Download Brief Reviews A Systems Analysis Approach to Understanding Long

Circulation Research
AUGUST
1974
VOL. 35
NO. 2
An Official Journal of the American Heart Association
Brief Reviews
A Systems Analysis Approach to Understanding Long-Range
Arterial Blood Pressure Control and Hypertension
By Arthur C. Guyton, Thomas G. Coleman, Allen W. Cowley, Jr., R. Davis Manning. Jr., Roger
A. Norman, Jr., and John D. Ferguson
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• The use of systems analysis as an experimental
tool for solving complex physiological problems is
not new. Actually, systems analysis is merely the
logical analysis of how systems perform. However,
modern usage of the term implies a more formalized type of logic, especially a type of logic that
includes quantification at each step in the analysis.
Several of the figures in this paper illustrate
systems analysis flow diagrams that show interrelationships between the different parts of simple or
complex mechanisms for the control of arterial
blood pressure. One can readily see that each part
of each systems analysis diagram is only a symbolic
way in which a composite of individual physiological phenomena fit together in a complete system.
The principal advantage of the formalized systems analysis approach to understanding any physiological mechanism is that it often allows greater
depth of thought than our minds can perform using
simple logical procedures. The mind has the capability of holding and analyzing perhaps five to ten
different sequential phenomena, each occurring at
different rates and each interrelated with the other
phenomena by various cross-linkages. However,
beyond this size of system it is almost impossible to
think through all the complex relationships simultaneously. On the other hand, the modern computer can handle literally thousands of such crosslinking interrelationships at the same time and can
develop answers that the mind alone cannot
achieve.
Now setting aside this philosophizing about
systems analysis per se, we will attempt to show
how the systems analysis approach has been useful
in the study of long-range arterial blood pressure
control and the understanding of hypertensive
From the Department of Physiology and Biophysics, University of Mississippi School of Medicine, Jackson, Mississippi
39216.
Circulation Research. Vol. 35. August 1974
mechanisms. During the past 12 years we have
gradually developed a complex analysis of circulatory function and control that involves about 400
basic physiological phenomena and their interrelationships (1). Most of this systems analysis has
dealt with control of arterial blood pressure. It has
produced some startling predictions that for the
most part have already been borne out by experimental tests. Some of these predictions are the
following. (1) Short-term arterial blood pressure
control is vested in an entirely different set of
pressure control mechanisms than is long-term
arterial blood pressure control: short-term control
is primarily a nervous function whereas long-term
arterial blood pressure control is principally a
function of the body's fluid balance system. (2) The
long-range level of arterial blood pressure can be
increased or decreased as a result of changes in
only three possible factors: (a) the rate of fluid
intake, (b) the ability of the kidney to excrete fluid,
and (c) the rate of fluid loss by nonrenal mechanisms. (3) Many if not most of the arterial blood
pressure control systems known to affect arterial
blood pressure acutely, such as the baroreceptor
control system and the renin-angiotensin system,
also have direct or indirect effects on different
aspects of.the fluid balance system, and it is
through these effects on fluid balance that they
participate in controlling the long-range level of
arterial blood pressure. (4) A primary increase in
total peripheral resistance per se does not cause
hypertension. Total peripheral resistance is a dependent variable in the overall system for control of
arterial blood pressure; often, but not always, it
increases at the same time that arterial blood
pressure increases. (5) For the most part, the
kidneys act as a servocontroller of the long-range
level of arterial blood pressure; they operate primarily through the fluid balance system. (6) Under
159
GUYTON. COLEMAN. COWLEY. MANNING. NORMAN. FERGUSON
160
normal circumstances, renal factors that determine
the glomerular filtration rate at different levels of
arterial blood pressure are quantitatively more
important for the control of arterial blood pressure
than are renal tubular mechanisms.
The preceding list of predictions includes several
important principles that are contrary to some
current physiological opinions. The present paper
attempts to show the physiological logic of these
predictions and their importance in the control of
arterial blood pressure and the genesis of hypertension.
BRIEF SURVEY OF THE BASIC MECHANISMS FOR ARTERIAL BLOOD
PRESSURE CONTROL
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Figure 1 is a block diagram showing the interrelationships of most of the factors that are believed
to be important in arterial blood pressure control.
In this block diagram a solid arrow between two
blocks indicates that an increase in the factor in
the original block causes an increase in the factor in
the subsequent block; a broken arrow indicates a
decrease in the subsequent block. By following the
block diagram from left to right, one will find that
the mass of blocks depicts an overall feedback
system for control of either total peripheral resist-
ance, cardiac output, or both and, thereby, for
control of arterial blood pressure. Most of the
individual feedback loops for arterial blood pressure control are as follows. (1) The baroreceptor
system acts through the sympathetic and parasympathetic nervous systems to control arterial blood
pressure. (2) The renin-angiotensin system acts
through vasoconstriction and fluid volume changes
to alter arterial blood pressure. (3) The chemoreceptor system is stimulated by ischemia of the
chemoreceptors when the arterial blood pressure
falls and operates through the sympathetic nervous
system to increase arterial blood pressure. (4) The
central nervous system ischemic system acts
through sympathetic stimulation to control arterial
blood pressure. (5) The renal-fluid output system
acts through changes in body fluid volume to
control arterial blood pressure. (6) The antidiuretic
hormone and thirst control system acts through
changes in body fluid volume to control arterial
blood pressure. (7) The aldosterone system acts
through changes in body fluid volume to control
arterial blood pressure. (8) The capillary pressure
and capillary filtration system acts through redistribution of fluid volume between the blood and
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Block diagram showing the principal factors in arterial blood pressure control. The broken lines
represent negative effects. CNS = central nervous system and ADH = antidiuretic hormone.
Circulation Research. Vol. 35. August 1974
161
ANALYSIS OF HYPERTENSION
the interstitial spaces to help control arterial blood
pressure. Finally, (9) the vascular capacitance
system acts through capacitance changes and
stress relaxation of vascular elements to help
control venous return and cardiac output and,
therefore, arterial blood pressure.
Many factors not shown in Figure 1 have indirect
effects on arterial blood pressure control and might
in the end prove to be important. Some of these
factors include the sympathetic effect on antidiuretic hormone secretion, the effect of sodium concentration on arteriolar resistance, the volume
receptor feedback mechanism for controlling fluid
volume, etc.
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A LONG-RANGE ARTERIAL BLOOD PRESSURE CONTROL MECHANISM: THE RENAL-BODY FLUID SYSTEM FOR FEEDBACK CONTROL
OF ARTERIAL BLOOD PRESSURE
The relationship of body fluid volume, especially
blood volume, to arterial blood pressure control has
been known from the beginning of circulatory
physiology. For instance, every physiologist and
every clinician accepts the facts that decreased
arterial blood pressure caused by loss of blood
volume leads to fluid retention by the kidneys and
eventual return of blood volume and arterial blood
pressure to normal and that the body fluid volume
plays an essential role in this pressure control
mechanism. On the other hand, it has been far
more difficult to prove the role of body fluid volume
in the control of arterial blood pressure in above
normal pressure ranges. Yet, a surge of activity in
this direction in the past few years has shown both
theoretically and experimentally that body fluid
volume and its relationship to arterial blood pressure is an essential ingredient in arterial blood
pressure control at all pressure levels (2-9). The
purpose of most of the remainder of this paper is
to detail both the logic and the experimental evidence in favor of this concept.
Mechanics of the Renal-Arterial Blood Pressure
Control Loop.—Figure 2 illustrates the basic mechanism by which the kidneys and the body fluids
help to regulate arterial blood pressure. Block 1
illustrates the relationship between arterial blood
pressure and urinary output. The broken curve in
this diagram shows the approximate effect of different levels of arterial blood pressure on urinary
output from the two isolated kidneys (10-14). The
solid curve illustrates the relationship between
arterial blood pressure and urinary output of the
two kidneys in the intact body (4-6). The reason for
the difference is that in the intact body arterial
blood pressure affects urinary output in several
indirect ways as well as by the direct hydrodyCirculation Research, Vol. 35, August 1974
namic effect of the arterial blood pressure itself.
Some of the indirect ways are as follows. (1) An
increase in arterial blood pressure inhibits sympathetic nervous system activity, which in turn allows
increased urinary output (15). (2) An increase in
arterial blood pressure (at least in the low-pressure
range) decreases the output of antidiuretic hormone, which increases urinary output (16). (3) An
increase in arterial blood pressure decreases the
secretion of renin and the formation of angiotensin,
which under some conditions also tends to increase
urinary output (17). (4) An increase in arterial
blood pressure is often related to decreased aldosterone secretion, which allows increased excretion
of both salt and water (18). Thus, block 1 shows
that with an increase in arterial blood pressure
there is a marked increase in urinary output.
Block 2 gives a summation of fluid balance; fluid
output is represented by the urinary output and the
nonrenal fluid loss, and fluid intake is in the form
of both free water and water in the foods along with
electrolytes. The output of this block is the rate of
change of body fluid volume (d [BFV ]/dt).
Block 3 illustrates integration of the rate of
change of body fluid volume, which means accumulation of body fluid volume. However, this
accumulation can be either positive or negative.
The output of block 3 is the body fluid volume
itself.
Block 4 illustrates the effect of body fluid volume
and other intrinsic factors of the circulation on
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Simplified systems analysis of the renal-body fluid feedback
method for control of arterial blood pressure. See text for
explanation. U.O. - urinary output, A.P. = arterial pressure,
BFV = body fluid volume, TRP = total peripheral resistance,
CO - cardiac output, t •= time, BR = basic resistance (vascular
resistance in fully diluted state), VC = vascular capacitance,
RVR - resistance to venous return, and Cap. dyn. = capillary
dynamics.
162
GUYTON. COLEMAN. COWLEY. MANNING, NORMAN. FERGUSON
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cardiac output. The body fluid volume is distributed among the extracellular fluids, the intracellular fluids, and the blood volume in accordance with
capillary dynamics, interstitial fluid dynamics,
and body fluid electrolytes. The portion of the fluid
that is distributed to the blood helps to determine
the blood volume, which in turn functions in
association with the total vascular capacitance to
determine the filling of the system. Finally, the
degree of filling of the system (the circulatory
filling pressure) operating in association with the
resistance of the vasculature (the resistance to
venous return) determines the venous return and
the cardiac output (19), which is the output of
block 4.
Block 5 illustrates the effect of cardiac output on
total peripheral resistance, which itself is a function of cardiac output, time, and basic resistance of
the arterioles. An increase in blood flow through
the entire body causes the phenomenon called total
circulatory autoregulation (20-22) in which the
total peripheral resistance increases. Thus, block 5
shows that an increase in cardiac output will, with
time, increase the total peripheral resistance.
Block 6 illustrates that the arterial blood pressure is the product of cardiac output and total
peripheral resistance.
It is clear from Figure 2 that this feedback loop is
a negative feedback control mechanism for control
of arterial blood pressure. Thus, an increase in
arterial blood pressure causes a loss of fluid from
the body that reduces cardiac output, which in
turn reduces total peripheral resistance; both the
reduced cardiac output and the reduced total
peripheral resistance then reduce the arterial blood
pressure back toward normal. Conversely, a decrease in arterial blood pressure causes the retention of fluid and the progressive rise of arterial
blood pressure back toward normal.
But how important is this mechanism? Is it
merely a background system that is necessary for
maintaining a reasonable level of body fluid or is it
truly an active part of the overall pressure control
system? The answer to these questions can be
derived by studying very carefully one small part of
the system—the line that connects the output of
block 2 to the input of block 3. This line represents
the rate of change of body fluid volume (d[BFV ]/
dt). As long as this rate of change of body fluid volume is any value except zero, all of the other factors in this entire system will continue to change
(9). Thus, if arterial blood pressure becomes too
great while fluid intake and nonrenal fluid loss remain constant, d(BFV)/dt will become negative
and fluid will continue to be lost until the arterial
blood pressure returns precisely to the level required to achieve balance between fluid input and
output. Conversely, if arterial blood pressure falls
too low, fluid volume will continue to be retained
until arterial blood pressure has returned again to
the exact level that will cause balance between
fluid output and input.
Therefore, it is essential that the output of block
2, d(BFV)/dt, return precisely to zero. Furthermore, any proposed mechanism for long-range
arterial blood pressure control that fails to achieve
this result is conceptually doomed to failure, because a continual positive d(BFV)/dt will cause
progressive retention of fluid until the subject dies
of edema, and a continual negative d(BFV)/dt will
cause progressive loss of fluid until he dies of
dehydration. To explain the importance of this
principle, we need to consider some basic problems
of control theory as they relate to the interaction of
different types of pressure control systems.
BASIC PRINCIPLES OF INTERACTION BETWEEN SHORT-TERM AND
LONG-TERM PRESSURE CONTROL MECHANISMS
Several basic principles of control systems as
they apply to arterial blood pressure control are
illustrated in Figures 3-6. Two types of control
systems are considered: the proportional control
system and the integral control system. The proportional control system is illustrated by the baroreceptor-vasoconstrictor feedback control system,
the renin-angiotensin-vasoconstrictor feedback
control mechanism, and most of the other pressure controls besides the fluid balance control
system. The only integral system that has been
shown to be important for control of arterial blood
pressure is the renal-body fluid pressure control
system. However, this system is affected by many
subsystems; the most important of these is the
control of body sodium, which plays a major role in
determining body fluid volume and its distribution
among the various fluid compartments. We shall
say relatively little about sodium, because the close
relationships between sodium and body fluid volume are already well established and because
essentially all of the factors which we will consider
that alter fluid volume, especially extracellular
fluid volume, cause parallel and almost proportional changes in body sodium at the same time.
FUNCTION OF A PROPORTIONAL CONTROL SYSTEM
Figure 3A illustrates the basic ingredients of a
simple proportional system for control of arterial
blood pressure. The inputs to block 1 are the
arterial blood pressure and a pressure reference
Circulation Research. Vol. 3.5. August 1974
163
ANALYSIS OF HYPERTENSION
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FIGURE 3
A: Basic essentials of a proportional control system showing
quantitative ualues under three separate conditions: (1) normal
conditions. (2) instantaneously after the basic arterial blood
pressure level has been increased to 150 mm Hg but before the
control system has had time to begin acting, and (3) after the
control system has become active and has reduced the actual
arterial blood pressure back near to the pressure reference level.
B: Graph of the response of arterial blood pressure to a sudden
increase in the basic arterial blood pressure from 100 mm Hg to
150 mm Hg when the proportional control system of Figure 3A is
operative. Note that the feedback gain is 4, which is represented
by the ratio of Y to E. C: Proportional feedback system; the
same as that of Figure 3A except that a sub loop has been added
Circulation Research, Vol. 35, August 1974
level—the desired arterial blood pressure. The
output of block 1 is the error, i.e., the difference
between the actual arterial blood pressure and the
desired pressure level. Block 2 represents a feedback loop that multiplies the error by a factor G to
give output Y. The input to block 3 is composed of
the basic arterial blood pressure that would exist if
there were no control system and -Y, which is the
compensation that is caused by the control system.
The output of block 3 is the actual arterial blood
pressure.
Figure 3A illustrates a basic control arterial
blood pressure of 100 mm Hg. Let us assume that
the pressure reference level in Figure 3A is also 100
mm Hg. Then assume that the basic arterial blood
pressure level is suddenly elevated to 150 mm Hg,
as might be caused by increasing the blood volume
or by constricting the- peripheral arterioles. The
instantaneous effect before the feedback control
system has time to operate is an increase in the
actual arterial blood pressure to 150 mm Hg,
because the feedback at this instant is still zero.
However, within seconds, minutes, or days, depending on the delay factors in the control system,
the feedback achieves its objective. Since the
reference pressure remains 100 mm Hg, elevation of
the arterial blood pressure to 150 mm Hg gives an
error output from block 1 of 50 mm Hg, which in
turn feeds through block 2 to block 3 to correct the
actual arterial blood pressure back toward its
normal value. Once the total system has settled
down to its final steady state, the values at
different points in the system will have changed
from initial values (shown in the top parentheses of
the figure) to the steady-state values (shown in the
bottom parentheses). Thus, the arterial blood pressure rises from 100 mm Hg to 150 mm Hg without
the control system but returns to only 110 mm Hg
when the control system becomes activated. One
can also see in Figure 3A that the final steady-state
error is 10 mm Hg, and the final steady-state
correction, Y, is 40 mm Hg. Thus, in block 2 there
is a gain factor of 4. The equation that relates the
to allow complete adaptation of the baroreceptors in the
baroreceptor control mechanism. The values in parentheses
show the sequential changes in quantitative values at different
points in the loop when the basic arterial blood pressure is
suddenly elevated from 100 mm Hg to 150 mm Hg. D: Graph of
the changes in arterial blood pressure following a sudden rise in
basic arterial blood pressure from 100 mm Hg to 150 mm Hg
when the control system of Figure 3C is operative. The net
feedback gains of the control system at different times for the
solid curve are illustrated at the top. The numbers on the curves
represent the half times for adaptation of the receptors.
164
GUYTON. COLEMAN. COWLEY. MANNING, NORMAN. FERGUSON
final steady-state arterial blood pressure to the
basic uncontrolled level of arterial blood pressure
is:
Arterial blood pressure = basic arterial blood
pressure — (arterial blood pressure — reference
pressure level) x gain.
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Figure 3B illustrates the function of this control
system; it shows an initial overshoot in actual
arterial blood pressure when the basic arterial
blood pressure rises from 100 mm Hg to 150 mm Hg
but a rapid return of the actual arterial blood
pressure to a controlled level of 110 mm Hg once
the control system has become effective.
A proportional control system of this type is
represented by the baroreceptor system, which
becomes fully effective in 10-30 seconds (23). The
feedback gain of the baroreceptor system remains
relatively constant for the first few hours, but many
different studies have shown that this feedback
gain decreases markedly by the second or third day
(24-26).
Another example of a proportional system that
requires approximately 20 minutes to become fully
effective is the renin-angiotensin-vasoconstrictor
feedback control mechanism for arterial blood
pressure control. Cowley et al. (27), and Cowley
and Guyton (28) have shown that this mechanism
has a feedback gain of approximately 1.6 in the
arterial blood pressure range between 65 mm Hg
and 100 mm Hg, but its gain falls essentially to zero
when the arterial blood pressure rises above 100
mm Hg. Unfortunately, what happens to the gain
of the renin-angiotensin-vasoconstrictor feedback
mechanism for pressure control many hours or days
after it is elicited is yet undetermined, primarily
because appropriate quantitative experiments
have not been devised, although extensive research
has been performed on this system.
THE ADAPTIVE (RESETTING) PROPORTIONAL CONTROL SYSTEM
Figure 3C illustrates the basic essentials of one
type of adaptive proportional control system.
Blocks 1, 2, and 3 are exactly the same as those in
Figure 3A. However, in addition, blocks 4, 5, and 6
show adaptation (or resetting) of the feedback
portion of the control system. Immediately after
the control system begins to correct an abnormal
arterial blood pressure there is still no adaptation
of the feedback. Therefore, the entire error from
block 1 is passed through block 6 directly to block 2
to cause feedback control of arterial blood pressure.
Figure 3D shows the initial overshoot in arterial
blood pressure when the basic arterial blood pres-
sure rises from 100 mm Hg to 150 mm Hg and then
the immediate correction of the pressure back to
110 mm Hg as the feedback achieves its goal.
However, with time the net error that drives the
feedback control system (output of block 6) gradually decays toward zero; this decay will not stop
until the input of the integral block (block 5)
reaches exactly zero. This necessity for the input
to reach exactly zero is a basic property of the integral loop. However, for the input to block 5 to
return to zero, it is essential that the input to block
4 also return to zero. Thus, blocks 4, 5, and 6 represent a subloop utilizing an integral control system to control the overall feedback gain. As the
net feedback error approaches zero, the overall gain
of the feedback decreases from 4 to approach zero
(Fig. 3D). At the same time the arterial blood
pressure approaches the uncontrolled state as its
limit. The rate of approach of the arterial blood
pressure to its uncontrolled state is determined by
the numerical value of k,, which is one of the input
factors to block 4 of Figure 3C. The solid curve of
Figure 3D illustrates the change in arterial blood
pressure when there is a half time of adaptation of
12 hours, the dotted curve a half time of 6 hours,
and the broken curve a half time of 24 hours.
The results shown in Figure 3D are qualitatively
the same as those found for control of arterial blood
pressure by the baroreceptor system. Cowley (unpublished observations) has found a half time of
adaptation of the baroreceptor system in dogs of
approximately 8 hours, McCubbin et al. (24) and
Kezdi and Wennemark (25) have found that complete adaptation occurs in dogs within 2-3 days,
and Krieger (26) has found that complete adaptation occurs in rats within 24-48 hours.
It is clear from Figure 3D that a proportional
adaptive pressure control system such as that
probably represented by the baroreceptor system
cannot be useful for control of arterial blood
pressure beyond the first few days. However, the
adaptation process of such a control mechanism
also allows the control system to reset itself to a
new range of arterial blood pressure operation. For
instance, the normal baroreceptor system has a
high degree of gain in a pressure range of 100 mm
Hg to 125 mm Hg but a very poor gain at pressures
above 160 mm Hg or below 80 mm Hg. Therefore, if
the arterial blood pressure should change to a value
outside the normal operating range for the baroreceptors, the baroreceptor mechanism would become of little value or perhaps even useless in
helping to moderate arterial blood pressure
changes. On the other hand, if the baroreceptor
adapts (resets) to the new pressure level, its high
Circulation Research, Vol. 35, August 1974
165
ANALYSIS OF HYPERTENSION
degree of gain could then become applicable to the
new pressure level rather than to the original
normal pressure level.
Thus, by utilizing the process of adaptation, the
baroreceptor system maintains its capability for
buffering the arterial blood pressure against acute
changes in pressure regardless of the steady-state
pressure level. This fact is exceedingly important
for short-range pressure control. For example, if the
baroreceptors did not adapt, every severely hypertensive person would be essentially without a
functioning baroreceptor feedback control mechanism, and the pressure level would be far more
labile than it is usually; this condition could be
very dangerous.
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THE INTEGRAL ARTERIAL BLOOD PRESSURE CONTROL MECHANISM
Figure 4A illustrates the essentials of an integral
arterial blood pressure control mechanism. It
shows, simply, that without any feedback compensation the actual arterial blood pressure is equal to
Pressure (K)0)
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31.
A: Basic essentials of an integral feedback mechanism of
pressure control such as the renal-body fluid pressure control
system. The values in parentheses show successive changes in
quantitative values around the loop following a sudden change
in basic arterial blood pressure from IOO mm Hg to 150 mm Hg.
B: Progressive changes in arterial blood pressure following a
step increase in basic arterial blood pressure in the system
illustrated in Figure 4A. Note that the net gain of this system
begins at zero but approaches infinity with time.
Circulation Research, Vol. 35. August 1974
the basic arterial blood pressure. Block 1 calculates
the difference between the actual arterial blood
pressure and the reference pressure level, giving an
output error. Block 2 multiplies the output error
times a constant k] to give the rate of correction of
the difference between actual arterial blood pressure and the pressure reference level. Block 3
integrates this rate of error correction, and block 4
subtracts the correction from the basic arterial
blood pressure to give the actual arterial blood
pressure.
The numbers in parentheses in Figure 4A represent the initial starting values, the immediate
values after the basic arterial blood pressure has
suddenly been increased to 150 mm Hg, such as
might be caused by peripheral arteriolar constriction, and the values after a final steady state has
been achieved, respectively. Immediately after the
basic arterial blood pressure level is increased from
100 mm Hg to 150 mm Hg, the actual arterial blood
pressure rises to this value (Fig. 4B). However, the
correcting system begins to work and the degree of
correction progresses with time, slowly returning
the arterial blood pressure back toward the reference pressure level of 100 mm Hg. As long as there
is any error difference between the actual arterial
blood pressure and the reference pressure level, this
feedback mechanism will continue to integrate,
and the system will reach a steady state only when
the two become precisely equal. Theoretically, this
condition will occur only after an infinite period of
time, but from a practical point of view it will occur
in the arterial blood pressure control system within
a few days to a few weeks (9).
Figure 4B illustrates the course of the return of
arterial blood pressure to the control reference level
even though the basic arterial blood pressure level
caused by a persistent abnormality of the circulatory system might remain elevated to 150 mm Hg
indefinitely. This process, of course, assumes that
the basic abnormality does not interfere with the
feedback control system itself but, instead, with
some other portion of the circulatory system besides those portions involved in the feedback control. Figure 4B also shows that the gain of the
feedback control system at zero time starts at zero,
but eventually becomes infinity. It is important to
remember the infinity gain, because it plays a
major role in some of the conclusions that we shall
draw later in this analysis.
INTERACTION BETWEEN A PROPORTIONAL CONTROL SYSTEM AND
AN INTEGRAL CONTROL SYSTEM
Figure 5A illustrates simultaneous function of a
proportional control system and an integral control
system that is the same as that in Figure 4A. The
166
GUYTON, COLEMAN. COWLEY. MANNING. NORMAN, FERGUSON
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FIGURE 6
A: Systems analysis showing the essential elements of an
arterial blood pressure control system comprised of parallel
proportional and integral components. The numbers in parentheses show sequential changes in quantitative values around
the loops following a step increase in basic arterial blood
pressure from 100 mm Hg to 150 mm Hg. B: Graph of the
sequential changes in arterial blood pressure following a step
change in basic arterial blood pressure from 100 mm Hg to 150
mm Hg. The different curves represent the results when the
following types of systems are operative. Curve A - a combined
proportional and integral control system as illustrated in Figure
5A, curve B - only a proportional control system, curve C only an integral control system, curve D - both proportional
and integral control systems with a cross-feed from the proportional control system to the integral system as illustrated by the
double line in Figure 5C, curve E = same as for curve D but with
receptor adaptation in the proportional system as shown in
blocks.4, 5, and 6 of Figure 5C. C: Combined proportional and
integral control system for arterial blood pressure control but
with a cross-feed from the proportional system to the integral
system and with adaptation of the proportional receptors (such
as adaptation of the baroreceptors).
numbers in parentheses show the progressive effects before and after a sudden change in the basic
arterial blood pressure from 100 mm Hg to 150 mm
Hg. The instantaneous effect on arterial blood
pressure (curve A, Fig. 5B) is a rise in arterial blood
pressure to 150 mm Hg with a subsequent rapid
return of the arterial blood pressure to 110 mm Hg
as soon as the proportional control system becomes
operative. With the baroreceptor system, the time
required is only a few seconds. Then over a prolonged period of time the arterial blood pressure
continues to fall to 100 mm Hg because of function
of the integral control system. Curve A in Figure 5B
shows that by the end of 4 days this pressure has
fallen only to 105 mm Hg, but after weeks it will
have fallen all the way to the precise reference
pressure level of 100 mm Hg.
Curve B in Figure 5B illustrates what would
happen to the arterial blood pressure if only a
proportional control system were present; the arterial blood pressure would never fall below 110 mm
Hg and would never return all the way to normal.
Curve C shows what would happen if only the
integral control system were present; the arterial
blood pressure would remain much too high at first
but nevertheless would fall to normal within a few
days. In fact, it would fall to normal much more
rapidly than it would with a combination of the
proportional control system and the integral control system.
Curves A and C illustrate that over a long period
of time the arterial blood pressure returns exactly
to the pressure reference level of the integral
• control system whether the proportional system is
present or not. The final long-range, steady-state
level of arterial blood pressure is dictated entirely
by the integral control system and not even to the
slightest extent by the proportional control system. On the other hand, the proportional control
system, if it acts rapidly at the onset of the circulatory abnormality, can prevent tremendous excesses of arterial blood pressure during the long
period of time required for the integral control
system to exert its total power. Unfortunately, this
initial advantage of the proportional system prevents the integral system from reacting as rapidly
as it otherwise would.
Cross-Feed between the Proportional System
and the Integral System.—In Figure 1, it is clear
that there are many cross-feeds between individual
blocks of the total arterial blood pressure control
system. Figure 5C illustrates a typical example of
this condition by showing that the output of the
proportional feedback, Y, is fed into the integral
feedback loop. When the baroreceptors and volume
Circulation Retearch, Vol. 35, August 1974
ANALYSIS OF HYPERTENSION
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receptors are excited, the signals from these receptors decrease the sympathetic signal to the kidneys
and also decrease the secretion of antidiuretic
hormone (ADH); both of these effects then act as a
positive stimulus causing the kidneys to excrete
increased quantities of urine (29). Thus, the proportional system (the baroreceptor system) enhances the rate of integration of the feedback
correction by the integral control system (the
renal-body fluid pressure control system).
Curve D in Figure 5B illustrates the effect of a
cross-feed in Figure 5C that is strong enough on
initial activation of the proportional system to
increase the rate of urine output by the kidneys by
fivefold. This amount is not an unreasonable figure
in view of data from Gauer and his associates (29)
and from Dobbs (30) for the effects of the baroreceptor system and the volume receptor system on
control of urinary output. Note especially that
curve D illustrates a much more rapid approach of
arterial blood pressure back to the initial pressure
reference level than is illustrated by curve A and
that curve D shows the effect of the cross-feed.
In addition to cross-feed from the baroreceptor
system to enhance the rapidity of response of the
body fluid pressure control system, many similar
cross-feeds from other pressure control systems
such as those from the renin-angiotensin-vasoconstrictor system, the renin-angiotensin-aldosterone system, the volume receptor feedback system,
the chemoreceptor pressure feedback control system, the central nervous system ischemic feedback
control system, and the ADH feedback control
system can be demonstrated.
Failure of the Cross-Feeds to Alter the Ultimate
Pressure Level of Adjustment.—In Figure 5B,
curve D readjusts the arterial blood pressure to
precisely the same level that would have been
reached by the integral control system. Thus, the
cross-feed in this figure has no effect whatsoever on
the final steady-state level of arterial blood pressure; it affects only the rapidity with which the
arterial blood pressure eventually returns to the
pressure reference level. However, there are instances when cross-feeds or abnormalities in the
body can alter the pressure reference level of the
integral control system and in this way can alter
the arterial blood pressure level in the long-term
steady-state condition. This process will be discussed in detail later in this paper in relation to the
role of the kidney in long-term arterial blood
pressure regulation.
Therefore, a parallel proportional control system
does not participate in the determination of the
long-range level of arterial blood pressure as long as
Circulation Research, Vol. 35, August 1974
167
the integral control system is still operative and the
pressure reference level of the integral system
remains unaltered.
Effect of Adaptation (Resetting) of the Proportional System.—Blocks 4, 5, and 6 in Figure 5C are
the same adaptation (resetting) blocks as those
illustrated in Figure 3C. Curve E in Figure 5B
illustrates the effect which results when the rate of
adaptation is approximately that which occurs
with resetting of the baroreceptor system. In the
present example, the abnormal arterial blood pressure of 150 mm Hg will be corrected to 110 mm Hg
within a few seconds followed by a further progressive decrease to the final pressure level dictated by
the integral control system. However, curve E
shows that the initial progress toward the final
steady-state pressure level is not as rapid when
adaptation of the proportional system occurs as it
is without adaptation, although in the later stages
this adaptation effect participates little. The important advantage of this system is that the adaptation process automatically adjusts the range of
the proportional system so that it can buffer
short-term pressure changes that occur over a
period of seconds, minutes, or hours. Thus, a
combination of an adaptive baroreceptor system
and a long-term body fluid integral pressure control system can give essentially all of the advantages of both types of systems—the rapidity of
short-term control and the precision of the integral
system for long-term control.
INTERACTION BETWEEN AN INTEGRAL AND A PROPORTIONAL
CONTROL SYSTEM WHEN ONE SYSTEM ATTEMPTS TO CONTROL
THE ARTERIAL BLOOD PRESSURE TO ONE PRESSURE REFERENCE
LEVEL AND THE OTHER TO A DIFFERENT PRESSURE REFERENCE
LEVEL
Figure 6A illustrates the combination of a proportional control system that has one pressure
reference level (#1) and an integral control system
that has a different pressure reference level (#2). At
first both of the reference pressure levels begin at a
normal value of 100 mm Hg, and both the basic and
the actual arterial blood pressures begin at 100 mm
Hg. However, let us assume that the baroreceptor
proportional control system suddenly changes its
pressure reference level to 62.5 mm Hg. This
change could easily occur as a result of mechanical
stresses applied to the baroreceptor region of the
carotid arteries. Also assume that simultaneously
the pressure reference level of the renal-body fluid
integral control system changes from a normal level
of 100 mm Hg to 160 mm Hg. The two control
systems would then be pitted against each other to
control the arterial blood pressure (Fig. 6B). Because the proportional system acts rapidly (if it is
168
GUYTON, COLEMAN. COWLEY, MANNING. NORMAN. FERGUSON
A.
Basic
Arterial
Pressure
(00)
i r i.
IJ \
Rote of Error
Correction
("of)
B.
Integrol Control
. I6O-1
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0
2
4
6
8
IO
12
14
FIGURE 6
A: Combined proportional and integral systems for arterial
blood pressure control but with each of the two systems having its own separate pressure reference level. The values in
parentheses show the sequential changes in quantitative values
around the loops when the proportional pressure reference level
is suddenly changed from 100 mm Hg to 62J5 mm Hg and the
integral pressure reference level is changed simultaneously from
100 mm Hg to 160 mm Hg. The arterial blood pressure at first
decreases because of action of the proportional system, but later
the integral system becomes the absolute controller of the
pressure. B: Graph of the principles demonstrated by Figure6A,
showing instantaneous decrease in arterial blood pressure but
ultimate absolute control of the pressure by the integral control
system.
of the baroreceptor type), the initial control function would be exerted entirely by the proportional
control, and with a feedback gain of 4 the arterial
blood pressure would fall immediately 80% of the
way toward the 62.5-mm Hg reference level, i.e.,
from 100 mm Hg to 70 mm Hg. If no integral
pressure control system were present and if the
proportional system did not adapt, the pressure
would remain at 70 mm Hg indefinitely thereafter.
The dotted curve in Figure 6B illustrates the
approximate course of pressure changes if there
were only the integral control system. The combination of both the proportional and the integral
systems causes the effect illustrated by the solid
curve in Figure 6B. Once the pressure has fallen to
70 mm Hg, the integral system slowly integrates its
correction factor, Z, and this factor builds up
inexorably, never stopping, until the integral control system has succeeded in bringing the arterial
blood pressure up to its pressure reference level.
Thus, with time the arterial blood pressure approaches the pressure reference level for the integral control system and disregards entirely the
pressure reference level for the proportional system. The difference between the solid curve and
the dotted curve illustrates that the proportional
system slows events markedly and therefore delays
the inevitable effect of the integral control system
but does not alter the final effect.
The half times for approach to steady-state
values in Figure 6B are not too dissimilar from
those for the renal-body fluid integral control
system (9); these half times have not yet been
determined with precision, and undoubtedly they
change markedly under different conditions.
Therefore, when there is competition between an
integral control system and a proportional control
system, the final steady-state value of control is
precisely that dictated by the integral control, and
the proportional system does not participate in the
determination of this value.
SIGNIFICANCE OF THE INFINITE GAIN
INTEGRAL PRESSURE CONTROL LOOP
IN THE BODY
FLUID
Obscuring of the Significance of the InfiniteGain Integral Control System by the Proportional
Pressure Controls.—The significance of the ability
of the renal-body fluid infinite-gain integral control system to overcome the proportional pressure
control systems in determining the long-range level
of arterial blood pressure has generally gone unappreciated, because the rapidity of action of the
proportional controls obscures the significance of
the body fluid integral system. This extreme effect
is illustrated in Figure 5, which shows that whenever a proportional system operates simultaneously
with the integral system, it is the proportional
system that causes the immediate adjustment of
pressure; the integral system then makes only an
additional small correction to reach the exact
pressure level. In the curves in Figure 5B the
proportional system has a gain of only 4, which is
not unreasonable for the baroreceptor system by
itself, but if we consider all of the proportional
systems including the renin-angiotensin system,
the aldosterone system, the other nervous controls
besides the baroreceptors, and so forth then the
immediate proportional gain could be as high as
10-50 (31). This gain could return the arterial blood
pressure to within only a few mm Hg of its normal
Circulation Research, Vol. 35. August 1974
169
ANALYSIS OF HYPERTENSION
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level despite considerable abnormality in the basic
circulatory system. Therefore, the significance of
the integral control system could easily be obscured.
Another way in which the proportional control
systems can obscure the role of the body fluid
integral feedback mechanism is to alter other
factors in the circulation to such an extent that one
fails to recognize that the fluid volume system is
playing a significant role in pressure regulation. An
important example of this type of alteration is the
effect of vasoconstrictor agents on blood volume.
For instance, in pheochromocytoma patients the
blood volume is considerably reduced, and, yet, the
mean arterial blood pressure is elevated (32). At
first, one would expect the low blood volume to
indicate that fluid volumes are not participating in
the elevated pressure. However, this theory is far
from true because the excess norepinephrine and
epinephrine in the circulation has actually contracted the circulatory system until even a normal
b'jod volume overstretches the system.
Omnipotence of the Body Fluid Integral Feedback System for Control of Arterial Blood Pressure.—The curves in Figures 5 and 6 demonstrate
that in each of the four states discussed in which
the integral control system was competing with a
proportional system the final steady state of arterial blood pressure was determined absolutely and
completely by the integral control system. Mathematically, the relative potency of two control
systems operating in parallel is equal to the ratio of
their feedback gains. Since the feedback gain of the
integral control system approaches infinity with
time and the feedback gain of the proportional
system is finite, the ratio of potency of the integral
control system versus all the parallel proportional
controls together equals infinity divided by a finite
number; in other words, it equals infinity.
Therefore, mathematically, one would predict
that the body fluid integral pressure control system
would completely override all of the other pressure
controls in the determination of the arterial blood
pressure level.
DETERMINANTS OF THE LONG-RANGE STEADY-STATE LEVEL OF
ARTERIAL BLOOD PRESSURE
Beginning with the basic axiom that an integral
control system has the capabilities of infinite gain,
several additional conclusions about long-range
arterial blood pressure control can be developed.
First, referring again to Figure 2, the precise
factor in this control system that is controlled with
infinite gain is the output of block 2, d(BFV)/dt or
the rate of change of body fluid volume. In the
Circulation Research, Vol. 35. August 1974
steady state, d(BFV)/dt always reapproaches zero
with infinite gain.
Second, for the steady-state condition we can
work backwards from the output of block 2 to
arterial blood pressure to determine all of the
possible factors that can be important in long-term
determination of arterial blood pressure. Thus,
Figure 7A illustrates the portion of Figure 2 that
relates arterial blood pressure to the output of
block 2. Furthermore, since both blocks 1 and 2 are
algebraic relationships, each one of these blocks
can be reversed (Fig. 7B). For the steady-state
condition, the term urinary output can be changed
to urinary volume load, which is defined as the
volume of fluid ingested in each unit period of time
that must eventually be excreted by the kidney.
However, it must be emphasized that this reversal
process and interchange of terms is valid only for
the steady-state condition, because only then will
urinary volume load equal urinary output. Yet,
since the long-range level of arterial blood pressure
is a steady-state phenomenon, Figure 7B becomes
uniquely valuable for understanding long-range
pressure control, i.e., it delineates the possible
factors that can affect arterial blood pressure in the
long-range steady-state condition. These factors
are (1) the urinary volume load consisting of the
A.
Arterial
3
d
ressure
1
)
+ 1®
Output
Urinary
A. P.
B.
Fluid
intake
d(BFV)
dt
=0
Non-renal
fluid loss
Fluid
intake
D/%_N
JL+ Urinary
\ ~ / volume load
Non-renal
fluid loss
a.
Arterial
Pressure
4
U. V. L.
FIGURE 7
A: Blocks 1 and 2 of the renal-body fluid system for pressure
control as illustrated in Figure 2. This figure shows that, in the
steady-state condition, the output of block 2 (d[BFV]/dt) must
equal exactly zero. B: Rearrangement of the factors shown in
Figure 7A to illustrate the two primary determinants of longrange arterial blood pressure level: (/) the urinary volume load
(U.V.L.) with its two components, fluid intake minus nonrenal
fluid loss and (2) the renal function curve relating urinary
volume load to arterial blood pressure (A.P.). U.O. = urinary
output and BFV •= body fluid volume.
170
GUYTON. COLEMAN. COWLEY. MANNING. NORMAN. FERGUSON
rate of fluid intake minus the rate of nonrenal fluid
loss and (2) the renal function curve (block 2 in Fig.
7B), which depicts the relationship of arterial blood
pressure to urinary volume load in the steady-state
condition.
Thus, the renal function curve and the urinary
volume load are the two primary long-range determinants of arterial blood pressure, and the longrange steady-state level of arterial blood pressure
can be altered only by altering one of these primary
determinants.
200-1
2
a:
3
CO
C/5
Ld
100
§ »1
PRESSURE REFERENCE LEVEL OF THE BODY FLUID INTEGRAL
SYSTEM
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The two primary determinants of arterial blood
pressure can be viewed as the two primary factors
that set the pressure reference level of the body
fluid integral pressure control system. This fact is
illustrated graphically in Figure 8, which shows
lines representing two levels of urinary volume load
(I and II) and three different renal function curves
(A, B, and C). Line I represents the normal urinary
load when there is normal fluid intake, and curve A
represents the normal renal function curve. The
point where the load line crosses the function curve
(point 1) exactly defines the pressure level to which
the body fluid integral system will slowly adjust the
arterial blood pressure; point 1 defines the normal
long-range arterial blood pressure operating point
and, therefore, also defines the long-range arterial
blood pressure reference level, because this operating point is the pressure level that the integral
control system will eventually approach in bringing
fluid input and output back to balance.
However, the pressure reference level (the longrange operating point of the system) can be
changed by changing either of the two primary
determinants of this level. Thus, if the urinary
volume load is increased from line I to line II while
the renal function curve remains normal, the new
pressure reference level becomes the pressure at
point 2, and the arterial blood pressure will thereafter be regulated around that level as long as the
urinary volume load remains at the elevated level.
The renal function curve could also become curve B
or curve C and intersect lines I or II to determine
the other possible reference levels depicted by
points 3, 4, 5, and 6.
Renal function curve C is the curve that has been
determined for dogs with 70% of their renal mass
destroyed (4-6). In this case, when the fluid intake
is normal, the long-range steady-state arterial
blood pressure adjusts to the level of point 3, only 6
mm Hg above normal. However, increasing the
0
1
2
3
4
5
6
7
8
9
URINARY VOLUME LOAD (times normal)
FIGURE 8
Renal function curves depicting the relationship between urinary uolume load and arterial blood pressure. Curve A shows the
approximate normal renal function curve as extrapolated quantitatively to the human body from measurements in animal
experiments. Curve B represents the approximate renal function curve for Goldblatt kidneys. Curve C represents the
approximate curve for animals that have lost 70% of their renal
mass. The broken lines (I and II) represent two different levels of
urinary volume load, illustrating that for a given volume load
there is one single precise arterial blood pressure level to which
the arterial blood pressure will be controlled for any given renal
function curve. Therefore, the point of crossing between the
renal function curve and a volume load line represents the
pressure reference level to which the long-range arterial blood
pressure level will be controlled.
normal fluid intake 3.5-fold increases the pressure
reference level (and eventually the actual arterial
blood pressure) to the level of point 4 or to greater
than 160 mm Hg; the arterial blood pressure
control system will thenceforth automatically control the arterial blood pressure around this level.
Renal function curve B has been derived from
data in Goldblatt hypertension (33, 34). The pressure reference level becomes set to a very high level
almost regardless of the urinary volume load (34).
Difference between the Instantaneous Determinants of Arterial Blood Pressure (Cardiac Output
and Total Peripheral Resistance) and the Determinants of the Long-Range Steady-State Arterial
Blood Pressure Level.—It is a matter of definition
that the level of arterial blood pressure at any given
instant is equal to total peripheral resistance times
cardiac output or, to be more exact, total peripheral resistance times cardiac output plus right
atrial pressure. This relationship between total
peripheral resistance and cardiac output holds at
all times whether the arterial blood pressure is in a
Circulation Research, Vol. 35, August 1974
ANALYSIS OF HYPERTENSION
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transient state of adjustment toward its long-range
pressure level or whether it has already reached
that level. On the other hand, the above two determinants of the long-range level of arterial blood
pressure apply only to the final steady-state condition. For instance, the arterial blood pressure might
at a given time be 150 mm Hg because the cardiac
output is 7.5 liters/min and the total peripheral resistance is 20 mm Hg/liter blood flow min~'. However, the reference level for long-range pressure
control that is dictated by the two determinants of
the long-range pressure reference value might at
that same time be 100 mm Hg. Because of this difference, the pressure control system will progressively change either cardiac output, total peripheral resistance, or both until the arterial blood pressure approaches 100 mm Hg, which is the pressure
reference level. Thus, both cardiac output and total
peripheral resistance are dependent variables in
the long-range pressure control system.
CRITICAL ROLE OF THE RENAL FUNCTION CURVE IN ARTERIAL
BLOOD PRESSURE CONTROL
Referring once again to Figure 8, we can continue
additional mathematical deductions. First, the
normal renal function curve (curve A) shows very
little rise in pressure even with marked changes in
urinary volume load. Thus, even though the load
increases 3.5-fold between points 1 and 2, the
arterial blood pressure increases only 5 mm Hg.
Therefore, it is primarily the characteristics of the
renal function curve itself that determine arterial
blood pressure and not the factors that constitute
the urinary volume load, the intake of fluid, and
the nonrenal loss of fluid. Furthermore, fluid intake
by the normal person and the nonrenal loss of fluid
from the body fall within a relatively narrow range;
thus, the volume load only rarely is an important
determinant of arterial blood pressure as long as
the kidneys function normally. Therefore, for the
normal person, the long-range control of arterial
blood pressure is determined almost entirely by the
arterial blood pressure level of the plateau in the
renal function curve.
In abnormal states of kidney function both the
pressure level and the slope of the renal function
curve can change drastically. Curve B in Figure 8,
which represents the approximate curve of a Goldblatt hypertensive animal, shows that the pressure
level of the renal function curve has become greatly
elevated and, operating through the body fluid
pressure control system, should theoretically also
elevate the long-range level of arterial blood pressure. Curve C in Figure 8 represents a much steeper
Circulation Research, Vol. 35, August 1974
171
curve; this type of curve is found when the renal
mass is reduced. In this state the level of fluid
intake, in addition to the average pressure level of
the renal function curve, is clearly an important
factor in pressure control.
FACTORS THAT DETERMINE THE SHAPE OF THE RENAL FUNCTION
CURVE
Despite the tremendous amount of research that
has been directed toward understanding renal
function, studies have only recently begun to
elucidate the precise factors that determine the
shapes and the quantitative values for the renal
function curves under different conditions, primarily because the importance of this subject to
understanding pressure control is only now becoming appreciated. However, because of the extreme
importance of this curve in determining the longrange level of arterial blood pressure, it is important to discuss what is presently known about this
problem.
Figure 9 illustrates the general nature of a
systems diagram for expressing the roles of different factors in determining the shape and the
quantitative values of the renal function curve. In
the upper left corner is the arterial blood pressure
input and to the right side is the urinary volume
output. Although much of the quantitative information needed to fill in the details of this diagram
is still missing, nevertheless we can already predict
the general factors that are most likely to be
important in determining the shape of the renal
function curve. For instance, it is immediately
clear that the urinary volume output at each level
of arterial blood pressure is determined by the
difference between glomerular filtration rate and
tubular reabsorption rate. Therefore, one can rapidly separate the factors that affect the renal
function curve into those that determine the relationship of arterial blood pressure to glomerular
filtration rate and those that determine the relationship of arterial blood pressure to tubular reabsorption rate.
A simple listing of the factors that determine the
relationship of arterial blood pressure to glomerular
filtration rate includes (1) intrinsic afferent arteriolar resistance, (2) degree of sympathetic stimulation of the afferent arterioles, (3) glomerular filtration coefficient, (4) effect of renin secretion on
glomerular filtration, (5) plasma colloid osmotic
pressure, (6) renal interstitial pressure, and (7)
postglomerular vascular resistance. A change in
any one of these factors can alter the relationship
between arterial blood pressure and glomerular
GUYTON, COLEMAN. COWLEY. MANNING. NORMAN. FERGUSON
172
Sympothttic
Stimulation
1
Arttriat PrtMurt
'
Rtnal Blood
Glonwular
Filtration
Pr«ilur»
Prttturt
Proximal
Tubular
Pr«tBur«
Prtalomtnjlar
Prttturt
Drop
Intrinsic
Rltittanct
AMtftnt
A
^
intarstHlal
Pmsurt
A
PTP.
/(GFR,IP)
Glomarulor
Filtration
Rot«
AAR.
/ ( G F R , IR.SS, RS)
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PrtcopHlory
R««r«tonc«
t
R«nol Copilory
Pr«uur«
T R R .
/ ( K C P , PCOP, GFR, ADH, AW, No Lood.IP, T M , CFC)
TV
Ploimo Colloid
Oimotic Pr«>»ur«
V
ADH
A
f
Aldottiron* No Lood
A
V
Tubular
Mot.
Tubular
Rtobwrption
Rot*
V
CatUlary
Filtration
Co«fficitnt
FIGURE 9
A systems diagram showing most of the important factors that determine the shape and the
quantitative values for the renal function curve. PTP = proximal tubular pressure, GFR glomerular filtration rate, IP - interstitial pressure (total pressure in the kidney tissue), AAR afferent arteriolar resistance. LR - intrinsic resistance (resistance of afferent arterioles when they are
completely vasodilated), SS - sympathetic stimulation, RS «= renin secretion, TRR =. tubular
reabsorption rate, RCP - renal capillary pressure (pressure in peritubular capillaries), PCOP plasma colloid osmotic pressure, ADH - antidiwetic hormone, Aid - aldosterone, TM - tubular
mass, and CFC - capillary filtration coefficient of peritubular capillaries.
filtration rate and, therefore, can also alter the
relationship between arterial blood pressure and
urinary volume output.
The factors that affect the relationship between
arterial blood pressure and tubular reabsorption
rate include (1) plasma colloid osmotic pressure,
(2) antidiuretic hormone, (3) aldosterone, (4) sodium load, (5) tubular mass, (6) renal interstitial
pressure, (7) precapillary resistance, (8) postcapillary resistance, (9) peritubular capillary filtration
coefficient, and (10) other things such as intratubular pressure, factors that control tubular active
transport, back leakage through the walls of the
tubules, etc. Any one of these factors can, therefore, also affect the relationship between arterial
blood pressure and urinary output.
Difference between the Renal Function Curve
Measured in the Isolated Kidney and That Measured in the Intact Animal.—When a kidney is
removed from the body and perfused at different
arterial blood pressures, the renal function curve is
essentially that illustrated by the broken curve in
Figure 10. Curves of this type, but with the
coordinates transposed, have been measured by
Selkurt (10), Thurau and Deetjen (13), Shipley and
Study (11), Thompson and Pitts (12), Navar et al.
(14), Fourcade et al. (35), and many others.
On the other hand, if one measures this curve in
the intact animal and allows a steady-state condition to develop at each measuring point, he derives
the solid curve in Figure 10. For this procedure, an
animal is placed on various levels of fluid intake
and allowed to come to a new steady state. Then
the urinary output, which in the steady state is
equal to the urinary volume load, and the arterial
blood pressure are measured, and the points are
plotted to give the renal function curve illustrated
by the solid curve. Also, since in the steady state
Circulation Research. Vol. 35. August 1974
ANALYSIS OF HYPERTENSION
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I
2
3
4
5
6
7
8
9
Urinary Volume Load and Urinary Output
(times normal)
FIGURE 10
Renal function curves as determined for the isolated kidney
(broken line) and for the kidney in the intact animal (solid line).
The curve for the isolated kidney is a composite drawn from
data published by Selkurt (10), Shipley and Study (11),
Thompson and Pitts (12), Navar et al. (14), Thurau and Deetjen
(13), and Fourcade et al. (35). The crosses on the curve for the
intact kidney represent composite points from data determined
in our laboratory.
the urinary output equals the urinary volume load,
the abscissa is labeled as both of these.
Using this process of measurement, there is
extremely little change in arterial blood pressure
despite a very marked change in urinary volume
load in the normal animals as depicted by the solid
curve (4-7). One reason for this effect is that in the
intact animal increasing arterial blood pressure
affects urinary output in other ways in addition to
the direct hydrodynamic effect of the pressure
itself. This fact is illustrated in Figure 9 by the
broken lines which show that increased arterial
blood pressure increases urinary volume output by
an inhibition of renal sympathetic stimulation
(15), an inhibition of renin secretion (17), an
inhibition of ADH secretion (16), an inhibition of
aldosterone secretion (18), and probably in many
other less important ways. Furthermore, one can
show quantitatively that two of these effects, the
inhibition of renal sympathetic stimulation and the
inhibition of ADH secretion, can by themselves
alter renal function far more than can the direct
hydrodynamic effect of increasing arterial blood
pressure. Therefore, it is very easy to understand
that all of these additional effects can readily
summate with the hydrodynamic effect to change
the slope of the broken curve in Figure 10, i.e., the
Circulation Research. Vol. 35, August 1974
173
curve that results when the hydrodynamic effect
alone is operative, to that of the solid curve, i.e.,
the curve that results when all of these effects are
operating in parallel.
A second reason for the shift from the broken
curve to the solid curve in Figure 10 is that some
factors associated with volume changes in the
body, but not with pressure per se, have parallel
direct effects on kidney function which summate
with the effects of arterial blood pressure. For
instance, an increase in water loading has a direct
effect on ADH secretion that is independent of the
pressure effect (36). Therefore, this parallel effect
can obviously enter into the control system equally
as well as the direct effects operating through
pressure and can help to change the renal function
curve of the isolated kidney, the broken curve, to
the solid curve that is recorded in the intact animal.
One can readily understand that it is the longrange steady-state renal function curve (solid curve
in Fig. 10) that is important in long-range arterial
blood pressure control and not the curve that is
obtained in the isolated kidneys. Even the curve
that has been obtained in the isolated kidneys
would provide a good control system for arterial
blood pressure, but the extremely low slope of the
solid curve in Figure 10 illustrates that all of the
other feedback functions to the kidneys that make
the slope of this curve very shallow enhance markedly the potency of the renal-body fluid system for
arterial blood pressure control.
RELATIVE IMPORTANCE OF PRETUBULAR MECHANISMS OF THE
KIDNEY VERSUS TUBULAR MECHANISMS FOR PRESSURE
CONTROL
The available quantitative evidence indicates
that the pretubular renal mechanisms play a
greater role in arterial blood pressure control than
do the tubular mechanisms. This statement is an
anathema to some investigators in the field of
hypertension, perhaps because the majority of
present day renal physiological research is directed
toward tubular mechanisms. However, the following evidence indicates that it is primarily pretubular renal mechanisms that control arterial blood
pressure rather than tubular mechanisms. (1) Any
factor that increases the resistance to blood flow
between the systemic arteries and the glomeruli
increases the animal's arterial blood pressure. This
effect occurs in the Goldblatt preparation. (2)
Renal afferent arteriolar sclerosis is essentially
always associated with hypertension (37). (3) Recent studies of long-term development of hypertension in patients following mild acute glomerulone-
GUYTON, COLEMAN. COWLEY, MANNING. NORMAN. FERGUSON
174
that ADH causes marked water reabsorption by the
tubules (40). This effect, too, is compensated for by
an increase in glomerular filtration rate which
overcomes the marked increased tendency for
water reabsorption. In other words, in both primary
aldosteronism and inappropriate ADH syndrome a
small to moderate rise in arterial blood pressure
can automatically compensate for the tremendous
enhancement of tubular reabsorption.
Therefore, the arterial blood pressure seems to be
less affected by changes in tubular function than
by pretubular abnormalities, which is presumably
the explanation for the fact that the hypertension
of primary aldosteronism is usually less severe than
many other types of hypertension.
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phritis have shown that the primary lesion is
glomerular sclerosis with no involvement of the
tubules (38). (4) Some tubular lesions cause excessive salt and water loss rather than salt and water
conservation. In these patients there is a tendency
for the arterial blood pressure to remain normal or
to fall (39), and it is sometimes necessary to give
these patients both salt and water to keep them
from going into a lethal state of dehydration with a
subsequent fall in pressure and death. (5) In
primary aldosteronism, which is known to promote
marked reabsorption of sodium from the tubules
and, therefore, to cause marked reabsorption of
water, only moderate hypertension occurs in the
early stages, although the fluid retention effects of
this condition occur from the very beginning of the
disease. Experimental studies in dogs have demonstrated the cause of this phenomenon: the increased reabsorption of sodium and water is compensated for by increased glomerular filtration rate
as soon as the arterial blood pressure rises only a
small amount (18). (6) In the inappropriate ADH
syndrome in which tremendous quantities of ADH
are secreted, the patient develops only a slight
elevation in arterial blood pressure despite the fact
A SEHVOCONTROL FUNCTION FOR THE KIDNEYS IN LONGRANGE CONTROL OF ARTERIAL BLOOD PRESSURE
If the diagram in Figure 7B is revised for arterial
blood pressure control, we get Figure 11. This figure
shows the two determinants of arterial blood pressure: (1) the renal function curve and (2) the
urinary volume load with its component parts,
fluid intake and nonrenal fluid loss. However, the
renal function curve has been expanded to a family
of curves. Both the pretubular and tubular renal
PRE-TUBULAR PRESSURE CONTROL FACTORS
Plasma colloid
Glomerular
osmotic pressure filtration
coefficient
Sympathetic
Intrinsic
afferent
stimulation
arteriolar
resistance
1 +
Renin
Renal
Postglomerular
secretion interstitial vascular
pressure
resistance
1+
1+
1+
1-
Fluid Intake
( No intake)
/ i \
\J
Urinary Volume
Load
a.
<
'
' Normal
t'volun* load
ARTERIAL
PRESSURE
U. V. L.
Non-Renal
Fluid Loss
i\
f+
Plasma colloid
Capillary
osmotic pressure filtration
coefficient
t+
ADH
Aldosterone
V
f +•
Precapillary Postcapillary
No
Tubular Renal
interstitial resistance resistance
load mass
pressure
TUBULAR PRESSURE CONTROL FACTORS
FIGURE 11
Composite diagram showing the two primary determinants of arterial blood pressure control—the
urinary volume load (U.V.L.) and the renal function curve—and the secondary factors that can affect arterial blood pressure by shifting the level of the renal function curve. A system of this type is essentially the same as that of a servocontrol mechanism, with the kidney acting as a servocontroller for
arterial blood pressure regulation and the factors impinging on the kidney operating to adjust the
pressure reference level to which the servocontroller adjusts the arterial blood pressure level. A.P. arterial pressure and ADH - antidiuretic hormone.
Circulation Research. Vol. 35. August 1974
175
ANALYSIS OF HYPERTENSION
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factors that can alter the shape and the quantitative values for the renal function curves are listed
in this figure. A change in any one of these tubular
or pretubular factors, as well as other changes not
illustrated, can alter the shape or the level of the
renal function curve.
In Figure 11 sodium intake is illustrated in
parentheses adjacent to fluid intake, indicating
that fluid intake is determined to a great extent by
sodium intake. In animal experiments, one finds
that an animal on a high-sodium intake will drink a
sufficient amount of water to provide almost exactly an isotonic saline fluid intake. Sodium load is
also one of the factors that determines the level of
the renal function curve.
The selection of the renal function curve that is
operating at any given time for arterial blood
pressure control is determined by a multiple of
pretubular and tubular renal mechanisms. As long
as all of these factors remain constant, the animal
operates on a single renal function curve, and the
arterial blood pressure over a period of many hours
or days adjusts to precisely the level at which this
renal function curve crosses the urinary volume
load line of the animal. If the urinary volume load
remains constant, as illustrated by the vertical
broken line in block 2 of Figure 11, then the
long-term level of arterial blood pressure can be
increased or decreased by changing one or more of
the pretubular or tubular factors that affect the
renal function curve. But, once the renal function
curve has been charged to a new curve, the arterial
blood pressure becomes controlled with infinite
gain to the new arterial blood pressure reference
level as defined by the point at which the function
curve crosses the urinary volume load line. In other
words, changing either pretubular or tubular factors can change the reference level to which the
kidney will regulate the arterial blood pressure.
This process represents the typical operation of a
servocontroller (41); thus, the kidney can be considered to be a servocontroller of arterial blood
pressure.
The importance of the concept presented in
Figure 11 is that it allows the research worker to
focus his attention on the key determinants of
long-range arterial blood pressure control. However, research workers have been tremendously
preoccupied with studying acute changes in total
peripheral resistance and cardiac output as the
bases of arterial blood pressure control. These
factors do determine the instantaneous arterial
blood pressure, but measurement of cardiac output
and total peripheral resistance at any given time
Circulation Research, Vol. 35, August 1974
cannot in any way predict what the ultimate
steady-state level of pressure control will be. Instead, these two factors turn out to be uncontrolled
variables in the long-range arterial blood pressure
control system. Simply to prove the point, in both
animals and patients, arteriovenous fistulas can
be opened and closed at will, an effect that can
change the total peripheral resistance many fold;
yet, after the new steady-state pressures have been
achieved several days later, the arterial blood
pressures will be the same as before (42). Therefore,
of what predictive value is the total peripheral
resistance for the final steady-state level of arterial
blood pressure?
Thus, this type of analysis gives one a new view
of the basic, important factors for long-range arterial blood pressure control. It also delineates by
mathematical and experimental deduction different possible causes of hypertension. An abnormality of any one or more of the factors illustrated in
Figure 11 can theoretically cause hypertension (or
hypotension if the abnormality is in the opposite
direction). Almost all of the known causes of
hypertension are in fact represented by one or more
of these factors. Also, the mathematical analysis
presented in this paper indicates that any cause of
hypertension must act by changing one or both of
the two basic determinants of the long-range arterial blood pressure level, the renal function curve
and the urinary volume load. Since quantitatively
the more potent of these determinants is usually
the renal function curve, hypertension will rarely
occur without some pathological or physiological
shift in this curve.
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Circulation Research, Vol. 35, Augiat 1974
Brief Reviews: A Systems Analysis Approach to Understanding Long-Range Arterial Blood
Pressure Control and Hypertension
ARTHUR C. GUYTON, THOMAS G. COLEMAN, ALLEN W. COWLEY, Jr., R. DAVIS
MANNING, Jr., ROGER A. NORMAN, Jr. and JOHN D. FERGUSON
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Circ Res. 1974;35:159-176
doi: 10.1161/01.RES.35.2.159
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