidney.
Whole body autoregulation has been demonstrated
in dogs in which the nervous system was eliminated by
spinal decapitation so that the rapidly acting reflex eftabolites.

910

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The American Journal of Medicine

fects on vascular resistance did not occur to obscure

slower acting local autoregulatory events (151.In these
animals, the total flow through the circulation (cardiac
output] was decreased by removal of whole blood while
the arterial pressure was recorded and total peripheral
resistance was calculated (see Figure 3).
Arterial pressure was abruptly lowered to 50 mm Hg
by opening the arterial system to a blood reservoir fixed
at a constant height above the animal. Both cardiac
output and arterial pressure decreased immediately as
blood was removed, but this was accompanied by essentially no change in total peripheral resistance since
cardiovascular reflexes were absent. Whole body autoregulation was demonstrated over the subsequent 30
minute period by a gradual decrease in total peripheral
resistance to 45 per cent of control. This vasodilatation
of vessels resulted in blood being autotransfused back
into the animal since the blood reservoir was at a height
set to equilibrate with arterial pressure at 50 mm Hg.
The autoregulatory vasodilatation and re-expansion of
blood volume resulted in a return of cardiac output to
within 92 per cent of the initial control value. Conversely
too, from other experiments described herein, it is also
clear that within a period of several hours, an increased
cardiac output from volume overload can lead to an
increased blood pressure, mostly because of a secondary

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OF BLOOD

0 204060
-MINUTES
-

-HOURS-

FLOW AND ITS ROLE IN HYPERTENSION-COWLEY

I---MEAN

ARTERIAL
PRESSURE
1% of normal)

CARDIAC
OUTPUT
(% of normal)

TOTAL
PERIPHERAL
RESISTANCE
(% of normal)

I 2

012345

3
-

MONTHS

Figure 4. Illustration of the response to expansion of blood volume with an assocj@d increase in cardiac output under three conditions. A, with no autoregulatipn
the increase in arterial pressure is directly proportional to the increase in cardiac
output. B, with strength of autoregulation exhibited over a short period, arterial
pressure is directly related only initially to the increase in cardiac output. After
several hours, an increase in cardiac output of only 10 per cent sustains arterial
pressure at 43 per cent above normal. C, long-term autoregulation following several
months enables the same increase in cardiac output (10 per cent) that resulted in
only a slight increase in pressure in the short-term state seen in A, to now sustain
pressure at 100 per cent above normal

increase in the total peripheral resistance, rather than

a direct result of increased flow.
Rapid Versus Long-Term Control of Tissue Blood Flow.
The autoregulatory
events thus far presented have involved relatively brief time periods and were studied
under well controlled conditions. But how then does the
vasculature respond over a period of days and months
to situations which would result in the long-term overperfusion or underperfusion
of tissues?
It is clear from a number of observations
that the
vasculature
is capable of adjusting tissue flow quite
close to normal under these situations. It is also apparent
that mechanisms
in addition
to those involved
in
short-term autoregulation are called into play. Although
the exact nature of these events is unclear, for the
present discussion
we shall refer to these vascular
changes as long-term autoregulation.
Among the many examples of this phenomenon,
perhaps the most dramatic illustration of long-term tissue autoregulation
is the adjustment of blood flow observed in patients with coarctation of the aorta. Measurements have shown that despite increased arterial
pressure in the upper extremities with normal or below
normal pressure in the lower extremities, the blood flow
per unit mass of tissue is nearly equal in both locations

[16]. Such opposite adjustments

in vascular resistance
between the upper and lower extremities in the presence of the same hormonal milieu cannot be explained
on the basis of any circulating substance nor by any
known neural mechanisms.
There are undoubtedly
multiple
and complex
mechanisms
involved in these long-term autoregulatory vascular responses. These may or may not include
those immediate events which are observed in shortterm isolated perfused organ studies. Long-term autoregulation
appears to develop as a result of mechanisms which traditionally
have not been defined as
autoregulation
but which are probably also directly or
indirectly related to oxygen delivery and are local in
origin. The most striking long-term adjustment
anatomically is the gradual alteration of vascular architecture
by changes in wall thickness and length, and the growth
or retardation of new and existing vessels. Such changes
are well known to accompany
normal growth and
maturation, and it should not be surprising that similar
changes also accompany
various types of long-term
stress to the system. These slowly developing structural
changes appear to contribute to the adjustments in total
peripheral
resistance which have been observed in
established hypertension.
Some of these changes may

June 1980

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AUTOREGULATION

OF BLOOD FLOW AND ITS ROLE IN HYPERTENSION-COWLEY

result from changes induced by the high pressure per

se.
Our present understanding of these events leads us
to conclude that short-term autoregulation is a selflimiting process which can only compensate to the extent that existing vessels are able to constrict or dilate,
excellent for short-term stresses such as exercise.
However, in situations of chronic volume overload or
a prolonged alteration in tissue metabolic rates (hyperthyroidism), the needs of tissues appear to be best
met by more or less permanent vascular alterations in
structure.
Capabilities of Converting Flow-Dependent Hypertension into Resistance-Dependent Hypertension by
Autoregulation.
It is important to know the over-all
strength or ability of autoregulatory mechanisms to return tissue blood flow towards normal, for this determines the extent to which the blood volume and cardiac
output will be altered during hypertension. The degree
of the increase in arterial pressure which can be
achieved with a 10 per cent increase in cardiac output
is illustrated at three different time-dependent strengths
of autoregulation. The changes seen in Figure 4 were
estimated using a mathematical model of the ciroulation
in which the strength of autoregulation was adjusted to
simulate the steady-state values observed in volumeexpanded, partially nephrectomized, animals and anephric patients. In the absence of autoregulatiori, (Figure
4A) a 10 per cent increase in cardiac output would sustain approximately a 10 per cent increase in arterial
pressure. This is the type of response observed with
rapid blood volume expansion (10 minutes) in the absence of baroreceptor reflex mechanisms [lo].
However, in the presence of an autoregulatory response equivalent to that which has been shown to occur
over a time period of 1 to 2 hours, a comparable increase
in cardiac output (10 per cent) is associated with a 43 per
cent increase in arterial pressure (Figure 4Bj [15].
The long-term strength of the autoregulatory mechanism which develops over days and weeks far exceeds
that observed acutely (Figure 4C). On the basis of evidence from patients with coarctation of the aorta and a
variety of animal studies, it appears that the system is
capable, in time, of sustaining a 100 per cent increase
in arterial pressure with only a 10 per cent increase in
cardiac output [16].
It is important to recognize that even with a large
sustained volume overload, as occurs when fluid intake
is increased to seven times normal in subjects with reduced renal mass, the large initial increase in cardiac
output is nearly normal at the end of several weeks.
Experimentally it has been necessary, to administer
massive volume overloads to demonstrate the transient
increases in fluid volumes and cardiac output. The autoregulatory events cannot be unmasked using a very
slow expansion of body fluids since the long-term autoregulatory adjustments occur at nearly the same slow

912

June 1980 The American Journal of Medicine

rate as body fluid accumulation, and, consequently,

large changes in fluid volumes or cardiac output do not
occur. Since even massive volume loading is associated
with less than a 10 per cent increase in cardiac output
and fluid volume at the end of one to two weeks, one
would not expect to be able to detect clinically (using
any available means) alterations of cardiac output or
volumes during hypertensive states associated with slow
accumulation of salt and water. The preceding analysis
indicates that an overexpansion of blood flow of only
5 per cent (clinically undetectable) could sustain an
increase in arterial pressure in excess of 50 per cent of
normal. Thus, the amount of excess volume and flow
needed to initiate the long-term autoregulatory changes
in resistance is probably extremely small. Measurement
of cardiac output or blood volume in a person with
long-standing hypertension can, therefore, provide little
information as to whether or not flow or volume had any
significant role in initiating the hypertensive process.
The more powerful long-term autoregulatory events
appear to develop only over many days or weeks. Sudden changes in fluid volume or redistribution of body
fluids accompanying postural changes or exercise are
adjusted by reflexes, hormones, physical factors such
as stretch of vessels, capillary fluid filtration and renal
diuresis. But, if fluid volumes remain expanded over
prolonged periods enhancing the cardiac output, autoregulatory mechanisms act to increase vascular resistance and adjust local flow rates to an appropriate
level.
It should be apparent that there are possibly certain
clinical types of hypertension in which these mechanisms could play a significant role in the long-term adjustment of total peripheral resistance. These include
particularly that group of situations in which renal
function is in some way chronically impaired resulting
in fluid retention. For example, coarctation, bilateral
renal artery constriction, reduction.of functional renal
mass, glomerulonephritis and pressure-induced nephrosclerosis. In all of these situations, expanded blood
volume and increased cardiac output may occur at some
stage of development of hypertension which finally
expresses itself by an increased total peripheral resistance.
Under What Conditions is Autoregulation Expected
to Occur? Unfortunately, the concept of autoregulation
has often been inappropriately applied. Some investigators have attempted to use the concept to account for
the increased total peripheral resistance in all forms of
hypertension. Others have tried to apply it to all situations of short-lasting and long-lasting volume overload.
When the observed hemodynamic changes have not
been in agreement with what might be predicted by
autoregulation, the validity of the theory has been
questioned. For this reason it is important to examine
some of the conditions that must be met in order to observe autoregulation.

Volume 66

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OF BLOOD

First, an autoregulatory increase in vascular resistance

can only occur when the expansion of blood volume
results in overperfusion of body tissues. This volume
expansion may be real, or it may be reflected as only a
change in the effective volume, the meaning of which
is as follows: The ratio of total blood volume to total
systemic compliance [arteries and veins) determines the
degree of fullness of the entire systemic vasculature.
This degree of fullness can be altered by either a
change in real volume within the vessels or by a
change in the absolute size or compliance of the total
systemic vasculature. When the systemic filling pressure is altered by a change in size or compliance, with
no change in the real volume, the same hemodynamic
consequences result as would be seen with a real
volume change. Thus, it is referred to as a change in
effective volume. It is the systemic filling pressure
that provides the driving force for venous return to the
heart [l7]. Since either a real or effective volume
change can affect the filling pressure and thereby the
cardiac output, measurements of the total blood volume
per se are of limited value in studying the hemodynamic
mechanisms of hypertension. Unfortunately, the effective volume or the degree of filling of the vasculature cannot yet be clinically determined so that interpretation of clinical volume data is difficult.
The second condition to be met if autoregulation is to
be observed is that the heart must be capable of adequately increasing its cardiac output when subjected
to an increased load. In cardiac failure, even a large
overexpansion of total blood volume need not result in
increased cardiac output or tissue overperfusion. On the
other hand, normal heart subjected to chronic volume
overload will hypertrophy and could sustain an even
greater cardiac output and magnify autoregulatory
events.
Third, all the systems responsible for delivery of tissue
oxygen and other tissue nutrients must be normal. If the
oxygen carrying capabilities of the blood are depressed
as in anemia, an increased tissue blood flow would not
be perceived as excessive, and increased vascular resistance by autoregulation would not result. Similarly,
expansion of the blood volume space with isotonic saline solution would decrease the hematocrit and thereby
decrease the oxygen carrying capability of the blood.
Drugs which can potentially alter the dissociation constant of hemoglobin could also influence autoregulatory
mechanisms.
Fourth, the metabolic needs of the tissue must remain
unchanged since changes in the metabolic rate alter
tissue flow requirements which can alter tissue blood
flow independently of the blood volume status, For
example, thyrotoxicosis greatly enhances metabolic
needs and is associated with sustained increases in
cardiac output. It is, therefore, important to know if any
interacting hormones or drugs have influenced the tissue metabolic requirements before attempting to in-

FLOW

AND ITS ROLE IN HYPERTENSION-COWLEY

terpret observed alterations of cardiac output and total

peripheral resistance. Many substances do have such
actions including thyroid hormones, corticosteroids,
catecholamines, insulin, certain vitamins, and many
other hormones and drugs.
Fifth, the fluids which have initiated the expansion
of blood volume must be held within the vasculature.
Situations which lead to increased capillary filtration
or renal diuresis can readily obscure changes in vascular
resistance expected on the basis of autoregulation.
Dilution of plasma proteins must always be considered
in this regard.
Thus, there are many events that can obscure what
at first might be expected to result in a predictable autoregulatory response. These must always be included
in our interpretation of hemodynamic changes.
Does the Sequence of Volume Expansion and Autoregulation Occur in all Forms of Hypertension?
Clearly, volume expansion with consequent autoregulation of flow need not be the only mechanism that increases peripheral resistance during the development
of hypertension. Some forms of hypertension appear to
be initiated solely by constriction of both renal and peripheral arterioles, with changes in body fluid volumes
and cardiac output being only secondary consequences
of a high total peripheral resistance. Examples of such
situations are renovascular hypertension or renal tumors, or trauma with release of renin and formation of
angiotensin, or pheochromocytoma with abrupt release
of norepinephrine.
Forms of Hypertension in which Autoregulation Can
Explain the Changes in Vascular Resistance. Salt
loading: The form of hypertension in which autoregulation best explains the observed increase in total peripheral resistance is that of pure volume expansion.
These sequential hemodynamic changes, shown in
Figure 1,have been observed in anephric man in whom
blood volume was expanded by hemodialysis 1181.The
vascular adjustments in this form of hypertension are
not a result of changes in sodium ion concentration since
expansion of the extracellular fluid volume using dialysis to maintain a constant sodium ion concentration
yields similar changes [19].
Renal artery stenosis: Hypertension experimentally
induced by constricting the renal artery of the sole remaining kidney (in the presence of adequate salt and
water) results in expanded blood volume with increased
cardiac output and arterial pressure. Thereafter, the
sequence of hemodynamic events is generally similar
to that observed in the salt-loading model of hypertension shown in Figure 1. Blood volume and cardiac output return toward normal over one to two weeks, and
total peripheral resistance gradually increases to sustain
the state of hypertension [20]. Constriction of a single
renal artery in the presence of a normal contralateral
kidney is less clear, but it appears to result in a similar
but less dramatic sequence of changes.

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In the presence of stenosis of a single remaining

kidney with salt and water intake maintained very low,
volume expansion probably does not occur and hypertension is sustained by excess renin release and angiotensin formation [Zl]. With the increased peripheral
resistance and pressure there is an associated decrease
in cardiac output. In time, however, cardiac output increases towards control levels. This situation emphasizes that autoregulation can operate in two directions
in that it can in time return either excess or depressed
flows toward normal.
Long-term infusion of norepinephrine
into renal artery: It has recently been observed in our laboratory
that the long-term infusion of norepinephrine into the
renal artery of a single remaining kidney results in hypertension which is associated with yet a different sequence of hemodynamic changes [22]. In this instance,
pressure increases gradually during the first week but
during this time there is no detectable expansion of
extracellular fluid volume or blood volume. Hypertension is sustained initially by an increased cardiac
output which appears to be increased by the venous
constriction from high circulating levels of norepinephrine. By the 10th day of norepinephrine infusion,
cardiac output is nearly normal and hypertension is
sustained by an increased total peripheral resistance.
This model is unique in several respects. First, cardiac
output becomes increased with no expansion of the
absolute blood volume, probably due to an increase in
the effective volume. Second, the vascular changes
in this model are not associated with sodium retention,
a condition which some people have believed necessary
to initiate the autoregulatory response and which in fact
occurs in salt-loading as described.
Essential hypertension:
Increased cardiac output of
nearly 20 per cent in the early stages of some forms of
human hypertension with normal peripheral resistance
has been reported by many investigators. This pattern
is reversed in older patients with well-established essential hypertension who show normal or below normal
cardiac output and a markedly increased peripheral
resistance [23]. Although the time scale is considerably
extended compared to the laboratory models of hypertension, the sequence of hemodynamic changes is
similar and may be at least partly autoregulatory in
nature.
Forms of Hypertension in which Autoregulation Does
Not Explain the Observed Sequence of Hemodynamic
Changes. Primary angiotensin-induced hypertension:
Prolonged intravenous angiotension II infusion in dogs
in amounts equivalent to nearly eight times the normal
rate of formation, increases arterial pressure to about
160 mm Hg over the first day of infusion. Cardiac output,
however, is immediately decreased by 20 per cent and
remains less than normal throughout a 10 day experimental period, blood volume remains constant [24].
Under these circumstances, therefore, hypertension is
sustained from the onset by an increased total periph-

914

era1 resistance from angiotensin II and later by an alteration of renal function [see next section). Although
not yet studied for sufficiently prolonged periods, it
would be expected that in time autoregulation would
result in a tendency for resistance to decrease and cardiac output to increase towards control levels.
Mineralocorticoid-induced hypertension: Recently
it has been reported that experimental hypertension in
dogs and pigs induced by prolonged administration of
deoxcorticosterone acetate (DOCA) together with 1 per
cent NaCl is not associated with an initial increase in
cardiac output [25,26]. Although these results have been
interpreted as evidence against autoregulation in this
form of hypertension, this may not be the case. Experimental variations in the measurement of cardiac output
can readily exceed the relatively small and slowly occurring changes that might accompany this form of hypertension. Even a 5 to 10 per cent increase in cardiac
output (as explained herein] could lead to an autoregulatory increase in total peripheral resistance, so interpretation of these studies must proceed with caution.
Recent evidence suggests that vasoconstrictor actions
associated with elevated plasma vasopressin levels
could also complicate the interpretation of this form of
hypertension, but the precise role of vasopressin in this
situation remains to be elucidated [27]. Whatever the
case in these experimental models, primary aldosteronism in man appears to be associated with a transient
hypervolemia and increased exchangeable sodium,
which returns to control in several weeks [28], suggesting the postulated autoregulatory sequence. It should,
therefore, be recognized that autoregulation need not
be observed with some forms of hypertension, which
is well illustrated by angiotensin II hypertension as
discussed herein. These findings, however, do not invalidate the application of the autoregulatory concept
in those forms of hypertension in which it clearly
applies.
Is an Initially High Cardiac Output and Autoregulation
a Cause of Hypertension ? It is widely believed that
autoregulation can in itself cause hypertension since the
intrinsic vascular changes result in an increased state
of total peripheral resistance. It is becoming clear,
however, that the widely held belief that hypertension
results solely from an increase in total extrarenal peripheral resistance per se is a misleading oversimplification. This is because the long-term level at which arterial pressure stabilizes can only be changed if the increases in peripheral vascular resistances include the
renal vasculature.
The role of renal vascular resistance and renal excretory function in the long-term control of arterial
pressure has been developed in great detail over the past
decade by Guyton and associates [29]. These studies
have demonstrated that the long-term level at which
arterial pressure is regulated is ultimately determined
by the ability of the kidney to produce urine at a given
perfusion pressure and by the total volume (i.e., filtration

June 1989 The American Journal of Medicine Volume 68

AIJTOREGULAIION

pressure) load presented to the kidney. Thus, in hypertension. renal function must be altered in such a way
as to require increased perfusion pressures in order to
allow the kidney to filter and excrete amounts of salt and
water equivalent to the levels of daily intake. If the arterial pressure level is not sufficient, fluid will accumulate until such a systemic renal perfusion pressure
is achieved. Since we have seen that autoregulatory
mechanisms
possess
considerable
compensatory
strength, only a small amount of fluid retention and
increased cardiac output is required to do this. so small
that in the steady-state
condition they are nearly undetectable.
The renal-fluid
volume mechanism for determining
arterial pressure occurs slowly and is often masked by
prevailing
more rapidly acting reflex and hormonal
mechanisms.
However, in time this pressure-diuresis
system prevails over all the other systems and determines the long-term level of arterial pressure.
There are of course many ways to influence
renal
function and thereby alter the body-fluid volume status.
These include iritrinsic afferent arteriolar constriction,
sympathetic
or humoral
arteriolar
vasoconstriction
(angiotensin), stenosis of the renal artery. compression
of the kidney, decreased glomerular capillary permeability, excessive tubular reabsorption of salt and water
(aldosterone), and reduction of nephron population by
surgery or disease.
One of the major consequences
of the renal-body
fluid volume pressure control system is that increases
in total extrarenal peripheral resistance per se can cause
only a temporary state of hypertension unless resistance
is also changed within the kidney. If renal resistance is
not simultaneously
altered, an increase in pressure will
merely reduce body fluid volumes by inducing natriuresis and diurcsis until a normal pressure is once again
reached. This ineffectiveness
of a pure change in peripheral vascular resistance exclusive of the kidney is
illustrated in patients who have undergone closure of
an atrioventricular
fistula. The immediate increase in
peripheral resistance results in a dramatic increase in
arterial pressure. In time, pressure returns to normal as
the blood volume is reduced, and fluid and electrolytes
are again returned to a normal level of arterial pressure.
Similarly, amputation
of all four limbs immediately
increases total peripheral
resistance over 50 per cent,
but in time the increased arterial pressure associated

OF RLOOD FLOW AND ITS ROLE IN HYPERTENSION.-COWLEY

with this increased resistance returns toward normal.

Normal pressures are also generally observed in a variety of diseases which result in a decrease in total peripheral resistance
to flow such as Pagets disease,
beriberi and hyperthyroidism.
Here then is the issue that causes perhaps the greatest
difficulty in understanding
hypertension.
If arterial
pressure is determined
only for short periods by the
systemic (extrarcnal) vascular resistance and cardiac
output, what then do these variables have to do with
hypertension?
The answer to this is that individually
they have very little to do with the long-term level of
arterial pressure. The cardiac output and total peripheral resistance arc variables which are dependent
on
a veIy complex autoregulatory system geared to regulate
blood flow through tissues. They can be altered independently of one another, in the same or opposite directions to sustain any level of arterial pressure. As we
have just seen, arterial pressure can be increased with
a reduced cardiac output and a high total peripheral
resistance;
or it can be increased
with a normal or
slightly increased cardiac output in the presence of a
high total peripheral
resistance; or with an increased
cardiac output and a reduced total peripheral resistance
as is seen in the initial phase of volume load in hypertension.
Cardiac output and total peripheral resistance can,
therefore, be manipulated
in a variety of ways to produce any level of arterial blood pressure. For this reason,
regulation of cardiac output cannot explain hypertension. This mechanism can only account for the gradual
increase in total peripheral resistance initiated by the
expansion of blood volume. Since volume expansion
and increases in cardiac output need not necessarily
occur in the development
of hypertension,
autoregulation is. therefore, observed in only certain forms of the
disease.
ACKNOWLEDGMENT
The many contributions
made by Dr. Arthur C. Guyton
over the past 15 years in the theoretic development
and
application
of the concerts
of autoregulation
are
gratefully acknowledged.

Appreciation
is also extended
to Drs. Thomas G.
Coleman and Thomas E. Lohmeier for their helpful
criticism of the manuscript.

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