Some Problems and Solutions for

Modeling Overall Cardiovascular Regulation*

ARTHUR C. GUYTON. THOMAS G. COLEMAN,
R. DAVIS MANNING, JR., AND JOHN E. HALL
Department of PIyxiolugy and Biophysics,
U~tit~ersi{v
of Mississippi Medicul Center, Juckson, Mississippi39,716

ABSTRACT
A brief history of the development of mathematical models of the cardiovascular system
is presented. Until the advent of computers, very little modeling of transient physiological
phenomena was done, but this is now commonplace. The problem of stability in complex
physiological models fortunately is averted by the fact that the physiological controls are
themselves highly stable. The reason for this is that evolution has eliminated unstable
feedback loops because they are lethal. Indeed, enough safety fackvr has been provided in
the design of the body so that even poor mathematical models are often quite stable. An
especially important use of complex cardiovascular models has been to derive new concepts
of cardiovascular
function. One such concept is the princ.ple of infinite gain for
long-term control of arterial pressure, which states that the long-term >:vel of arterial
pressure is controlled by a balance between the fluid intake and the output of fluid by the
kidneys, not by the level of total peripheral resistance as has been a long-standing
misconception based on acute rather than chronic animal experiments.

INTRODUCTION
The goal of this paper is to recall some of the history in the development
of mathematical modeling of cardiovascular regulation and especially to
point out some important concepts that have come from this effort.
The entire discipline of physiology attempts to explain the mechtisms by
which the body functions. Therefore, from the beginning, physiologists have
been inveterate modelers. Unfortunately, though, most of this modeling has
been nonquantitative, most being done in the mind rather than in a formal
way. Not that we object to mental modeling, indeed far from this, but when
the models become complex, the mind, with all of its preconccc:ions, often

*Supported

USPHS Grant-in-aid

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72:141-155

G3sevier Science Publist Ing Co., Inc., 1984

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ARTHURCGUYTONETAL

plays horrendous tricks and leads to very false understanding of even some of
the most basic principles of physiology.
In the 1940s and 195Os, algebraic and graphical analysis of simple
physiological mechanisms began to appear. These used mainly algebraic
equations or multiple intersecting graphical curves to analyze steady-state
function, but the number of equations or graphical curves was usually limited
to a maximum of 8 to 10. On rare occasions, differential equations were
used; a prime example was the development of a system of equations by
Hodgkin and Huxley that described the generation of an action potential [ 111.
for which these two authors received the Nobel prize. The solution of these
equations was a task that would have deterred all but a very few physiologists
from completing the project. Yet, with the advent of analog and digital
computers, such systems and equations are now commonplace, and the
solution times are typically a fraction of a second.
Our own work in mathematical analysis of circulatory function anti
regulation began in the early 1950s with the use of complex graphical
analysis [2]. This proved to be an excellent method for studying steady-state
conditions or the change from one steady state to another. However, as one
would expect, such methodology was almost useless for ana.l_yzingsequential,
rapidly changing events in circulatory function. When analog computers
became available in the 1950s and digital computers in the 1960s. our models
proceeded rapidly through progressive stages of sophistication, as shown in
Figures 1, 2, and 3 [3. 41. Figure 1 illustrates the relationship of the kidney
output of fluid to the overall fluid balance of the body as well as to arterial
pressure and cardiac output. The negative feedback loop of this figure has
bccomc fundamental in essentially all mathematical analyses of long-term
circulatory function. Therefore. let us list the functions of the successive
blocks: (1) effect of increasing arteriJ1 pressure (AP) on urinary output of
fluid $JO); (2) subtraction of output of fluid from intake of fluid to the body
(Intake) to give rate of change of eutracellular fluid volume @K/L/~): (3)
integration of rate of change of fluid volume to give actual extracellular fluid
volume (ECFV); (4) effect of changing extracellular fluid volume cn blood
volume (RV); (5) effect of changing the blood volume on the mean systemic
pressure (MSP) that forces blood from the systemic circulation back toward
the heart; (6) subtraction of right atria1 pressure (RAP) from mean systemic
pressure to determine pressure gradient from the systemic circulation back to
the jieart (MS P-RAP); (7) division of pressure gradient by resistance to
venous return (RVR) to give venous return (VR) to the heart. which is also
equal to c;lirdiac output JO); and (8) multiplication of cardiac output by
total peripheral resistaLtice(TPR) to give arterial pressure (AP), which was the
starting point in block 1. Thus, this simple mathematical loop describes a
negative feedback operation that will eventually stabilize (a) the arterial

CARDIOVASCULAR

MODELING

143

RAP

FIG. 1. A simple model showing

;1s the r& of the kidney in long-term
and Coleman

[ 3) with permission

the basic components

of circulatory
function ~1s\vclI
control of the circulation.
(Reprinted
from (iuyton

from W. B. Saunders

Co.)

Ado

FIG. 2.
involving
(Rcprintcd

An expansion
local vascular
from <;uyton

mutt

of the moel in Figure 1, with several additional

feedback loops
function
of the hcrlrt.
control, nenous
control, and pumping
and C&man
[3j with permission from W. R. Saunders Co.)

144

ARTHURCGUYTQNETAL.

CARDIOVASCULAR

MODELING

145

pressure, (b) the cardiac output, (c) the extracellularskid vahune, and (d) the
blood volume.
The model of Figure 2 [3J added still other important ,factors in the
control of the circulatian, including: (a) two nervaus fkedba& mechanisms,
the baroreceptor and chemoreceptor mechtisms for feedbaclc
control of the
,
arterial pressure; (b) the role of local control of blood flow by the tissues in
affecting the resistance to blood flow through the s$stemic circulation; 2nd
(c) the role of cardiac function in circulatory control. With this model, it was
now possible to simulate a considerable share of the operational charactcristics of the circulatory system. But the mare complex mechanisms still
required much more information, which led to the model in Figure 3 [4]. This
made1 is hardly different from that of Figure 2 except that. multiple inp it
variables have been added so that almost any change in any major condition
of circulatory function can be studied. The model of Figure 3 has about 30
separate negative feedback loops, and models developed after this one have
many mare laaps. Let us pause for a few moments and discuss some of the
problems in the use of such models.
THE PROBLEM OF ESTABLISHING
FUNCTIONS AND PARAMETERS

THE INDIVIDUAL

Mast physiologists are deterred at the very start from building even simple
models, to say nothing of large ones, because they say that sufficient detailed
information is not available in the literature. However, a special characteristic of physiological simulation makes it possible t<) succeed even though ori
first thought one might not believe it possible. Namely, through evolution the
animal body has developed an operating system that is remarkably stable
against wide variations in almost any single input parameter. The principle of
biological variability is well known. No two persons have exactly the same
quantitative functions far operation of the separate mechanisms, and no two
will have nearly the same values far the different input variables. vet, each
human being is a successful operating system. To give a simple example, the
normal go-year-old person has a heart capable of pumping ktnly about
one-half as much blood as a 20-year-old person. Yet, even the W-year-old
normally is not in heart failure and can function quite adequately as long as
he does not exercise beyond the limit of tis hearts pumping capacity.
Therefore, even if a model builder should fail to choose exact parameters for
the average human being, almost any chosen parameter within a reasonable
from + 300 per cent to -75 per cent of the mean
range -sometimes
value-will
be that of some individual who is operating reasonably normally.
The reason for this amazing functional capability is the vast number of
negative feedback control loops in the functional systems of the body. such
as the one illustrated in Figure 1. Evolution has developed a setof powerful.

146

ARTHURC.GUYTONETAL.

no-nonsense control loops, usually highly damped, that will provide appropriate compensation for large variability of input variables.
THE PROBLEM OF STABILITY
The next question that we must ask is why a system such as that in Figure
3, with hundreds of functional interactions, does not decay immediately into
uncontrollable instability. Here again, the answer is that evolution has
eliminated essentially all positive feedback loops from the functioning body.
The only instances in which po&tive feedback loops are present are to
perform special tasks (such as trans&ssion of nerve impulses) that function
in a negative-feedback way within some other mechanistic loop. Therefore,
despite the imprecision of functional data for biological systems, nature has
fortunately provided the animal body with such an inherently stable operating system that even very inaccurate attempts at simulation nevertheless can
often give rise to very helpful concepts.
THE PROBLEM OF RAPID SOLUTION OF THE EQUATIONS
If one needs a model that can simulate rapid transients as well as very
long-term transients, the mathematical problem of achieving continuous
solutions without using inordinate computer time often becomes very difficult, because the model usually will have many short-time-constant loops
interdigitated with very long-time-constant loops, leading to extremely stiff
equations. For instance, the model of Figure 3 has time constants that range
from as short as a few thousandths of a minute up to more than a month,
more than a ten-million-fold ratio. Obviously, the strategy for continuously
solving equations of this type can be quite complex. One way to achieve a
solution is to segment the model so that the short-time-constant loops can be
brought to steady states, and then long iteration intervals are used to solve
the long-term loops. Unfortunately, though, this type of solution requires
knowledgeable development of a specific strategy for each specific model.
Recently, we have been attempting to develop a method that is semiautomatic for shifticg the time frame of the solutions. The basis of this method is
to keep account, in an appropriate array, of the degree of oscillation of the
differential input to each separate integrator in the model. Then this inforsnation is used to adjust automatreally the time constant of each integrator as
necdcd for different time frames of solution. Under most conditions, this
procedure can smooth out the variables in the short-term loops, preventing
them from oscillating, and allowing their use in the continuous solution of
the Bong-term variables when input variables are changed. However, an
appropriate method is also needed to allow shift from one time frame of
solution to another. In experimental tests of such procedures, we have been
able to obtain reasonable solutions for reasonably simple models when the

CARDIOVA!KULAR

MODELING

147

time frame has been varied as much as 10,000-fold. However, with more
complex models, calculations increase approximately as the square of the
number of feedback loops, and progress beyond our present experimental
approach must be hoped for.
SOME REPRESENTATIVE CARDIOVASCULAR
THAT HAVE COME FROM MODELING

CONCEPTS

Simple models, or even intermediate models such as that in Figure 2, tie

valuable mainly to prove that the modeler can put his preconceived ideas into
mathematical notation. But when one proceeds to more complex models,
such as the one in Figure 3, the world suddenly changes, because again and
again solutions provided by the model fail to fit as expected. In most
instances, it is the preconceived concepts that are wrong, in which case the
model serves beautifully to correct ones understanding, thus leading to a
better concept. Let us review briefly several such concepts that have come
from mathematical modeling of the cardiovascular system.

THE INFINITE-GAIN
PRINCIPLE
PRESSURE CONTROL

FOR LONG-TERM

ARTERIAL

One of our earlier models of renal function gave the solution in Figure 4
for the effect of progressively increasing a.rte<ti pressure. on renal blood flow,
glomerular filtration rate, and rate of urine output [5] Note especially the
very steep increase in urinary output when the arterial pressure rises above
approximately 60 mm Hg. This led to the concept analyzed graphically in
Figure 5, showing the relationship of the urinary-output curve to the intake
level of water and salt [6,7]. In any steady state, the intake and output must
be exactly equal. If they temporarily become unequal, the negative feedback
control loops will make appropriate adjustments until equality is again
established at the point called the equilibrium point in Figure 5. And in
reestablishing this balance between intake and output of fluid, the arterial
pressure also always returns to its original level. In separate studies, using the
circulatory models of Figures 2 and 3, the sequential changes in circulatory
and kidney function were then simulafed to determine the universal applictibility of the simple graphical analysis illustrated in Figure 5. From this came
the infinite-gain principle for long-term arterial pressure control. This principle is the following: so long as both the level of fluid intake and the curve
representing the relationship between arterial pressure and urine output
remain constant; the long-term level of arterial pressure will be controlled
with infinite feedback gain at the pressure level of the equilibrium point. An
experimental test of this principle is illustrated in Figure 6, which show.+ the
effect of a massive transfusion of blood on circulatory function in. dogs [g].

ARTHUR Cr.GUY-I03 ET AL.

148

Note the initia! large increases in arterial pnzssure, cardiac output, and
urinary output. However, the great increase in urinary output caused progressive loss of fluid from the body until the arterial pressure returned to exactly
the same level from which it started.
Figure 7 illustrates another test of this principle (4). Referring again to
Figure 5, one can see that the long-term level of arterial pressure could be
increased to a higher value if one shouilld increase the level aE sjlt md water

L+

Oi

I50

ARTERIAL

PRESSURE

hm.Hg)

%
d

z
z
3

1~.
amtrcli.

5.

~iraphi~at

txpl;untd

ARTERIAL

rcprwmration

in the test.

PRESSURE

[mm Hg)

of the infinite-gain

principle

fur arteM

prc~surc

CARDIOVASCULAR

MODELING

149

4
3
2
I
L
2205
200
175
150
125
100
75
i
pb,,,,,,_
5O fNFUSlON PERIOD
0-O

60

120

TIME ( minutes)
FIG. 6. Exptximrntal
test of the infinite-gain
principk,
showiq
rctum of the arterial
prc:,sure to the original control kvel after ;I massive transfusion. (Modified from lJ&bs anti
Ciuyton

[8] with penmission

from the .~nreric*m ,~ofrm~~ r$ iuhhgr~.)

intake. And another way to increase the pressure would be to shift the
renal-function curve to the ight in the diagram. In effect, these two changes
would increase the kset point for arterial pressure control to a level much
higher than the 100 mm Hg indicated by the equilibrium point in Figure 5.
Then :he pressure should be controlled, again with infinite gain, around this
new set point. Figure 7 3~ trates a simulation of such charrges, using the
-model of Figure 3. That is, the renal1 output curve of Figure 5 cKasshifted to
the right by removing 70 per cent of the kidney mass, and the water and salt
intake to the animal was increased severalfold (4). Looking at the curve
second from the bottom, one sees that the simulated arterial pressure rises
over a few days from 100 mm Hg to a new steady-state value of 140 mm )-Ig
and holds exactly at that level thereafter, because the set .>oint of the
infin+gain
control mechanism has been raised to this new level But observe
also in this figure the many other changes that take place in the circulation in
order to achieve the final result,. There are important successive changes in
extracellular fluid volume, blood volume, degree of aMonomic nervous
stimulation. cardiac output, total peripheral resistance, aQd urinary output.
Next, to show that the simulation predicts the changes actually observed in
animal experiments, Figure 8 illustrates average curves, obtained from studies
in dogs in which experimental tests of the simulation iHI h;igurc 8 were

ARTHURCGUYTONETAL.

150

6
s

DAYS
FIG. 7. Circulation: overall regulation. Simulation of the kculatory changes caused by
suddenI> increasing the set point of the kidney-body-fluid
pressure control system to a
higher Ievcl. (Reproduced from Guyton, Coleman. and Grringer [4] uvith ptxmission from
.d/lrltd Rtww qf Pl~~w~icq~. Vol. 34 ? 1972 by Annual Reviews Inc.)

performed [7]. Note the almost exact correspondence between the curves in
Figures 7 and 8.

The a!!)ove studies suggest that there are only two primary determinants of
the long-term arterial pressure: (1) the level of salt and water intake and (2)
the pressure level of the renal-function curve for urine output. Yet, a vast
majority of physiologists and clinicians alike have insisted for years that
arterial pressure is controlled either entirely or almost entirely by changes in
the resistance to blood flow through the systemic vascular system, ctiIed the

CARDIOVASCULAR

MODELING

151

total peripheral resistance. The reason for this widespread belief is that the
short-term level of arterial pressure is indeed controlled to a major extent by
changes in total peripheral resistance. However, in the short-term situation,
the kidney does not have time to readjust tihe blood volume and therefore
cannot establish its overriding effect in controlling arterial pressure. Yet,
when one puts both the short-term arterial pressure regulating mechanisms
and the long-term renal mechanism together in the same mathematical
model, it then is easy to show that changes in total peripheral resistance
should have no effect on the long-term level of the artetial pressure. This is
illustrated by the simulation in Figure 9 [9]. Note that the time scale of this
simulation is in days. The solid curves in this figure represent the sequential
changes in arterial pressure, blood volume, and extracellular fluid volume
following a threefold increase in total peripheral resistance at time zero. The
instantaneous effect is an increase in arterial pressure, as shown by the
uppermost curve, but this elevation of the arterial pressure causes rapid loss
of fluid through the kidneys, with depletion of both the extracellular fluid
volume and the blood volume until the arterial pressure returns exactly to the
original starting level. This is the effect that is also predicted by the principle

DAYS

Frc. 8. Average data from dog expzrimcqtts verifying the simulated results illustrated
in Figure 7. (Modified from Guyton [7\ with permission frorl W. B. Saunders CO.)

ARTHURCGUYTONETAL.

152

-w____

-_a_

--_I--

IS!
-2

of

infiniic

gain for arterial pressure control bv_ the kidney-body-fluid-volume

S\StSltl

Thercforc, it appears that changes in total peripheral resi *tance arc not the
mt;m~ bv which the long-term arterial pressure Icv& IS controlled. To test this
still further, Figure 10 illustrates the effect in multiple clinical conditions of
abnormal total peripheral resistances on arterial pressure and cardiac output
171.Note that the arterial pressure is normal in all of these conditions. On the
other hand. the cardiac output is reciprocally proportional to the total
peripheral resistance. This is mathematically exactly what one would expect,
because the arterial pressure is regulated by an independent mechanism, and
cardiac output is equal to arterial pressure divided by total peripheral
rG?;t ancc.
S-l-t: DY OF PHYSIOLOGICAL MECHANISMS WHEN DIRECT
EXPERIMENTS CANKOT BE PERFORMED
In physiological research we are now reaching the point where most
mechanisms that can bt; studied easily :lave been studied. Yet, many still

CARDIOVASCULAR

MOT,ELING

ARTERIAL

153

PRESSURE

50

oi
40

60

80

100

120

140

160

TOTAL PERIPHERAL RESISTAWCE (pet cent of normal)

FIG. 10. Data from the clinical literature showing th,at changes in total peripheral
resistance do not affect the long-term arterial pressure level. Instead, the cardiac output
changes reciprocally with the changes in total peripheral resistance. (Rcprintcd from
Guyton [7] with permission from W. B. Saunders Co. Note: the cardiac-output value for the
loss of all four limbs is a calculated value.)

unstudied but very important mechanisms are beyond atiack by presently

available direct experimental methods. Therefore, probably the most important role that can be played by the use of complex mathematical models is
to analyze and to understand these mechanisms, because indirect information
from the interactions of these mechanisms with other, already weil-studied
mechanisms can be used to work out with reasonable precision their functional attributes. As an example, Figure 11 illustrates the computer simulated
effects on arterial pressure and renin secretion that would be caused by
constriction of either the afferent arterioles or efferent arterioles of the
kidneys or both. There is no method available for selectively constricting
these vessels in an experimental animal. Yet the effects that such constriction
can have on circulatory function can be computed.
There is good evidence that the most common type of hypertension, called
essential hypertension, may result at least partly from constriction of the
efferent arterioles, probably along with constriction of the afferent arterioles
as well. Therefore, note in the figure the predicted results when afferent and
efferent arterioles are constricted together. The predictions are (1) that
hypertension will occur, and (2) that the rate of renin secretion will fall to
very low values. These are the exact events that are known to occur in the
early stages of essential hypertension before pathological changes develop in
the circulation. Other predictions from this same simulation, but not shown

ARTHUR C. GUYTON ET AL.

154
220 200 I
180 160 140 120 100 b
3.0
2.0
1.0
0
1

AFFEREWT tnd/or Eff EREHl RESISMHCE

(X normal)

FIG. 11. Simulation of the effect of increased renal affercnt or efferent arteriolar
resistance. or both, on arterial pressure and rate of renin secretion by the kidneys.
(Reprinted from A. C. Guyton. Sintulutiort Exercises. Dept. oi Physiology and Biophysics,
Univ. of Miss. School of Med.)

in

the figure, also match up with essential hypertension. Therefore, even

though it is generally stated that the cause of essential hypertension is
unknown, the mathematical model at least suggests a plausible cause.
Thus, the value of mathematical models is not nzrely to describe what we
already know, but also to give insight into mechanisms and concepts that are
not accessible to direct experimental attack.
REFERENCES
1
2
3

A. L. Ho&kin and A. F. Huxley, Quantitative description of mcmbranc current and its

applicatic rn to conduction and excitation in nerve. J. Ph.~wol. (Zmui. ) 117:S()o (1952).
A. C. Guyton. Determination of cardiac output by equating venous return curves with
cardiac respond curves, Phvsiol. Rev. 35:123 (1955).
A. C C;uvton and T. G. Coleman, Long-term regulation of the circulation; intcrrclationship.4 witIt hod) fluid volumes. in Pl~~rwtul BUSCY o/ Circuhrto~~~ Trtrmport, Rqplhw
umi E.YCIwg~c
(E. B. Reeve and A. C. Ciuyton, Ed,.). W. B. Saunders, Philadelphia,
1967. p. i 79.
A. C. (iuvton. T. G. Colernan, an.1 II. J. Grctnger. Circulation: CSvt~allregulation, .~rm.
Rw. PJqwol. 34:13 (1972).
A. C. Guyton, J. B. Langston. and G. Navor. Theory for renal autoregulation by
feedback at the juxtagl~omerular apparatus, <in*. Res. 14:1-187 (1964).

CARDIOVASCULAR

MODELING

155

A. C. Guyton, T. G. Coleman, A. W. Cow-Icy,Jr., R. D. Manning, Jr., R. A. Norman,

Jr., and J. D. Ferguson, A systems analysis approach to understanding long-range,

arterial blood pressure control and hypertension, Circ. Res. 35:159 (1974).
A. C. Guyton, Circu!utoy Ph_vsio!ogvIII: Arteriui Pressure und Hjpertension, W. B,
Saunders, Philadelphia, 1980.
W. A. Dobbs, Jr., J. W. Prat?ler, and A. C. Guyton, Relative importance of nervous
control of cardiac output and arterial pressure, Amer. J. Curdiol. 24507 (1971).
A. C. Guyton and T. G. Coleman, Quantitative analysis of the pathophysiology of
hypertension, Circ. Res. 24(Suppi. 1): I-l (1969).