Autoregulation Versus Other Vasoconstrictors
in Hypertension
A Critical Review
THOMAS G. COLEMAN, P H . D . , ROBERT E. SAMAR,
AND WILLIAM R.
PH.D.,
MURPHY, P H . D .
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SUMMARY Hypertension is a disease of relatively normal blood flow and increased vascular resistance.
The search for neural and humoral vasoconstrictors to explain this pattern has not produced convincing
evidence in most cases. Autoregulatory vasoconstriction is an alternative explanation supported by Borst,
Ledingbam and others; the validity of this idea is strengthened by frequent observations of relatively normal
cardiac output and blood flow distribution in hypertension. Autoregulatory vasoconstriction has been combined
with concepts of renal excretory function to form the following theory: Renal excretion is determined by
arterial pressure — pressure must be high enough to maintain salt and water balance — and autoregulation
provides the hemodynamic pattern of vasoconstriction with normal flow. Several different types of experiments
point to the kidney as the long-term controller of blood pressure. However, data relevant to the autoregulatory
part of the theory are conflicting. In some experiments, autoregulation is suggested by changes in flow that
precede changes in resistance. In other experiments, no change in flow has been observed. In some experiments, volume expansion appears to be an intermediary between kidney dysfunction and the
autoregulatory response. In other instances, volumes are normal or low. Flow relative to metabolic needs,
venous capacity, and the abruptness of the hypertension-producing perturbation become important considerations in understanding these results. The argument that autoregulation supplies vasoconstriction in most
cases of hypertension is based on interpretation of many different observations that are unfortunately relatively
indirect. Controversy over vasoconstrictor mechanisms in hypertension is fostered by a lack of direct experimental results either supporting or refuting the various possibilities. (Hypertension 1: 324-330, 1979)
KEY WORDS • hypertension • autoregulation • cardiac output
• vasoconstriction • arterial blood pressure • renal excretion
H
YPERTENSION is generally characterized
by increased arterial pressure and increased
vascular resistance. The search for a
vasoconstrictor mechanism to explain the increased
total peripheral resistance has focused on humoral
factors such as renin, and on overactivity of the
autonomic nervous system. But in many instances,
changes in these suspected variables are small in relation to the increases in resistance observed, and additional phenomena, such as subtle effects, cumulative
effects, or supersensitivity, have been postulated.
None of these explanations has been entirely satisfac-
• total peripheral resistance
tory and further examination of the relationships
between arterial pressure, blood flow, and vascular
resistance in hypertension seems warranted. This
paper reviews autoregulatory phenomena and the
possibility that autoregulation is responsible for the
vasoconstriction seen in hypertension.
Total and Regional Blood Flow in Hypertension
In hypertension, measurements of cardiac; output
and regional blood flow in a wide variety of instances
have shown values within the normal range for these
variables.1 Measurement of cardiac output sometimes
shows values that are outside of the normal range but
these observations can often be explained in terms of
accepted pathophysiological mechanisms. For instance, elevated cardiac output in young hypertensive
patients appears to be a response to increased
From the Department of Physiology and Biophysics, University
of Mississippi Medical Center, Jackson, Mississippi.
Supported in part by NIH Grants HL 11678 and HL 07270.
Address for reprints: Thomas G. Coleman, Ph.D., Department of
Physiology and Biophysics, University of Mississippi Medical
Center, Jackson, Mississippi 39216.
324
VASOCONSTRICTION IN HYPERTENSION/Co/eman et al.
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metabolism and oxygen consumption.2 Elevated cardiac output in end-stage renal disease seems to be due
to the underlying anemia;3 the increased flow is an appropriate response to decreased red cell mass. In some
instances, such as in very severe hypertension, inappropriately low blood flows are observed. Figure 1
shows a sampling of cardiac indices from nine hypertensive patients on chronic hemodialysis.4 In these
patients, subnormal cardiac indices correlated with
very high plasma renin levels; our interpretation is
that angiotensin-induced vasoconstriction dominates
the control of blood flow in this situation and reduces
flow to levels that are below those that would normally
be mediated by metabolic demands. The data points
shown in the left half of figure 1 are in the normal
range and are typical of the vast majority of instances
in which cardiac output is observed to be normal in
hypertension.
A variety of techniques have been used to estimate
regional blood flow in hypertension. Brod et al.5 found
elevated total peripheral resistance and normal cardiac output along with vasoconstriction in skin and
kidneys in patients with essential hypertension. He did
note, however, that skeletal muscle in the arm was not
vasoconstricted. In experimental animals, microspheres have been used to measure blood flow and it
appears that in most instances the tissues all receive a
normal blood flow.*'7 Therefore, although there are
some exceptions, hypertension can in general be
characterized by a vasoconstriction that occurs in all
organs. It should be noted that both angiotensin8 and
autonomic nerves8 do not affect all vascular beds
equally and therefore produce a redistribution of
vascular resistance and blood flow.
Vasoconstriction, at least in benign cases of hypertension, does not represent a fixed resistance. For instance, the values of increased cardiac output and
decreased total peripheral resistance observed in exercising hypertensive patients are nearly the same as in
exercising normotensive subjects. Lowenstein et al.10
observed a renal vasodilation during saline loading in
essential hypertensive patients that was actually
greater than that seen in normotensive subjects.
Therefore, the vasoconstriction appears to be functional in these instances and vasodilatory stimuli can
acutely lower total peripheral resistance in the face of
a chronic vasoconstriction.
Autoregulation as a Vasoconstrictor in Hypertension
An explanation that is consistent with a generalized
elevation in peripheral resistance and normal tissue
perfusion is that increased resistance in hypertension
is due to autoregulation of blood flow. Autoregulation
in this case means that an individual tissue can intrinsically regulate its own blood flow via changes in
vascular resistance. Borst and Borst-de Geus11 and
Ledingham and Cohen12 were among the first to apply
this concept in detail to the genesis of hypertension.
Borst and Borst-de Geus were analyzing the hypertension that accompanies overindulgence in licorice and
were trying to connect increased arterial pressure and
Q
325
tt)
s 1
I
I
10
I
100
PLASMA RENIN ACTIVITY
(ng. Angio I/ml./hr.)
FIGURE 1. Cardiac index as a function ofplasma renin activity in hypertensive patients undergoing chronic
hemodialysis.
vasoconstriction with expanded body sodium. They
suggested that because of autoregulation, fluid retention will cause "an increase in cardiac performance
. . . [that will] . . . ultimately be reflected in a rise in
arterial pressure only; cardiac output will remain normal." Ledingham and Cohen" replied that if this were
the case than "a phase of increased cardiac output
[would] be demonstrated during the development of
hypertension." Ledingham and Cohen had already
shown that a transient phase of decreased cardiac output preceded vasodilation in the reversal of renal
hypertension after unclipping the renal artery.13
Guyton and colleagues used mathematical methods to
analyze the possible temporal relationships in an
autoregulatory response.1*116 Their analysis predicted
that temporary derangements in flow and volume
could occur at the onset of hypertension; the
magnitude and time course of these changes would depend on the severity of the stimulus and the responsiveness of the circulatory system. However, almost
every aspect of these changes was transient in this
analysis and little derangement was predicted for established hypertension.
A similar hemodynamic pattern was observed in
Guyton's laboratories in a series of experiments in
dogs. Langston et al. 1 ' showed that subtotal nephrectomy plus saline produced a hypertension that was
reversible when the saline administration was discontinued. Douglas et al.17 showed that increases in blood
volume, exchangeable sodium, and interstitial fluid
pressure temporarily accompanied the onset of
hypertension in this model. In the same preparation,
Coleman and Guyton1* further showed that right
atrial pressure and cardiac output were elevated at the
326
HYPERTENSION
150-
VOL 1, No 3, MAY-JUNE
1979
The Kidney, Fluid Volumes and Vasoconstriction
MO-
Autoregulation in this analysis is only part of the
total explanation of arterial hypertension. The concept that has been widely reviewed and discussed is
IE: 120that renal dysfunction is the initiating event in
hypertension.11- "• 1 M l The idea is built around the
concepts of long-term salt and water balance and the
KX>kidneys' excretory capacity. Many factors influence
90renal excretion: physical composition of the blood,
nervous influences, aldosterone, antidiuretic hormone,
angiotensin, blood pressure, and possibly many other
yet undiscovered factors. Normally, salt and water
balance can readily be maintained by some combination of these factors working in concert to precisely
adjust excretion in response to the body's needs and in
response to capricious intake. However, in cases such
as renal disease, hyperaldosteronism, or pheochromocytoma, the normal balance of influences is
upset. Furthermore, most of these factors have a
limited capacity to alter salt and water excretion. At
very low blood pressure, for instance, excretion is impaired even though all of the factors may be attempting to facilitate excretion. The renal dysfunctionI4O-,
autoregulation theory postulates that when other
regulatory factors are upset or are not powerful
enough to maintain fluid blance, then increased blood
pressure is required as a last resort to maintain salt
and water balance.
Several different experimental approaches have
produced data that support the notion that renal
dysfunction is the most important factor in the initiation of hypertension. These include perfusion of
isolated kidneys, measurement of blood pressure and
sodium
excretion in the intact animal at different
FIGURE 2. 77ie time course of pressure, flow, and
resistance changes in subtotally nephrectomized dogs made levels of excretion and in different experimental
models, and cross transplantation of kidneys. The
hypertensive by isotonic saline infusion. (Reproduced from
results in general support the theory outlined above.
Coleman TG, Guyton AC: Hypertension caused by saltFor instance, Thompson and Dickinson21 found that
loading: III. Onset transients of cardiac output and other
greater than normal blood pressures were needed to
circulatory parameters. Circ Res 25: 153, 1969 with perproduce normal excretion in perfused kidneys from
mission.)
renal hypertensive rabbits. In a similar protocol, Tobian et al." found a depressed excretory function in
perfused kidneys from the Dahl strain of spontaneously hypertensive rats; that is, normal excretion
onset of hypertension. Figure 2 shows the arterial
could only be achieved at high perfusion pressure.
pressure, cardiac output, and total peripheral
Norman et al." found an altered blood pressureresistance relationships observed during the first 13
excretion relationship in intact spontaneously
days of isotonic saline infusion into a gToup of six subhypertensive rats and renal hypertensive rats. Crosstotally nephrectomized dogs. Increased cardiac output
transplantation studies have shown the kidney to be a
preceded the increase in total peripheral resistance.
fundamental component of hypertension in the Milan
These results are consistent with the idea that the instrain18 and the Dahl strain" of spontaneously hyperdividual tissues adjust their resistance, and subsetensive rats. Although not universally proven, and still
quently their flow, according to the local metabolic
very controversial in the case of essential hypertenneeds rather than in response to external signals. If
sion, the data generally support the concept that
autoregulation controls flow via resistance changes in
decreased excretory capacity is important in the
hypertension, we would expect hypertension to be
maintenance and probably in the cause of many
characterized by increased resistance and normal flow;
different forms of hypertension.
if humoral or nervous vasoconstrictors adjusted
resistance independent of the metabolic needs of the
Difficulties arise in trying to connect observations of
tissues, we would expect flow derangement to often be
renal dysfunction with subsequent vasoconstriction.
a part of the overall hemodynamic description of
The simplest explanation is that decreased excretion
hypertension.
leads to fluid retention and that the fraction of the
Id
130-
*=?
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VASOCONSTRICTION IN
retained fluid that remains in the circulation causes increased blood flow that, in turn, triggers the
autoregulatory vasoconstriction. The final result
would be increased pressure and increased resistance
with normal flow. If the autoregulatory response is
very powerful, little residual disturbance in volume
and flow would be necessary to maintain the
vasoconstriction. There is evidence both in support of
and in conflict with this simple explanation, and there
are also more complex explanations built upon the
basic principle of autoregulation of blood flow. Some
of these details are discussed below.
Detailed Considerations of Autoregulation in
Hypertension
Circulating Vasoconstrictors
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Autoregulatory vasoconstriction is definitely not
required to explain resistance increases in situations
where high levels of circulating vasoconstrictors are
present. Hyperreninemia with advanced renal disease
and increased catecholamine concentrations in
pheochromocytoma are two examples in humans as is
the hypertension produced by I.V. angiotensin infusion in animals. These cases account for only a small
percentage of the total incidence of hypertension,
however.
Hemodynamlc Transients
With regard to autoregulatory transients, some experimental results have shown a temporal hemodynamic relationship wherein changes in flow precede
changes in resistance. Some results have not shown
this. The response of the salt-loaded, subtotally
nephrectomized dogs described above show the temporal pattern of increased flow preceding increased
resistance. Bianchi et al." and Ledingham and
Cohen2* saw early elevations in cardiac output in renal
hypertension in rats. Ferrario saw increased cardiac
output in perinephritic hypertension™ and in Goldblatt
hypertension30 in dogs. But, the observed transients in
the latter study seem to be much too prolonged to be
ascribed totally to autoregulation. In contrast,
Fletcher et al.31 saw a gradual decrease in cardiac output with increasing blood pressure after wrapping rabbit kidneys with cellophane. Terris et al." did not see
any increase in cardiac output when pigs given deoxycorticosterone acetate (DOCA) became hypertensive,
but Conway and Hatton 33 saw small, temporary increases in cardiac output in unilaterally nephrectomized dogs given DOCA plus saline. We observed a
transient increase in the cardiac output of anephric
patients that accumulated excess salt and water during
hemodialysis.34 Onesti et. al." saw no change in cardiac output as hypertension developed in similar circumstances.
Tissue Metabolism
Consideration of the metabolic needs of the tissues
is essential in interpreting flow changes during the
onset of hypertension. Elevated flow during anemia or
HYPERTENSION/CO/WMO/J
et al.
327
at high altitude is probably the final result of
autoregulation rather than flow perturbations that are
in the transient phase of an autoregulatory response.
Similarly, the high cardiac output seen in many young
essential hypertensive patients might be considered an
appropriate response to changing metabolic needs and
the increased oxygen consumption in these circumstances. Therefore, changes in flow over the long
term probably represent a normal physiological
response to changing metabolic demands. In contrast,
acute changes of flow might be at variance with the
metabolic needs of the tissues and might be a signal
that an autoregulatory change in resistance is about to
occur or is in progress.
Several studies with beta-adrenergic receptor
blockade have been used to address the question of
autoregulation in hypertension. Drugs, such as
propranolol, have been shown to lower cardiac output
and increase oxygen extraction without appreciably
changing oxygen consumption and metabolic rate.
Spontaneous hypertension in rats3* and DOCA plus
saline hypertension in dogs33 both occur just as readily
after beta-blockade as before. Cardiac output in these
instances has been observed to not rise at all during
the onset of hypertension or to remain below the
pretreatment level. Therefore, increased blood
pressure and vasoconstriction occurred with a blood
flow that was less than normal. This response has been
interpreted as evidence against the role of autoregulation in the genesis of hypertension.37 However, autoregulation may function perfectly adequately in betablockade; for instance, marked vasodilation is seen
during exercise after beta-blockade.38-3" It might be
then that autoregulatory vasoconstriction is a part of
the genesis of hypertension during beta-blockade,
although the normal or reference level of autoregulated blood has been changed by the receptor
blockade. Growth rate was normal in the beta-blocked
spontaneously hypertensive rats of Pfeffer et al," indicating that the total metabolic needs were being
satisfied in these animals at the decreased blood flow
rates observed. Detailed interpretation of these studies
is difficult since the exact metabolic needs of the
tissues are not known, the mechanism of action of
beta-adrenergic blockers has not been fully delineated,
and the detailed mechanisms responsible for autoregulation remain unclear.
The Abruptness of the Hypertension-Producing Stimulus
Another important point involves the methods used
to produce experimental hypertension. If we assume
that autoregulation is a rapidly responding and very
powerful mechanism, then transients in blood flow
would occur only infrequently and only very briefly.
This point is explored theoretically in figure 3. With
the same concept of autoregulation used in each of
two cases, only an abrupt, severe stimulus (fig. 3, left
panel) caused obvious flow disturbance. Focal renal
artery constriction might be a good example. A more
insidious disturbance (fig. 3, right panel) produced an
autoregulatory vasoconstriction in this hypothetical
328
HYPERTENSION
1, No
3, MAY-JUNE
1979
example without any overt (or experimentally
measurable) change in blood flow. Slowly progressing
renal disease might be a suitable example. Therefore,
according to this concept of autoregulation, changes
in flow over the long term probably represent the appropriate responses to metabolic needs or, in rare instances, represent the effects of severe disease. Transient flow changes that herald subsequent autoregulatory changes in resistance can be expected only
in protocols that use an abrupt stimulus.
ARTERIAL
PRESSURE
CARDIAC
OUTPUT
TOTAL
PERIPHERAL
RESISTANCE
Vascular Compliance
HYPERTENSION
PRODUCING
STIMULUS
TIME
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FIGURE 3. Hypothetical hemodynamic and autoregulatory response to a hypertension-producing stimulus. Left
panel shows flow disruption when an abrupt stimulus is
used. Right panel shows no observableflowchange when
the stimulus is gradual.
FLOW
OXYGEN
EXTRACTION
OXYGEN
UPTAKE
TOTAL
VASCULAR
RESISTANCE
DISTAL
VASCULAR
RESISTANCE
The connection between renal dysfunction and
autoregulatory vasoconstriction appears in the first
analysis to require sodium retention. But, evidence of
sodium retention and volume expansion is not always
found. Most notably, many measurements in subjects
with essential hypertension have shown normal or low
blood volumes. However, the hemodynamic response
to volume changes involves both the absolute value of
blood volume and the vascular compliance of the circulatory system. Situations might exist where there is
relative or functional vascular overhydration but normal or low measured values for total blood volume.
Such situations would be caused by decreased vascular
compliance. Therefore, a decreased vascular compliance can theoretically be just as effective as an increased absolute volume in promoting increases in
cardiac output.
There is some evidence for decreased venous compliance in human40 and experimental41 hypertension.
But also, estimates of venous pressure or mean circulatory filling pressure might help to show the combined contribution of volume and compliance in these
situations. Micropuncture studies in the spontaneously hypertensive rat have shown elevated
venous pressures42 and several different estimates of
mean circulatory filling pressure19' **• ** have shown increased values for this pressure in hypertension.
Therefore, in exploring the connection between renal
dysfunction and vasoconstriction, neither absolute increases or decreases in volume can be fully interpreted
without additional information about the compliances
and pressures within the circulation.
Acute and Long-Term Autoregulation
NUMBER &
AREA OF
COLLATERAL
VESSELS
MINUTES
DAYS
WEEKS
4. Schematic representation of the hemodynamic
response to occlusion of a major artery. Metabolism is initially maintained by acute vasodilation and increased oxygen extraction. Later events include full development of
collateral blood vessels.
FIGURE
VOL
Much of what we know about autoregulation comes
from studies outside of hypertension research. The
observation that body weight and blood flow increase
in direct proportion during growth could be interpreted as a manifestation of autoregulation. Shortterm studies show that active vasoconstriction occurs
in individual organs with increases in pressure and
flow; the responses might be related to metabolic or
myogenic factors or to other special properties of the
individual organs. To date, autoregulation of blood
flow has been observed in every organ studied including the brain, gut, coronary arteries, skeletal muscle and kidneys.
The autoregulatory response in individual organs
has been observed to be very rapid. It is not clear if
VASOCONSTRICTION IN HYPERTENSION/Co/eman et al.
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these changes might persist indefinitely in hypertension or if there might be further development of
vasoconstriction and a gradual substitution of longerterm mechanisms. There is some evidence in support
of a gradual change in mechanisms. For instance, in
hypertension, thickening of the media of the blood
vessel wall46 and a decrease in the minimum resistance
that can be obtained with maximum dilation46 signal a
change in vasoconstrictor mechanisms. Studies using
arterial ligation in the dog's leg have shown a very rich
and varied pattern of events following a decrease in
femoral artery blood flow due to arterial ligation.
Initially, the distal vasculature dilates and oxygen extraction increases.47 At the same time, collateral
vessels open around the main arterial ligation48 and
blood flow increases even more. As time -passes,
further development of collateral vessels around the
ligation,49 tends to re-establish normal perfusion.50
These responses are shown schematically in figure 4.
The net result is that a spectrum of processes and a
spectrum of time constants within these processes are
all involved at maintaining normal tissue perfusion.
Over the short term, arteriolar dilation and increased
oxygen extraction can make large contributions, along
with the opening of existing collateral pathways. Over
the long term, oxygen delivery and oxygen extraction
are maintained at normal values by a change in the
number and structure of blood vessels.
It would appear then that the proper level of blood
flow to the tissues is maintained by resistance changes
that involve this variety of mechanisms as one of the
highest physiological priorities of the intact organism.
If an unusual pressure level is needed to maintain salt
and water balance, then we would expect, according to
this theory, to get increased resistance in proportion to
the increase in pressure required without any obvious
disruption in total blood flow distribution. Transient
flow disruption might be seen in instances where
abrupt transitions in arterial pressure are taking place,
but abnormal flow would not be seen with more
gradual pressure changes.
Conclusion
There is evidence that autoregulation of blood flow
is a very powerful mechanism that can increase or
decrease vascular resistance as necessary. A role for
autoregulation of blood flow in hypertension comes
from a variety of indirect observations and from the
general observation that blood flow is normal in most
cases of hypertension. To our knowledge, experiments
to clearly substantiate or refute the concept that
autoregulation is the predominant source of vasoconstriction in hypertension have not yet been undertaken. Similarly, experiments to clearly validate or invalidate other putative vasoconstrictor mechanisms
are also missing. Protocols to critically evaluate the
role of autoregulation in hypertension might involve
attempting to produce hypertension in common experimental models with and without autoregulation
operative and then measuring the hemodynamic consequences. Such experiments are difficult if not im-
329
possible with the experimental tools available at this
time. Therefore, until the time that direct scientific
evidence becomes available, interpretation of many
different and less direct experimental results serves as
a forum for debate.
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Hypertension. 1979;1:324-330
doi: 10.1161/01.HYP.1.3.324
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