Arterial Pressure Regulation

Overriding Dominance of the Kidneys in

Long-Term Regulation and in Hypertens.ion

ARTHUR C. GUYTON, M.D. The body is endowed with many different arterial pressure regu-
THOMAS G. COLEMAN, Ph.D. lating mechanisms, some of which operate rapidly, some slowly;
ALLEN W. COWLEY, Jr., Php. some of which operate at low pressure ranges, some at normal
KONRAD W. SCHEEL, Ph.D. pressure ranges, and some at high pressure ranges; some of
R. DAVIS MANNING, Jr., M.S. which have weak feedback gains, some of which have moderate
ROGER A. NORMAN, Jr., MS. feedback gains, and one of which has infinite gain when suf-
Jackson, Mississippi ficient time is allowed for its control functions to reach the state
of equilibrium. The infinite gain pressure control system is
based on the effect of arterial pressure on renal output of
water and salt. If the arterial pressure becomes too high, the
output becomes greater than the net intake of water and salt,
and the body becomes progressively dehydrated until this de-
hydration causes the pressure to return all the way to normal.
It is this “all the way” response that is the cause of the inrfinite
gain. Because of the infinite gain of this control mechanism,
it is the one that determines the long range level of arterial
pressure.
Many factors can affect the operation of the renal-body fluid
mechanism for arterial pressure regulation. These include ner-
vous effects acting on the kidney, hormonal factors acting on
the kidneys, pathology of the kidney, and so forth. However, the
principle of infinite gain in this system requires that, in some
way, all long-term arterial pressure regulation must involve the
balance between intake and output of water and salt and almost
invariably involves the kidneys.

In recent years we have attempted to determine the manner in

From the Department of Physiology and which different pressure control systems function to provide
Biophysics, University of Miss~issippi
both short-term and long-term arterial pressure regulation.
School of Medicine, Jackson, Mississippi.
This study was supported by grants-in-aid These studies have encompassed both animal investigations
from the U.S. Public Health Service and and computer analyses of the interactinglmechanisms, and from
the American Heart Association. Requests them have come several new concepts, some of which we be-
for reprints should be addressed to Dr. lieve to be very important in understanding arterial pressure
Arthur C. Guyton, Department ‘of Physiol-
regulation. The most important has been a concept that, ex-
ogy and BiNo,physics, University Medical
Center, 2500 North State Street, Jackson, cept in one or two very rare exceptions (such as in dialysis of
Mississippi 39216. anephric patients), the kidneys are always the pivotal key in

584 The American Journal Of Medklne

 ARTERIAL PRESSURE REGULAi-lON - GlJYTON ET PL.

long-term arterial pressure regulation, both in arter al pressure rises too high, or indeed when the
normal states an 1 ;n hypertension. However, be- pressure increases in any part of the circulation,
fore this overriding dominance of the kidneys in the t:iood vessels slowly begin to stretch. a phe-
tong-term reguiaiion of arterial pressure and in nomencn called stress relaxation. This allows the
hypertension can be expla ned, it is necessary to pressure in each overly stressed segment of the
discuss some of the more important pressure con- circuation lo fall, thus returning the pressure
trol mechanisms and the manner in which they toward normal.
Interact with each other. (6) The Capillary Fluid Shift Mechanism. Often
when the arterial pressure is elevated, e.g., after a
THE MORE IMPORTANT PRESSURE massrve transfusion, the capillary pressure is also
REGULATING SYSTEMS elevated. This results in rapid transudation of fluid
At least eight arterial pressure regulating sys- out of the circulation into the tissue spaces; the
tems, already well known and well characterized, resulting decrease in blood volume initiates a se-
function continually. These are as follows: quence of events that returns the arterial pressure
(1) The Baroreceptor Mechanism. When the ar- back toward normal.
terial pressure rises it stimulates the barorecep- (7) The Renal-Body Fluid Mechanism. When ar-
tors, located mainly in the carotid sinuses and in terial pressure falls below normal, the decreased
the arch of the aorta; these in turn send signals pressure has a direct effect on the kidneys to re-
to the vasomotor center in the lower regions of duce the output of water and salt. This in turn
the brarn. From here signals pass through the causes a progressive increase of both water and
autonomic nervous system to relax the heart and salt in the body fluids as the person continues to
to dilate the peripheral blood vessels, which de- eat salt and to drink water. The increase in body
crease the arterial pressure back toward normal. fluid voiume in turn returns the arterial pressure
(2) The Chemoreceptor System. When the ar- toward normal [4].
terial pressure fails below about 80 mm Hg, the (8) The Aldosterone Mechanism. For a number
chemoreceptors located in the carotid and aortic of different reasons, a decrease in arterial pressure
bodies become stimulated because of poor de- causes an increase in aldosterone. One of the
livery of oxygen to the chemoreceptors and be- mechanisms for this is a decrease in arterial pres-
cause of poor removal of carbon dioxide. Signals sure causes formation of renin which then forms
from these are also transmitted through the vaso- angioterrsin as already explained. The angiotensin
motor center and autonomic nervous system, in in turn stimulates aldosterone secretion by the
this case raising the arterial pressure toward nor- adrenal glands [5]. In addition, other more direct
mal [l]. mechanisms also cause increased aldosterone se-
(3) The Central Nervous System lschemic Re- cretion. The aldosterone in turn causes the tubules
sponse. When the arterial pressure falls ex- of the kidneys to reabsorb increased quantities of
tremeiy low (usually below 40 mm Hg) ischemia salt, thus increasing the salt in the body fluids.
of the vasomotor center in the medulla oblongata The increased salt in turn sets into motion several
causes powerful signals to spread throughout the other mechanisms, including antidiuretic hormone
sympathetic nervous system. These constrict the (ADH) secretion, that cause the kidneys to retain
peripheral vessels and enhance heart activity, water as well. Therefore, the body fluid volume
thereby elevating arterial pressure back toward increases, and this in turn increases the arterial
normal [2]. pressure toward normal.
(4) The Renin-Angiotensin-Vasoconstrictor Mech- Aside from these powerful mechanisms for con-
anism. When the arterial pressure falls below trol of arterial pressure, other less powerful or still
100 mm Hg the kidneys begin to form increased questionable mechanisms also exist, such as: (a)
quantities of renin, and this in turn acts as an decreased arterial pressure causes increased se-
enzyme to split the vasoconstrictor substance cretion of ADH, which in turn causes both water
angiotensin from renin substrate, one of the retention and peripheral vasoconstriction; (b) tis-
plasma proteins. Vasoconstriction caused by the sue damage causes release of vasodilator sub-
angiotensin in turn elevates the arterial pressure stances, including histamine and perhaps brady-
back toward normal [3]. kinin, which decrease the arterial pressure: (c)
(5) The Stress Relaxation Mechanism. When the feedback control of prostaglandins to regulate

Volume 52, May 1972 585

ARTERIAL PRESSURE REGULATION - GUYTON ET AL.

normal range, but it becomes almost useless as

Figure 1. Approximate pressu#re ranges
the different well known arterial pressure
anisms.
renal function or peripheral resistance and thereby
to control arterial pressure; (d) other vasodilator
or vasoconstrictor mechanisms.
CHARACTERISTICS AND ROLES OF THE
DIFFERENT ARTERIAL PRESSURE
CONTROL MECHANISMS
If our bodies had one single arterial pressure con-
trol system that could maintain appropriate pres-
sure under all possible conditions, there would be
no need for a multiplicity of blood pressure con-
trols. Unfortunately, no such single all encolm-
passing control system has evolved. Instead, each
of the pressure control systems has its own in-
dividual characteristics which make it peculiarly
valuable under specific conditions.
Pressure Ranges for Function of Different Pressure
Control Systems. Figure 1 illustrates the dif-
ferent pressure ranges in which the eight well
charted pressure control systems operate. A few
of these, the stress-relaxation, capillary fluid shift
and renal-body fluid mechanisms, operate in all
pressure ranges, whereas the other five have
definite pressure limits. Therefore, one can see
how the different mechanisms can complement
each other.
Let us consider for a moment the three ner-
vous pressure feedback mechanisms. The baro-
receptor system is especially potent as an arterial
pressure regulator when the pressure is in the
a pressure regulator once the pressure has fallen
below 60 to 70 mm Hg [l]. But, by this time, the
chemoreceptors have begun to be stimulated very
powerfully and now also operate as pressure regu-
lators. Finally, when the pressure has fallen below
approximately 40 mm Hg, the chemoreceptors
will have responded almost to their limit, but the
central nervous system ischemic response (caused
by direct ischemia of the vasomotor center) elicits
extremely powerful sympathetic signals to keep
the pressure from falling still further [2]. There-
fore, it is frequently said that the central nervous
- system ischemic response provides a “last ditch
stand” to prevent the arterial pressure from falling
the last few millimeters of mercury to the point of
death.
Response Times of the Different Pressure Control
Systems. Aside from different pressure ranges
for function of for operation, the different pressure control sys-
regulating mech- tems also differ markedly in their response times
(Figure 2). The time scale shown on the abscissa
in Figure 2 is logarithmic, which emphasizes the
extreme differences in response times of the dif-
ferent mechanisms. The three nervous mechanisms
(the baroreceptors, the chemoreceptors and cen-
tral nervous system ischemic system) all respond
in seconds, and it is these that are extremely im-
portant for keeping the arterial pressure on an
even keel when a person changes posture, when
he bleeds rapidly, when he is centrifuged by a
tight turn of an airplane, and so forth. In an animal
whose baroreceptors and chemoreceptors are de-
nervated, the mean arterial pressure rises and
falls in a dispersed pattern of pressures through-
out the day between approximately 70 and 210
mm Hg, illustrating the extreme instability of pres-
sure when nervous controls are not functioning.
The pressure control systems with intermediate
response times are the stress relaxation system,
the renin-angiotensin-vasoconstrictor system and
the capillary fluid-shift system. These operate
within minutes or a few hours. They play impor-
tant roles especially in slow hemorrhage or in
overtransfusion.
Finally, the aldosterone and renal-body fluid
pressure control mechanisms do not have sig-
nificant effects on arterial pressure control for
several hours, but when they finally become ac-
tivated they continue to respond indefinitely.
Feedback Gains of the Different Pressure Control
Systems. One can express the effectiveness of a
control system in terms of its feedback gain. For

586 The American Journal of Medicine

 ARTERIAL PRESSURE REGULATION - GUMON ET AL.

instance, if the arterial pressure becomes ab-
normal but the control system in turn brings the
pressure halfway back to normal, the feedback
gain is one. That is, the “gain” is calculated by
dividing the amount of correction of the ab-
normality by the still remaining degree of ab-
normality. If a control system fails to correct an
abnormality at all, then its feedback gain is zero;
at the other extreme, if the control system cor-
rects the abnormality completely, then its feed-
back gain is infinity.
With this brief explanation of feedback gain,
let us study more closely the responses of the
pressure control systems in Figure 2. Note that
the nervous feedback system that has the highest
gain is the central nervous system ischemic re-
sponse, not the more widely studied baroreceptor
pressure control mechanism. The reason so many
people have overlooked this difference in po-
tency of the two systems is that the central nervous
system ischemic response operates only at very
low arterial pressures, whereas the baroreceptor
mechanism is an important pressure control sys-
tem even at normal arterial pressures, the pres-
sure range in which smost research workers study
arterial pressure. Yet, when a person is approach-
ing the low pressure levels preceding death, he
can be exceedingly thankful for the central nervous
system ischemic response.
Figure 2 depicts one major surprise; this is the
fact that, after many days of response, the renal-
body fluid pressure control system approaches
infinite gain. This effect has a number of qualifica-
tions that will be explained in detail later in this
article, but the very fact that the renal mech-
anism can achieve infinite gain under some con-
ditions illustrates the extreme importance of this
particular pressure control mechanism in long-
term regulation of arterial pressure. Yet, note also
that this mechanism is almost useless for regula-
tion of arterial pressure over a period of minutes,
hours or even for as much as a day or so. There-
fore, the other control *mechanisms often save
the life of the person during the first several days
of severe stress before the much more powerful
renal-body fluid system begins to take command-
ing control.
Most of the other pressure control systems have
relatively low gains, but since the gains are alge-
braically additive, one can see that a concert of
all the control systems operating together can
stabilize arterial pressure far more effectively than
can any one of them operating separately.
Direct Effect of Arterial Pressure ok Renal Output.
The physiologic basis of the renal-body fluid mech-
anism for regulation of arterial pressure is the di-
rect effect of arterial pressure on output of water
and salt from the kidneys [6]. This effect is illus-

Figure 2. Response times and maxi-

mum feedback gains in the optimum
pressure ranges for the different well
known arterial pressure control mech-
anisms. The dashed portions of the
curves are not well determined. From 6 13 30 I 2 4 8 16 32 I 2 4 6 161 2 4 6 r6----O”
Guyton AC, Coleman JG, Cowley AW Jr:
Regulation of Arterial Pressure. W. 5.
--T
seconds Minutes

Saunders Co. (to be published). TIME AFTER SUDDEN CHANGE IN PRESSURE

Volume 52, May 1972 507

ARTERIAL PRESSURE REGULATION - GUYTON ET AL.
0 I
50 200
Figure 3. Equilibrium between intake and output of water
and salt, illustrating the effect of arterial pressure on
renal output and, -therefore, the effect of arterial pressure
on this equilibrium.
trated by the solid curve of Figure 3. When the
arterial pressure falls to approximately 50 mm
Hg, urinary output falls to zero, and, therefore,
the output of water and salt also falls to zero.
On the other hand, when the arterial pressure rises
from the normal value of 100 up to 200 mm Hg,
the outpu& of both water and salt increase some
six- to eightfold. This effect of arterial pressure on
the output of water and salt has been demonstrated
in kidneys that have been removed from the ani-
mals bodies and also in intact animals. For
+,JHFk8
Figure 4. The feedback control loop of the renaLbody
fluid arterial pressure control mechanism. The dashed
arrow indicates a negative effect. Those portions of the
diagram in the heavy dashed enclosure represent the “de-
terminants” of arterial pressure. Those outs’ide the en-
closure represent the dependent variables of the system.
588
reasons that will be explained shortly, the up-
ward slope of this curve is far greater in intact
animals than shown in Figure 3.
The manner in which the renal-body fluid ar-
terial pressure control mechanism works is ex-
tremely simple, so simple in fact that it was the
first one of the pressure control mechanisms sug-
gested after the discovery of the circulation. In
Figure 3 the dashed line represents the net intake
of water and salt (defined as the intake minus the
nonrenal output such as through the gut or by
sweating). When the net intake exactly equals
renal output nothing at all happens, and the
arterial pressure is determined by the point at
which the two curves cross, called the “equilibrium
point” (Figure 3). However, if the arterial pres-
sure rises to 150 mm Hg, urinary output of both
water and salt increases to about three tiames
normal whereas the net intake remains at the
normal level. Therefore, both water and salt are
lost from the body until the arterial pressure falls.
When the pressure reaches 100 mm Hg, the out-
put and intake once again become exactly equal,
and the arterial pressure stabilizes at that point.
At no pressure level besides 100 mm Hg can the
output and input possibly be equal (Figure 3).
This applies for low pressures as well as high pres-
sures because at low pressures the intake will be
greater than the output so that fluid and salt
will accumulate in the body until the pressure rises
up to the level indicated by the equilibriu’m point.
Mechanisms of the Feedback Loop. The different
factors involved in the renal-body fluid pressure
control system are shown in more detail in Fig-
ure 4. The rate of change of extracellular fluid
volume is determined by the difference between
net intake of water and salt and renal output of
water and salt. If the rate of change is positive,
the extracellular fluid volume will increase. If
negative, it will decrease.
Let us assume that the arterial pressure has
fallen below the normal level. Referring again to
Figure 4, the output of water and salt becomes
less than the net intake. Therefore, the extracel-
lular fluid volume begins to increase. This in
turn causes the blood volume to increase, which
causes the circulatory filling pressure also to rise.
It has been shown both experimentally and mathe-
matically that increasing this filling pressure will
increase venous return [7], causing also an equal
increase in cardiac output. The increase in cardiac
ouput then increases the arterial pressure in two
The American Journal of Medicine
 ARTERIAL PRESSURE REGULATION .~- GUYTON ET AL.

separate ways. FIrsi, cardiac output exerts a di- sait. Therefore, the arterial pressure will be con-
rect effect on arterial pressure because of excess trolled to precisely that single pressure level,
amounts of blooc attempting to flow through the which means that the arterial pressure is then also
peripheral vessel.;. Second, excessive blood flow controlled wrth infinite gain.
through the vessels cause-5 local tissue vasocon- However, one must always qualify the infinite
striction-an effect called “autoregulation”- gain principle for arterial pressure regulation by
which decreases the flow toward normal [8,9]. noting that two other conditions must be satis-
This obviously also increases the total peripheral fied first: (1) the intake of water and salt must be
resistance, which- further increases the arterial defined and (2) the functional capabilities of the
pressure. At first, following an initial increase in kidneys must also be defined.
cardiac output, most of the rise in arterial pres-
sure occurs because of the direct effect of in- SIGNIFICANCE OF THE INFINITE GAIN
creased cardiac output. However, as the auto- PRINCIPLE IN LONG RAN& CONTROL OF
regulation mechanism becomes progressively ac- ARtERlAL PRESSURE
tivated over several days, most of the increase Interaction Between an Infinite Gain System and a
in arterial pressure thereafter is caused by the Finite Gain System. The other arterial pressure
secondary increase in total peripheral resistance. control systems besides the renal-body fluid sys-
When the arterial pressure rises high enough tem all have finite gains (Figure Z), which means
to make the renal output of water and salt equal that they return the arterial pressure only a cer-
the net intake, the extracellular fluid volume, the tain proportion of the way toward the control level
blood volume, the circulatory filling pressure and rather than all the way. Now let us see what hap-
all other elements of the feedback loop become pens if one of the finite gain systems competes
stable. with the infinite gain renal-body fluid system. A
Note again that there is only one state in which hypothetical situation in which the initial control
all factors in the control loop will remain stable. pressure level is 125 mm Hg is illustrated in
This occurs when the rate of change of extracellu- Figure 5. Suddenly, at zero time, the target level
lar fluid volume is equal to zero, that is, when the of the renal-body fluid system (the infinite gain
renal output of water and salt has returned to system) is set to 160 mm Hg. In other words,
precise equilibrium with the net intake of water something has happened in this system, such as
and salt. pathology of the kidneys, which makes it raise
The Infinite Gain Feature of this Control System. the pressure to 160 mm Hg instead of the initial
The infinite gain feature of the renal-body fluid 125 mm Hg. At the same time, we will also assume
pressure control mechanism lies in the fact that that the target pressure level of one of the rapidly
the renal output of water and salt can never re-
main indefinitely different from the net intake
of these two substances. Fortunately, the events
explained cause the renal output of water and
salt always to come back to equilibrium with the
net intake of water and salt. Therefore, this bal-
ancing mechanism between intake and output
always (so long as life continues) operates with
infinite feedback gain because it always reap-
proaches complete equilibrium when nonequilib- -3 ,,,_,_,
___....
_.. mqet level Of fl”iW goin system
.-...--..--..-
rium temporarily occurs.
To extend this concept of infinite gain to arterial 75’
0 2 4 6 6 IO 12 14
pressure control as well as to the control of water DAYS
and salt balance, once the net intake of water Figure 5. Interaction between two arterial pressure con-
and salt has been set, and once the functional trol mechanisms, one of which acts slowly but has in-
capabilities of the kidneys in relation to arterial finite gain and the other of which acts rapidly and has a
finite gain of 2.5. Note that once the infinite gain system
pressure have also been set, there is only one
reaches its level of infinite gain, the arterial pressure be-
single arterial pressure level that will cause equi- comes exactly equal to the target level of the infinite gain
librium between intake and output of water and system.

Volume 52, May 1972 589

ARTERIAL PRESSURE REGULATION - GUYTON ET AL.

acting finite gain systems is suddenly set to 90 state of the renal-body fluid control system and is
mm Hg. How will these two types of systems inter- the state that is always reapproached with infinite
act with each other? Since the finite system acts gain.
almost instantaneously, the pressure falls at first; To determine the different factors that can
but during the ensuing days, the renal-body fluid change the long-term level of arterial pressure, we
system begins to develop its overpowering feed- now need only to determine the factors that can
back gain, and in approximately fourteen days it alter the relationship between arterial pressure on
approaches the infinite gain state (although, the one hand and the balance between intake and’
theoretically, this approach would take infinite output of water and salt on the other hand. Most
ti,me). Therefore, by the fourteenth day, the infinite of these factors are illustrated in Figure 6 and
gain of the renal-body fluid mechanism causes the may be explained as follows:
pressure response to rise to the target level of (1) Note first in the figure that arterial pressure
the infinite gain system. directly increases renal output for hydraulic rea-
To express the message of Figure 5 in another sons, namely, increased glomerular filtration rate
way, whenever an infinite gain control system and decreased tubular reabsorption.
competes with a finite gain system, or even with (2) An increase in arterial pressure activates the
a large number of finite gain systems, the net gain nervous pressure control mechanisms (the baro-
of all the systems interacting together is still de- receptor, chemoreceptor and central nervous sys-
termined by the infinite gain system, because in- tem ischemic mechanisms), which in turn de-
finity divided by any finite value is still infinity. crease sympathetic stimulation of the kidneys
and also decrease the circulating epinephrine and
THE LONG RANGE DETERMINANTS OF
norepinephrine, both of which effects increase
ARTERIAL PRESSURE
the renal ovput of water and salt.
Even though the renal-body fluid arterial pressure (3) A decrease in arterial pressure increases
control ‘mechanism inundates all of the other pres- the output of renin, which has a direct effect on
sure control systems, this system itself can be the kidneys to affect renal output of water and
modified in many different ways to alter its own salt; this also increases the secretion of aldo-
target level of pressure control. Some of these sterone which in turn decreases the output of salt
ways in which this is done are illustrated in Figure and water. In addition a decrease in arterial pres-
6, which is an expanded version of that portion of sure increases aldosterone secretion in other ways
Figure 4 enclosed by dashes. In this figure the not fully understood, and this increased aldo-
rate of change of extracellular fluid volume has sterone secretion also decreases salt and water
been set to equal zero, which is the only stable output.

i j
I

Arterial
prerrure >
, ,
I
________------------;,,;,’ ‘.
.\
/-- _____-ex I’ 1’ ‘\ \
1 I’ Figure 6. The “determinants” of long-
\ I : term arterial pressure regulation. This
\._ Aldoaterone

tt ’ figure is an expansion of the dashed en-

closure of Figure 4.

The American Journal of Medicine

 ARTERIAL PRESSURE REGULATION - GUYTON ET AL.

Other factors not initiated by arterial pressure
changes that can affect the balance include (a)
renal pathology, which usually decreases renal
output of water and salt; (b) effect of vasocon-
strictors, vasodilators, diuretics, and so forth on
renal function; (c) nonrenal loss of water and
salt, such as through the gut, in the sweat, by
dialysis, or in any other way; (d) alteration in
the intake of water and salt.
The solid arrows and the dashed arrows in
Figure 6 illustrate, respectively, positive and nega-
tive effects that can alter the function of any one
of the factors in the figure. To give an example,
renin secretion can be altered positively by low
circulating salt level in the blood, or altered nega-
tively by decreased level of renin substrate in the
plasma. As another example, many different
changes in the central nervous system can alter
any one or all of the nervous factors that affect
renal output of water and salt.
Therefore, there are many different ways in
which the renal-body fluid mechanism for control
of arterial pressure can be altered.
Delineation of the Nondeterminant and the De-
terminant Factors of Arterial Pressure Regulation.
On studying Figure 6, one is at first impressed
with the many ways in which the long-term level
of arterial pressure can be altered. However, if he
studies the figure still more carefully, he will be.
gin to see that these do not include (except in-
directly) many of the factors most commonly con-
sidered to be the determinants of arterial pres-
sure control. Among these are (1) extracellular
fluid volume; (2) blood volume; (3) venous re-
turn; (4) cardiac output; (5) autoregulation; and
(6) total peripheral resistance.
Referring back to Figure 4, we see that all
these elements are outside the dashed enclosure.
Furthermore, the renal-body fluid pressure con-
trol system can automatically increase or decrease
these factors as needed until the arterial pressure
becomes adjusted to that precise level at which
renal output equals net intake. Such adjustable
elements as these in a control system, that is,
elements that are manipulated up or down to
achieve a given goal, are dependent variables.
Therefore, all these elements, although long
associated with arterial pressure regulation, are
not independent determinants of arterial pressure.
Instead, they are merely manipulated pawns in
the mechanism for bringing about the desired level
of arterial pressure.
On the other hand, all the elements in the
dashed enclosure of Figure 4, or in the expanded
version of this enclosure in Figure 6, are in fact
independent determinants of the long-term level
of arterial pressure, and a change in any one
of them will change the level to which the arterial
pressure will stabilize. Conversely, changing the
level of one of the dependent variables, such as
cardiac output, will do nothing more than change
the arterial pressure temporarily, because the total
control system will be set into play until it re-
turns the arterial pressure again to precisely the
level drctated by the determinants depicted in
Figure 6.
Determinant Factors in the Causation of Hyper-
tension. A corollary to the foregoing discussion
of determinants for arterial pressure regulation
is that these are the same determinants that can
cause hypertension. Thus, any factor that alters
the aldosterone block in Figure 6, the angiotensin
block, the renin block, the baroreceptor block, the
renal arterial pressure block (such as stenosis of
the renal arteries), the ADH block, the intake
block (such as excess salt ingestion), the non-
renal output block (such as insufficient dialysis)
or the renal pathology block can be a cause of
hypertension. Indeed, these are the different fac-
tors that are well known to be associated with hy-
pertension.
However, it is important to note some effects
that do not fall among the determinants of hy-
pertension. Probably the most important of these
is the effect of vasoconstrictors or vasodilators
on the nonrenal portion of the circulatory system.
The vasoconstrictor effect of angiotensin on the
nonrenal blood vessels is not included in Figure
6. Neither are the effects of epinephrine, nor-
epinephrine, prostaglandins or other vasoactive
agents on the nonrenal blood vessels included.
And the effect of sodium accumulation in the walls
of nonrenal vessels to cause their constriction is
not included. All these effects have been postulated
to be important in the development of hyperten-
sion, and, indeed, they can alter the total pe-
ripheral resistance. But note once again that total
peripheral resistance is only a dependent variable
in arterial pressure control and is not a determi-
nant. Alteration in total peripheral resistance
caused by any one of these factors can cause a tem-
porary change in arterial pressure, but this im-
mediately throws the fluid intake and output out of
balance, and the compensatory mechanisms will
not stop functioning until the arterial pressure
comes back precisely to where it was.

Volume 52, May 1972 591

ARTERIAL PRESSURE REGULATION - GUYTON ET AL.

ouput to equal net intake nor at a level too high

for intake to equal the output.)

A SIMPLIFIED METHOD FOR ANALYZING LONG

RANGE CONTROL OF ARTERIAL PRESSURE
Without going into all the details of Figure 6 and
all the interactions of the different control mech-
anisms, one can understand most of the principles
of long range arterial pressure control by plotting
renal fluid output and net fluid intake on the same
graph as shown in Figure 3. The renal output curve
of the graph depicts the effect of arterial pressure
d on water and salt output. The intake line on the
0

E graph (the dashed line) shows the fluid intake,

which is unchanged as the pressure changes.
The renal function curve in this figure is a
Arterial Pressure ( mm.Hg)
curve for two normal human kidneys operating in
Figure 7. Relationship between renal function curves for parallel and unaffected by any other factor be-
output of water and salt as measured in isolated kidneys
sides the direct effect of arterial pressure. This
(the dashed curves) and the approximate renal function
curve observed in the normal human being (the very dark curve was calculated by extrapolating curves ob-
solid curve). tained from studies in isolated animal kidneys.
In the intact human being the function curve is
However, vasoconstrictor and vasodilator sub- different and, on the basis of salt and water load-
stances almost always affect the kidney vascula- ing effects in human beings, appears to be ap-
ture at the same time that they affect nonrenal proximately that illustrated by the very dark curve
portions of the circulation. Referring back to Fig- of Figure 7. This curve crosses the normal intake
ure 6, it can be seen that these direct effects on curve at equilibrium point A. However, when the
the kidneys are part of the determinative complex intake of water and salt is vastly above normal,
of the renal-body fluid control mechanism and, the arterial pressure rises to approximately point
therefore, affect the final level of arterial pres- 0, which is the new equilibrium point with an
sure. It is this simultaneous effect on the kidneys arterial pressure of 118 mm Hg. If the function
that has led to the erroneous concept that re- curve of the kidneys of the intact human being
sistance changes in nonrenal vessels are immpor- were equal to that of isolated kidneys, the equi-
tant to arterial pressure control. ’ librium point would have been point H, and the
(Now for a word of apology. We have presented arterial pressure would have risen to 185 mm Hg
the foregoing concept and its importance in ar- instead of to 118 mm Hg. The cause of this dif-
terial pressu’re control in a very definite and al- ference is that in the isolated kidneys only a single
most dogmatic way. This concept first impressed factor, the direct hydraulic effect of arterial pres-
us when it appeared again and again in multiple sure on the kidneys, acts to control renal output
computer analyses [4,10,1 l] of arterial pressure of water and salt. In the intact body all the different
regulation involving as many of the different mechanisms illustrated in Figure 6 are acting.
arterial pressure control mechanisms as we could Therefore, when arterial pressure rises above
feed into the computer. It can easily be argued normal, it initiates both nervous and hormonal
that the computer frequently lies, which is quite effects that slowly alter renal ouput by other
true. However, the simple logic presented in the means in addition to the direct hydrauiic effect.
last few paragraphs is all that is needed to under- Therefore, the “hydraulic” renal function curve
stand the basic validity of this infinite feed- (which depicts the effect of arterial pressure acting
back gain principle as it applies to arterial pres- by the hydraulic mechanism alone) can be Catcu-
sure regulation. By its very nature, the balance lated to shift progressively upward and to the
between body fluid intake and output is an in- left, as illustrated by the “family” of dashed
finite gain system, and the arterial pressure can curves, although requiring a number of hours to
never stabilize at a level too low for the renal do so. Therefore, although an instantaneous rise in

592 The American Journal of Msdlclne

 ARTERIAL PRESSURE REGULATION - GlJYTON ET AL.

arterial pressure “o 120 mm Hg might only double

water and salt onput (the hydraulic effect) this
same increase in pressure, acting over a period
of time, can Increase the output as much as six-
fold or more after ail the mechanisms have be-
come active (the hydraulic plus the nervous and
hormonal effects)
Analysis of the Kidney’s Role in Different Types of
Hypertension. Figure 8 illustrates the simplified
method of analyzing the role of the kidney in
-.-----------_---
several common types of hypertension. In this
2-
figure are renal function curves from four differ- 0
P
ent conditions: (1) two normal kidneys: (2) aldo- Normal Intake
sterone stimulated kidneys; (3) following loss of
Low Intake
two-thirds of the renal mass; and (4) bilateral
Goldblatt kidneys. Likewise, there are three dif- 0 50 IO0 150 200

ferent levels of net intake of water and salt: (1) Arterial Pressure (mm.Hg)
normal intake; (2) high intake; and (3) low intake. Figure 8. A simplified method for analyzing the role of
the kidneys in different types of hypertension.
Under normal conditions, the equilibrium point
is point A, with an arterial pressure of 100 mm
“How can one explain the elevated arterial pres-
Hg. At a normal intake of water and salt, aldo-
sure in the early stages of essential hypertension,
sterone stimulated kidneys will cause the arterial
particularly in view of the fact that the renal out-
pressure to rise mildly (point B); loss of renal
put of water and salt in patients with essential
mass will cause the pressure to rise moderately
hypertension is completely normal?” A partial
(point C); and severe stenosis of both renal
answer to this question can probably be given by
arteries (Goldblatt kidneys) will cause marked rise
referring to Figure 9. This figure shows to the
in arterial pressure (point D).
left the renal output curve for the two normal
Note, however, that when the intake of water
human kidneys. Now let us see what the renal func-
and salt is greatly increased the aldosterone stimu-
tion curve is in essential hypertension. We have
lated kidneys will cause considerably increased hy-
already stated that the output of water and salt
pertension (point E), and the diminished renal
in the person with essential hypertension is
mass kidneys will cause extreme hypertension
normal. Let us assume that he has a mean arterial
(point G). On the other hand, the high intake of
water and salt hardly affects the pressure level in
the Goldblatt situation (point F).
At low intakes of water and salt, both the
aldosterone-induced hypertension and the hyper-
tension caused by loss of renal mass can be re-
verted to normal arterial pressures (point H),
whereas reduction of water and salt intake again
hardly affects the Goldblatt hypertension (point I).
The effects illustrated in Figure 8 for the differ-
ent types of hypertension are all well known, and
they illustrate how the basic principles derived in
this paper can be used in a productive, yet simple
way to understand the regulation of arterial pres- .

sure in different hypertensive states.

I
04
ROLE OF THE KIDNEYS IN 0 50 100 150 200

ESSENTIAL HYPERTENSION Arterial Pressure ( mm.Hg 1

Figure 9. Derivation of the renal function curve for the
One of the most crucial questions always asked two kidneys in a human being with essential hypertension.
about the role of the kidneys in hypertension is Explained in the text.

Volume 52, May 1972 593

ARTERIAL PRESSURE REGULATION - GUYTON ET AL.

pressure of 150 mm Hg. Therefore, we can plot clear that the function curve of the kidneys in the
point B in Figure 9 as one of the points that must person with essential hypertension is not normal.
lie on the function curve of the kidneys for this Therefore, contrary to the statement that is so
human being with essential hypertension. We can often made, function of the kidneys in essential
also plot at least two other points on this function hypertension is not normal. It is only the output
curve from other knowledge of renal function in that is normal, but to achieve this output the
the essential hypertensive patient. First, every arterial pressure must be considerably higher than
surgeon and every anesthesiologist knows that to the normal pressure, and this is not a normal
allow the arterial pressure of a patient with essen- state of renal function.
tial hypertension to fall acutely as much as 40 We can go still further in this analysis. The
mm Hg below his usual pressure level, that is, to fact that the renal function curve is shifted to the
allow the pressure to fall 110 mm Hg in the ex- right in essential hypertension, as depicted in
ample of Figure 9, will cause urinary output to fall Figure 9, does not necessarily mean intrinsic
essentially to zero. Therefore, we can plot point C pathology of the kidneys. Returning once again
in Figure 9 at a pressure level of 110 mm Hg and to Figure 6, one can see ample opportunities for
at a urinary output of zero. It is also known that many extrarenal factors to shift the renal function
increasing the intake of water and salt in a patient curve in the manner illustrated in Figure 9. There-
with essential hypertension will cause the output fore, it is clear that the infinite gain system of the
of the kidneys to rise to a high level with usually renal-body fluid mechanism is operative in essen-
moderate increase in arterial pressure. With this tial hypertension as in other types of hypertension,
information in mind, we can plot point D in Figure although the factor or factors that make the renal
9. On connecting these three points it is very function curve abnormal are still unknown.

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594 The American Journal of Medicine