A Steady-State Control Analysis of the
Renin-Angiotensin-Aldosterone System
By Edward H. Blaine, James 0 . Davis, and Patrick D. Harris
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ABSTRACT
This communication develops a steady-state block diagram about the
configuration of the renin-angiotensin-aldosterone system in relation to the
mineralocorticoid-dependent reabsorption of sodium. Two principal mechanisms appear to be involved in the control of renin secretion. The baroreceptor
hypothesis suggests that decreased stretch of the afferent glomerular arteriole
produces increased renin secretion. The macula densa theory, on the other
hand, suggests that renin secretion responds to alterations either in sodium load
or in sodium concentration at the macula densa. These two receptors are
presented as parallel feedback pathways which are independently capable of
altering renin secretion. This concept of independent receptor function is
supported by literature in which one of the receptor pathways was eliminated.
The system configuration for the renin-angiotensin-aldosterone system suggests
the hypothesis that the vascular receptor controls renin secretion in the
autoregulatory range of blood pressure and that macula densa control
dominates at pressures below the autoregulatory range. The control system
diagram also calls attention to certain unique features of the renin-angiotensinaldosterone system; it indicates that (1) a chronic low-sodium diet involves
changes in both input variables (extracellular fluid volume) and parameters
(hepatic blood flow) to maximize sodium reabsorption, (2) thoracic inferior
vena cava constriction opens the feedback loop so that the renal receptors do
not perceive increases in extracellular fluid volume, (3) congestive heart
failure reduces the overall gain of the system, and (4) a small nonhypotensive
hemorrhage primarily increases renin secretion through renal sympathetic nerve
stimulation.
KEY WORDS
mineralocorticoid-dependent sodium reabsorption
renal baroreceptor hypothesis
congestive heart failure
renal autoregulation
low-sodium diet
hemorrhage
macula densa receptor
constriction of thoracic vena cava
• In general, physiological mechanisms may
be organized into control systems with identification of feedback loops, controlled variables, and control functions. This form of
From the Department of Physiology, University of
Missouri School of Medicine, Columbia, Missouri
65201.
This work was supported by U. S. Public Health
Service Grants HL 05810, HL 10612, HL 20422, and
HL 12614 from the National Heart and Lung Institute.
Please send reprint requests to Dr. James O. Davis,
Department of Physiology, University of Missouri
School of Medicine, Columbia, Mo. 65201. Dr.
Blaine's present address is Howard Florey Laboratories of Experimental Physiology, University of
Melbourne, Parkville, Victoria 3052 Australia.
Received September 30, 1971. Accepted for
publication April 10, 1972.
Circulation Research, Vol. XXX, June 1972
organization emphasizes the properties of the
system which are related to the configuration
of the system or the interconnections within it
rather than to the characteristics of individual
components. In addition, this organizational
plan facilitates a predictive form of thinking
in which anticipated responses can be compared to experimental results. Most of the
literature on the renin-angiotensin-aldosterone
(R-A-A) system is concerned with the characteristics of particular segments, but few
authors have addressed themselves to an
integrated view of the entire system. Among
them, Guyton and co-workers have provided a
significant mathematical model of nephron
dynamics (1) and have analyzed the openloop characteristics of the renin-angiotensin
713
714
BLAINE, DAVIS, HARRIS
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system in the dog (2). The present communication analyzes available data to develop a
steady-state block diagram as a hypothesis
about the configurational properties of the
R-A-A system.
The present model is concerned primarily
with the mineralocorticoid-dependent reabsorption of sodium; the mechanisms which
control antidiuretic hormone or thirst have not
been included. The R-A-A system can be
divided into four segments: (1) relation of
renin secretion to the plasma concentration of
aldosterone, (2) relation of plasma aldosterone concentration to renal afferent arteriolar
pressure, (3) effect of sodium delivery to the
macula densa on renin secretion as a feedback
pathway, and (4) effect of afferent arteriolar
stretch on renin secretion as a feedback
pathway.
This format for subdivision of the system
emphasizes the two principal mechanisms
which have been hypothesized for control of
renin secretion. In the baroreceptor or stretch
hypothesis, the receptor is located in the
Plasma concentration of renin (GU/liter)
afferent glomerular arteriole and responds to
decreased stretch of the vascular wall by
producing increased renin secretion (3-6). The
macula densa theory, on the other hand,
maintains that renin secretion responds to
alterations either in sodium load (7-9) or in
sodium concentration at the macula densa
(10-12). The present model assumes that two
distinct receptors exist and postulates that two
pathways function as parallel additive limbs in
a negative-feedback control system. The alternative hypothesis that either receptor modifies
the sensitivity (or gain) of the other is
discarded in the development of the system
configuration.
This system description is represented by
numbered blocks which show components
where an input variable functionally determines an output variable. These steady-state
relationships are indicated by graphs (Figs.
1-6) which are based on a synthesis of existing
information from published data. In some
instances, hypothetical relationships are presented to conform with the other components
of the system. In most blocks, a normal
operating point is indicated. Variables in the
system are illustrated as arrows to and from
the sides of the blocks with the output, or
dependent variable, on the ordinate and the
input, or independent variable, on the abscissa
of the graphs within the blocks. In many of
the blocks, arrows enter from the top or the
bottom of the blocks to represent factors
which alter the basic relationship between the
input and output variables. By convention,
these factors are called "parameters" in the
system.
RELATION OF RENIN SECRETION
T O THE PLASMA CONCENTRATION
OF ALDOSTERONE (FIG. 1 ) *
Block l.—A certain portion of the total
amount of renin secreted by the kidneys is
metabolized by the liver (14,19-21). Thus, the
plasma level of renin reflects a dynamic
balance between its secretion and destruction,
which is expressed by the equation:
_
renin secretion rate (GU/day)
metabolic clearance rate (liter/day)
Several authors (14, 19-21) have found that
the percent of renin extracted by the liver
remains relatively constant over wide variations in plasma renin concentration. This
means that changes in renin secretion result in
linearly related changes in plasma renin
concentration. Schneider et al. (22) showed
that the amount of renin extracted by the liver
is also a function of acute changes in hepatic
plasma flow. Therefore, in accordance with
the Fick principle, hepatic plasma flow is a
x
The literature citations for Figures 1-5 indicate the
sources for the normal operating points and for the
shape of the curves. The normal operating points
represent generally accepted values for man. We
recognize that different experimental techniques in
different laboratories have provided a wide range of
normal values for these variables; however, for
simplicity in the figures, a single representative value
from the literature is presented. In some instances,
these representative values have been calculated or
estimated from published data. GU is the abbreviation
for Goldblatt unit.
Circulation Research, Vol. XXX, Jane 1972
715
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
I 3 )
Hepatic Blood Flow
Plasma
Pulmonary
Substrate
Concentration
Conversion
Rate
Angiotensinases
( 5 )
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(Al)
(AD|
To Block 6
Hepatic Blood Flow
FIGURE 1
Effect of renin secretion on the plasma concentration of aldosterone. Normal human operating points are the values shown on the axes in each block. Renin secretion rate (dR/dt)
(13, 14), plasma renin concentration (R) (13), rate of angiotensin 11 production (dAII/dt)
(15), plasma angiotensin 11 concentration (All) (15), aldosterone secretion rate (dAl/dt) (16),
and plasma aldosterone concentration (Al) (17, 18).
parameter which can alter the slope of this
relationship.
Block 2.—A relationship between the plasma concentration of renin and the rate of
angiotensin II formation in the blood of
anesthetized dogs was qualitatively demonstrated by Regoli and Vane (23). The
quantitative relationship is based on data by
Pickens et al. (24) who used a standard
bioassay technique to measure the amount of
angiotensin II which was generated by the
addition of standard amounts of partially
purified human renin to an incubation mixture. This measurement depended on the
presence of excess renin substrate in the
incubation mixture to give a zero-order kinetic
reaction (13). Although this degree of excess
substrate does not exist in the in vivo
Circulation Research, Vol. XXX, June 1972
condition (25), it seems likely that renin
substrate is continually replenished by the
liver as substrate is converted to angiotensin I.
Thus, although renin substrate concentrations
in vivo indicate first-order kinetics in some
conditions such as liver disease, the reaction
rate is usually linearly dependent on enzyme
concentration. Since these extreme alterations
in renin substrate concentration alter the
relationship between plasma renin concentration and angiotensin II production rate, renin
substrate concentration is a parameter. Angiotensin I is converted to angiotensin II on
passage through the pulmonary circulation
(26). Since any alteration in pulmonary
conversion rate also alters the slope of this
curve, this conversion by the lungs is also a
parameter.
716
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Block 3.—The relationship between the rate
of angiotensin II production and the plasma
concentration of angiotensin II has been
studied by Doyle et al. (27), using a
radioactive analogue of angiotensin II. These
investigators observed a linear relationship
between the rate of phenylthiocarbamyl angiotensin II-35S infusion and its plasma level in
the steady state. Thus, any change in production rate of natural angiotensin II probably
produces a linear change in vivo in the plasma
concentration of angiotensin II. Plasma and
tissue angiotensinases are a parameter for this
function, but as pointed out by Biron and
Huggins (28) they are probably of minor
significance due to the slow action of these
enzymes as compared to the rapid extraction
of angiotensin II by the peripheral vascular
beds.
Block 4.—Many investigators (29) have
provided evidence that angiotensin II stimulates aldosterone secretion. The work of BlairWest et al. (30) in sheep indicated that
angiotensin II infusion into the arterial supply
of an isolated adrenal gland affected the rate
of aldosterone production according to a
typical sigmoid dose-response curve. In the
majority of mammals, including man, angiotensin II is the primary regulator of aldosterone production, but the plasma levels of
sodium and potassium also influence the
secretion of aldosterone (30, 31) as does the
level of adrenocorticotropic hormone (ACTH)
(32).
Block 5.-Ayers et al. (33), Tait et al. (34),
and Davis et al. (35) have indicated that the
liver is the principal site of aldosterone
metabolism. In normal man (36) and in both
normal dogs and dogs with experimental heart
failure (35), the hepatic extraction of aldosterone approaches 100% and is relatively constant at various plasma levels of aldosterone.
These data indicate a linear relationship
between the rate of aldosterone secretion and
the plasma concentration of aldosterone.
However, since aldosterone extraction is almost complete in one passage through the
liver, its metabolism is flow limited (34, 35).
Consequently, hepatic blood flow is a parame-
BLAINE, DAVIS, HARRIS
ter which can alter the slope of the relationship between aldosterone secretion and plasma aldosterone concentration. The role of the
kidneys in the metabolism of aldosterone is
minor and has been omitted from the
diagram.
RELATION OF PLASMA ALDOSTERONE
CONCENTRATION TO RENAL AFFERENT ARTERIOLAR
PRESSURE (FIG. 2)
Block 6.—Aldosterone promotes sodium
reabsorption in distal nephrons and in extrarenal sites such as salivary glands, sweat
glands, and intestinal epithelium. Since the
evidence is conflicting in regard to an effect of
aldosterone on proximal renal tubules, only
the distal nephron will be considered in this
segment of the control diagram. Investigators
have demonstrated the sodium-retaining
effects of aldosterone or the less potent
mineralocorticoid, desoxycorticosterone acetate (DOCA), in dogs (38), sheep (39), and
humans (40). The data showed that, with
increased levels of aldosterone or DOCA,
sodium excretion decreased. Since sodium
reabsorption is reciprocally related to sodium
excretion, the data on the sodium retention
observed by these investigators provide the
function which represents the effect of plasma
aldosterone on sodium reabsorption.
Block 7.—This component is presented as a
linear relationship between extracellular fluid
volume and sodium reabsorption by the distal
nephron. This linearity implies (1) that
increased sodium reabsorption is associated
with increased water reabsorption and (2)
that increased sodium reabsorption is accompanied by increased antidiuretic hormone
(ADH) secretion, which helps to provide an
isotonic extracellular fluid. Recent evidence
(41) also suggests that angiotensin II directly
stimulates ADH secretion. This direct action
of angiotensin II on ADH secretion is possibly
a second mechanism for ensuring isotonic
reabsorption of sodium and water during
renal control of extracellular fluid volume.
Block 8.—Any change in extracellular fluid
volume is associated with a similar directional
change in vascular volume; however, the
nonlinear compliance of the venous vascular
Circulation Research, Vol. XXX, June 1972
717
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
I 7 }
|
ECF
UJ
85
ng/L
Plasma Aldosterone Cone.
4
Eq/day
Liters
«f
/dl
Blood VolumG
dis ,
/
4-
S
dNa
raccilular Fluid Vol.
o
E
-5
o
( 8 )
Liters
I 6)
o
14
Distal iodiutn Reabsorplion
Liters
Extracellular Fluid Vol.
Starling Forces
I 10 I
To Block 21
p
aa
Sj £
£ E
_ E
1 95"
P
i
100
a,t
mm Hg
aa
BV
§
p
erial Pressure
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To Block 11
( 9 )
mm Hg
5
Arterial Pressure
Liters
Blood Volume
1
i
Afferent Arteriolar Diameter
Effereni
'eriphera Vascular Tone
Arteriolar Diameter
Renal Nerves
Catecholamines
FIGURE 2
Effect of plasma aldosterone concentration on renal afferent arteriolar pressure. 'Normal human
operating points are the values shown on the axes. Rate of sodium reabsorption by the
distal nephron (dNa(Us/dt) (37), extracellular fluid volume (ECF) (37), vascular volume (BV)
(38), mean arterial blood pressure (Pal.t) (37), and mean afferent arteriolar pressure (Paa) (37).
tree and the presence of the cellular component of blood produces a nonlinear relationship. A plateau exists at the upper end of the
curve since the maximum capacity of the
vascular system is approached, and fluid will
accumulate in the extracellular space with
very little additional increase in the vascular
space. Therefore, in this range of extracellular
fluid volume, edema and ascites occur readily
and are associated with capillary pressures in
excess of 30 mm Hg (37). Vascular volume is
dependent on Starling forces such as oncotic
pressure, capillary pressure, and tissue pressure so these are illustrated as parameters
which, if altered, would produce a new
relationship. For example, a decrease in
plasma oncotic pressure would shift the
function downward and to the right since
Circulation Reiearch, Vol. XXX, June 1972
there would be a net movement of fluid into
the interstitial space.
Block 9.—The pressure within the arterial
system is determined by the volume of fluid
(cardiac output) that is available to fill the
arterial tree and by the size of the arterial
space (that is, by changes in peripheral vascular diameters). Several factors including the
sympathetic nerves, circulating catecholamines, intrinsic myogenic arteriolar tone, and
perhaps angiotensin II contribute to the
parameter "peripheral vascular tone." Data
presented by Coleman et al. (42) suggest that
changes in peripheral resistance are important
in maintaining an elevated blood pressure
after expansion of the extracellular fluid space,
since cardiac output rises initially and then
returns to control levels. The relationship
718
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between the degree of arterial filling and
arterial pressure has not been determined
experimentally since the arterial space has not
been measured directly.
Block 10.—Although pressure in the renal
afferent arteriole is slightly less than systemic
arterial pressure, it is assumed that for a given
state of the afferent arterioles, the distending
pressure within these vessels is a linear
function of the systemic arterial pressure. The
parameters renal afferent and efferent arteriolar diameter can affect this relationship by
altering the ratio of the pressure drops across
the afferent and efferent arterioles. Also,
changes in renal venous pressure or renal
venous compliance will produce changes in
the arteriolar diameters. All of these resistance
changes can be influenced by the renal nerves
and circulating catecholamines.
EFFECT OF AFFERENT ARTERIOLAR PRESSURE
ON THE MACULA DENSA—
ONE FEEDBACK PATHWAY (FIG. 3)
Block 11.—By use of micropuncture techniques in rats, Gertz et al. (45) demonstrated
that hydrostatic pressure within the glomerular capillaries is relatively constant above a
mean systemic arterial pressure of approximately 90 mm Hg. This is related to the
phenomenon of autoregulation of renal blood
flow and, for a given diameter of the efferent
arterioles, is determined primarily by resistance changes in the afferent arterioles (37).
Below a mean arterial pressure of 90 mm Hg,
glomerular capillary pressure is a linear
function of the systemic pressure. Above this
level, the pressure drop across the afferent
arteriole becomes a linear function of systemic
arterial pressure, i.e., as arterial pressure
increases, afferent resistance increases proportionally. This provides a glomerular capillary
pressure which is relatively constant and
independent of changes in systemic arterial
pressure above 90 mm Hg.
Block 12.—To obtain the effective filtration
pressure, it is necessary to subtract from the
glomerular capillary pressure the Starling
forces which oppose filtration across the
glomerular membrane. These forces are the
oncotic pressure of the plasma and the
pressure within the glomerular capsule.
BLAINE, DAVIS, HARRIS
Block 13.—Glomerular filtration rate is
simply an expression of the rate of ultrafiltration by the glomerular membrane and is solely
dependent on the effective filtration pressure
for a given level of glomerular permeability.
Hence, the curve relating glomerular filtration
rate to effective filtration pressure is essentially
a straight line. If one incorporates the concept
that the rate of glomerular filtration influences
hydrostatic pressure within the proximal
tubule, the slope of the line changes.
Block 14.—This graph shows that the
filtered load of sodium is directly proportional
to the glomerular filtration rate for any given
plasma concentration of sodium.
Block 25.—Approximately 85% of the filtered load of sodium is reabsorbed in the
proximal renal tubules. Several investigators
(46, 47) have indicated a glomerulotubular
balance for the proximal tubules by suggesting
that the percent reabsorption of sodium
remains constant over wide ranges of filtered
sodium load. If this is true, the relationship
between proximal reabsorption and the filtered load of sodium is linear. However, other
investigators (48, 49) have provided data
which indicate that the glomerulotubular
balance is not perfect. This means that
proximal reabsorption of sodium does not
increase to the same degree as an increase in
the filtered load. In this event, the relationship
between proximal sodium reabsorption and
filtered load would be curvilinear.
Block 16.—This component indicates a
mathematical relationship in which sodium
reabsorption in the proximal tubule is subtracted from the filtered load of sodium to
yield the sodium load which enters the loop of
Henle.
Block 17— Morgan and Berliner (43) used
a continuous microperfusion technique to
study sodium reabsorption in the short loops
of Henle in the rat. When perfusion rate was
increased from 10 nliters/min to 40 nliters/
min, the amount of reabsorbed sodium
as a fraction of delivered load decreased from
80% to 50%. This means that the graph for loop
reabsorption of sodium as a function of
Circulation Research, Vol. XXX, June 1972
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
719
I 13 )
ni
•^
E
From Block 10
E
95
cnmHg
E5
Afferent Arteriolar Press.
Tubular Pressure
Efferent Arteriolar Diameter
Glomerular Permeability
I 14 )
I 15 )
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I 16 )
Eq/day
24
Filtered Load of Sodium
Loop Load
FIGURE 3
Effect of afferent arteriolar pressure on the macula densa. Normal human operating points
are the values shown on the axes. Clomerular capillary pressure (PJ, plasma colloid osmotic
pressure (oncotic pressure), renal tubular pressure (tubular pressure), effective filtration pressure (Pfil), glomerular filtration rate (GFR), filtered load of sodium (F Na ), rate of proximal
tubular sodium reabsorption (dNap^/dt), and sodium load to the loop of Henle (dNa loop /dt)
(43), sodium load to the macula densa segment (MD LoadNa) (37, 43), and rate of sodium
transport by the macula densa ceVs (dNa MD /dt) (no data available). In a recent communication, Brenner et al. (44) reported u value of 60 cm HtO for glomerular capillary pressure in
a unique strain of Wistar rats with glomeruli on the renal cortical surface.
delivered load from the proximal tubules is
curvilinear.
Block 18.—The sodium load which is
presented to the macula densa is the sodium
load which is delivered by the proximal tubule
Circulation Research, Vol. XXX, June 1972
to the loop of Henle minus the amount of
sodium reabsorbed by the loop.
Block 19.—This element represents a relationship between the sodium load at the
macula densa and the rate of sodium reab-
BLAINE, DAVIS, HARRIS
720
EFFECT OF HYDROSTATIC PRESSURE
ON THE AFFERENT ARTERIOLE—
A SECOND FEEDBACK P A T H W A Y (FIG. 4 )
Block 21.—Several investigators (51) have
demonstrated that changes in the head of
hydrostatic pressure in the afferent arteriole
alter the resistance to flow through the
afferent arterioles. These changes in resistance
must reflect changes in radius of the afferent
arteriole, which result from changes in the
tone of the smooth muscle in the vessel wall.
Although at the present time there are
insufficient data to identify the actual output
variable for this component, it is suggested
that changes in afferent arteriolar radius and
vascular tone alter the degree of "stretch" of
some element in the wall of the afferent
arteriole. It should be pointed out that
decreased stretch does not necessarily imply
decreased afferent arteriolar diameter. For
example, renal autoregulation appears to
involve a change in intrinsic smooth muscle
contractility, and a decrease in arterial pressure is associated with renal arteriolar dilation
and increased renin secretion. Presumably,
this alteration in afferent arteriolar stretch
affects the renin-release mechanism since
Blaine et al. (5) reported increases in renin
secretion with reduction in renal perfusion
pressures in kidneys with no sodium delivery
to the macula densa. Afferent arteriolar
compliance is a parameter for this component
and is affected by nerve activity, myogenic
contractility of the afferent arterioles, the state
of the elastic components of the vessel wall,
and the renal interstitial pressure.
21
P
aa
From Block 10
Stretch
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sorption by the macula densa cells. According
to the hypothesis of Vander and Carlson (8),
the macula densa cells behave in a fashion
qualitatively similar to the cells of the
ascending limb of the loop of Henle. When
the sodium load to the early distal tubule is
increased, the macula densa cells increase
their rate of sodium transport and presumably
raise the intracellular concentration of sodium
(8). Vander and Carlson (8) have suggested
that these changes in macula densa sodium
lead to a reduction in renin secretion. If these
characteristics are assumed for the macula
densa cells, the effects of such diuretics as
furosemide (8, 11) on renin secretion can be
explained adequately. Under these conditions,
even though the sodium delivery to the
macula densa segment is high, the diuretics
might inhibit sodium transport by the ascending limb and macula densa and, consequently,
decrease the intracellular concentration of
sodium to enhance renin secretion (8).
Postulation of this mechanism implies that
aldosterone acts on the renal tubules at a site
distal to the macula densa since Geelhoed and
Vander (50) have shown that aldosterone
does not have a direct inhibitory effect on
renin secretion. In contrast, it has been
postulated (10-12) that the macula densa
receptor is sensitive to sodium concentration
in tubule fluid rather than to sodium load,
with an increase in sodium concentration
being associated with increased renin secretion. In this hypothesis (1, 10), it has been
suggested that the renin-angiotensin system
participates in the regulation of renal blood
flow and glomerular filtration rate through an
intrarenal feedback mechanism.
Stretch
/
To Block 22
Afferent Arteriolar Press.
T
Afferent Arteriolar
Compliance
t
Renal Nerves
FIGURE 4
Effect of hydrostatic pressure on the afferent arteriole.
Normal human operating points are the values shown
on the axes. Renal afferent arteriolar pressure (P aa )
(37) and stretch of the afferent arteriolar wall (Stretch)
(no data available).
Circulation Research, Vol. XXX, Jane 1972
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
721
EFFECT OF AFFERENT ARTERIOLAR STRETCH
ON RENIN SECRETION—A CONCEPT
OF PARALLEL FEEDBACK PATHWAYS (FIG. 5)
I 20 )
24 )
(IR/dl
To Block 1
nin Sec Rale
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Block 20.—Vander and Carlson (8) postulated that renin secretion is inversely proportional to the rate of sodium transport by the
macula densa cells. This implies the presence
of a component which has a characteristic
curve with a negative slope. Renin is stored in
granules in the highly differentiated juxtaglomerular cells of the afferent arteriole (52),
and it has been postulated that a substance is
formed by the macula densa cells and
influences the release of renin from these
granules (53). Although nothing is known of
such a "renin-releasing factor," it could be a
proteolytic enzyme that degrades the membrane which surrounds the granules. The
presence of some factor—electrical, mechanical, or chemical—is necessary if one postulates
an overall system configuration which has
parallel or additive feedback pathways.
Block 22.—According to present hypotheses
(3, 5) renin release is inversely proportional
to hydrostatic pressure within the arteriole.
Recently, convincing evidence (5, 6) has been
provided for a renal vascular receptor which
responds to changes in arteriolar hydrostatic
pressure. This concept has been supported by
several authors including Skinner et al. (4),
who showed that graded constriction of the
aorta above the renal artery gave proportional
increases in renin secretion. This concept
indicates the presence of a component which
has a negative slope. As before, it is suggested
that the output of this element is a hypothetical renin-releasing factor which acts on the
renin storage granules to influence the rate of
renin release.
Block 23.—This relationship represents simple addition of the two receptor outputs as
parallel feedback pathways.
/
/
cc
Renin Release facior
A!H
1
'
t
Na Intake
Renal Nerves
Caiecholamines
niolensin 11
An
FIGURE 5
Effects of afferent arteriolar stretch and macula densa sodium transport on renin secretion.
No quantitative data are available for these components. Macula densa sodium transport
(dNa MD /dt), renin-releasing factor (RRF), renin secretion rate (dR/dt).
Circulation Reusarch, Vol. XXX, June 1972
722
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Block 24.—This component illustrates the
concept that an increase in the postulated
renin-releasing factor affects the membrane of
the renin storage granules to increase renin
secretion. This block also includes three
factors as parameters which alter the synthesis, storage, or release of renin. Sodium intake
may be of particular importance since sodium
depletion produces increased renin concentration within the kidney (52, 54). Moreover,
Bunag et al. (55) have shown that dogs on a
low-sodium diet release more renin after
reduction of renal perfusion pressure than do
sodium-replete dogs. Experiments with hemorrhage as the stimulus for renin secretion
have produced similar findings (56). Thus, a
negative sodium balance shifts the characteristic curve upward and to the left. Recent data
indicate that renal nerve stimulation and
norepinephrine infusion (57) increase renin
secretion in the nonfiltering kidney in which
the afferent arterioles are dilated with papaverine. Thus, the renal nerves and circulating
catecholamines also influence renin release,
possibly by a direct action on the juxtaglomerular cells. Bunag et al. (58) and Vander
(59) found that direct infusion of high levels
of ADH into the renal artery suppresses renin
secretion. More recently, Tagawa et al. (60)
demonstrated renin suppression in sodiumdepleted conscious dogs with more physiological levels of ADH. Since there was no
detectable change in sodium excretion in these
studies, it is likely that ADH acts directly on
the renal arterioles or on the juxtaglomerular
cells.
Action of Potassium and Angiotensin II on
Renin Secretion.—Potassium is a factor which
alters renin secretion but which has not been
illustrated in the system diagram (Fig. 6).
Increased plasma levels of potassium are
associated with decreased renin secretion
(61-64). In addition, direct infusion of a
hyperkalemic solution into the renal artery
rapidly reduces renin secretion (65). Thus,
potassium could have a direct effect on renin
release either by stabilizing the membrane of
the renin storage granules or by altering the
production of renin-releasing factor. Alterna-
BLAINE, DAVIS, HARRIS
tively, potassium might act on the renal
tubules upstream from the macula densa to
inhibit sodium reabsorption (66) and thus
increase the macula densa sodium load and
reduce renin secretion. Preliminary experiments by Shade and Davis (unpublished)
support the latter interpretation, since potassium infusion into the renal artery of a
nonfiltering kidney had no influence on renin
secretion.
Renal artery infusion of physiological levels
of angiotensin II suppressed renin secretion
(58, 67, 68). Also, angiotensin II has a
natriuretic effect (69), and there is some
evidence (70) that angiotensin II exerts its
action on the distal tubule beyond the macula
densa. In this event, the macula densa would
not sense the change in renal tubule sodium
and, therefore, angiotensin II might act
directly on block 24 to inhibit renin release. If
inhibition of renin secretion is a physiological
function of angiotensin II, there would be a
negative feedback loop within the larger
feedback loop of the R-A-A system. This
smaller loop might have a relatively low gain
which would allow the larger loop to be
dominant during homeostasis.
FUNCTIONAL ROLE OF THE RECEPTOR PATHWAYS
IN THE OVERALL SYSTEM (FIG. 6)
The proposed receptor pathways for renin
secretion are illustrated as parallel limbs
which are independently capable of altering
renin secretion. In this configuration, it is
assumed that one receptor is sensitive to the
pressure in the arterial system and that the
other is sensitive to changes in sodium
delivery to the macula densa. This working
hypothesis does not eliminate the possibility
that the macula densa receptor may function
by altering the sensitivity of the vascular
receptor. The latter possibility is consistent
with the evidence that a low sodium intake
potentiates the renin response to a decrease in
renal perfusion pressure (55). According to
the system diagram (Fig. 6), one may test this
concept of independent receptor function by
eliminating, i.e., opening, one of the individual receptor pathways and providing experimental stimuli which are known to stimulate
renin secretion in the normal kidney.
Circulation Research, Vol. XXX, June 1972
723
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
12!
iRl
JRdi
14!
151
161
17!
dNa dls ,.'dl
dAl.di
~~
dAH ill
|AD|
Hepatic Blood Flo*
[Substrate] Pulmonary
Conversion
Rate
Angioiensirases
Plasma ACIH
|Nal.|K|
Hepatic Blood Flo*.
AOH
1141
191
18]
ECF
BV
r
Plasma |Na]
^r
Glomerular Perm.
t
All. An. Oia.
f
Tubular Press.
Ell. An. Dia.
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
1171
Ell. An. Da.
f
I
Renal Nerves
Cateclralamines
Peripheral
Vascular
j O i,e
T
Starling Forces
H8|
dNa
loop/dl
/<+>\
MO.loadNa
dR/dt
All. An. Compliance
Catecholamines
Renal Nerves
Na intake
FIGURE 6
The steady-state renin-angiotensin-aldosterone control system. Only the general form of the
relationship for each component is illustrated in this figure. For definitions of abbreviations
see Figures 1-5.
Vascular Receptor.—Selye and Stone (71)
developed a renal model in rats in which the
tubular elements were destroyed but the renal
vasculature was intact. Although data on renin
secretion were not available, this so-called
"endocrine" kidney did exhibit a high content
of a reninlike substance. Thus, these early
studies suggested that intact tubular structures
were not necessary for renin production and
storage. In a somewhat similar manner, Blaine
et al. (5) developed a nonfiltering kidney
model in dogs for studies on the renin
secretory mechanism. In the system diagram
(Fig. 6), elimination of glomerular filtration
Circulation Research, Vol. XXX, June 1972
would isolate the proposed renal vascular
receptor. Thus, by using temporary renal
ischemia and ureteral ligation in combination
with renal denervation and adrenalectomy,
blocks 12-20 in the control system and the
effects of the renal nerves and circulating
catecholamines (blocks 10, 21, 24) on the
proposed vascular receptors could be eliminated. Using this model, Blaine and Davis
(72) observed that renin secretion was
stimulated in the anesthetized dog by a
pressure reduction of only 10-15 mm Hg with
no change in renal blood flow. This strongly
supports the existence of a vascular receptor
724
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which can independently promote renin secretion during small fluctuations in arterial
pressure.
Macula Densa Receptor.—Vander and Miller (7) showed that the increase in renin
secretion which is produced by aortic constriction was prevented by simultaneously administering a diuretic which increased the sodium
load to the macula densa. Subsequently, many
investigators have interpreted data which
were obtained with diuretics and hypertonic
saline infusions to implicate the macula densa
in the control of renin secretion. Unfortunately, many of these experimental techniques
affected the distribution of blood flow within
the kidney (73, 74) and conceivably could
also have influenced the renal vascular receptor. Thurau et al. (10) attempted a direct
stimulation of the macula densa by retrograde
injection of hypertonic saline into the distal
tubules and concluded that the macula densa
was stimulated by an increased concentration
of sodium. More recently, Cooke et al. (12)
found that ethacrynic acid did not stimulate
renin release in dogs which had obstructed
ureters, but renin secretion increased immediately after reestablishment of urine flow.
These findings are also evidence for the
existence of a macula densa receptor.
Vander and Carlson (8) have suggested
that the rate of sodium transport by the
macula densa cells is the stimulus for renin
secretion. They further hypothesized that the
macula densa cells increase their rate of
sodium transport when the sodium load to the
macula densa increases. In this hypothesis, the
macula densa cells behave similarly to the
cells of the ascending limb of the loop of
Henle, which also increase sodium reabsorption when sodium delivery is increased (74,
75). In this theory, then, the rate of sodium
transport by the macula densa is a function of
sodium load. This hypothesis implies that both
sodium concentration and volume flow are
involved and that the macula densa computes
the product of the two factors, the sodium
load, and responds to it. In this regard, the
suggestion of Thurau et al. (10) that sodium
BLAINE, DAVIS, HARRIS
concentration is sensed by the macula densa is
a simpler hypothesis.
The system diagram (Fig. 6) emphasizes
the important point that the function of the
macula densa as a sodium receptor in the
normal animal is strictly dependent on the
rate of glomerular filtration (block 13); that
is, autoregulation of glomerular filtration rate
essentially determines the function of this
receptor pathway. If autoregulation was perfect, that is, if there was no change in
glomerular filtration rate with changes in renal
perfusion pressure, there would be a zero
slope for the relationship in block 11 and the
gain of this entire receptor pathway would be
zero. Thus, the role of the macula densa in
renin release in the autoregulatory range
depends on imperfect autoregulation of glomerular filtration rate. However, even if
autoregulation is imperfect, the gain of this
receptor pathway and, consequently, the
effect of this receptor mechanism would be
very low. Another mechanism which would
produce an increase in gain of this pathway
would be "parametric forcing," that is, a
change in at least one of the parameters of this
pathway. For example, alterations in plasma
sodium concentration (block 14) could activate the macula densa receptor for renin
release without a loss of autoregulation of
glomerular filtration rate.
Implication of Parallel Feedback Pathways.—A parallel configuration, as illustrated
in Figure 6, makes it functionally possible for
the macula densa and the vascular receptor to
compliment each other. In the normal range of
blood pressure, autoregulation of glomerular
filtration rate could sufficiently reduce the gain
of the macula densa pathway to allow
domination by the vascular receptor pathway
in the control of renin release. At mean
systemic pressures below approximately 90
mm Hg, autoregulatory phenomena would
disappear and the gain of the macula densa
pathway would be markedly increased. At
blood pressures below 90 mm Hg, the afferent
arteriole becomes fully dilated since the
resistance drop across the afferent arteriole
Circulation Research, Vol. XXX, June 1972
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
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becomes negligible (45). With maximal dilation, tension in the wall of the afferent
arteriole would become relatively low and
approximately constant. Thus, at pressures
below the autoregulatory range, the gain of
the vascular receptor pathway would be
substantially reduced. These considerations,
which are derived from our best estimate of
the control system configuration for the R-A-A
system, suggest that the receptors are anatomically in parallel but functionally in series.
This system configuration also suggests the
hypothesis that the vascular receptor dominates in the autoregulatory range of blood
pressure and that the macula densa receptor
dominates at pressures below the autoregulatory range. However, one must alter this
concept if parameters beyond block 11, such
as plasma sodium concentration, change to
activate a subsequent segment of the macula
densa pathway which could have high gain.
Discussion
STEADY-STATE RESPONSES TO PHYSIOLOGICAL
AND PATHOLOGICAL CHANGES
IN THE R-A-A SYSTEM (FIG. 6)
The renin-angiotensin-aldosterone system is
responsive to several normal and abnormal
conditions that occur in animals. This system
reacts to these conditions by using negative
feedback to move the system variables toward
their normal operating points. Negative feedback is represented in the system diagram
(Fig. 6) by blocks 20 and 22 since these
components have characteristic curves with
negative slopes. In the remainder of this
discussion, the system diagram (Fig. 6) will
be examined to ascertain the manner in which
several physiological and pathological conditions influence the R-A-A system to elicit
negative feedback and, therefore, to maintain
system homeostasis.
Low Sodium Intake.—A chronic low sodium intake, as is known to occur in many
alpine areas of the world, will decrease total
extracellular fluid volume (block 8) and
subsequently decrease glomerular filtration
rate (block 13). This, in combination with a
slightly decreased plasma sodium concentration (block 14) (76), could decrease the
Circulation Research, Vol. XXX, June 1972
725
sodium load delivered to the macula densa
(blocks 11-19) and could conceivably reduce
sodium transport at the macula densa. According to this view (8), the sodium concentration
in the macula densa cells will decrease to
increase renin secretion (blocks 20, 24, 25). In
a similar manner, a decrease in afferent
arteriolar pressure will decrease stretch of the
afferent arterioles (block 21) causing an
increase in renin secretion (blocks 22-24). The
increase in renin secretion by both receptor
pathways will increase aldosterone production
(block 4) and the plasma concentration of
aldosterone (block 5), which in turn will
increase sodium reabsorption (block 6) as a
compensatory mechanism to restore the extracellular fluid volume. In addition to changes in
the input and output variables for each
component of the system, changes in several
parameters of the system will augment the
effect of the increased secretion of renin and
aldosterone. For example, sufficient contraction of the extracellular fluid volume will
decrease hepatic blood flow, which will
decrease metabolism of both renin (block 1)
and aldosterone (block 5). These reductions
in metabolism will result in increased plasma
concentrations of renin and aldosterone. Thus,
a chronic low-sodium diet disturbs the system
by both input variable (extracellular fluid
volume) and parameter (hepatic blood flow)
changes, both of which induce a compensatory system response to maximize sodium
reabsorption and to increase extracellular fluid
volume toward the normal operating point.
Caval constriction.—Thoracic inferior vena
cava constriction is a potent stimulus to the
R-A-A system (77, 78) in that constriction of
the inferior vena cava above the diaphragm
results in hepatic congestion and sequestration
of a large portion of the blood volume in the
large veins of the lower body. With venous
pooling, venous and capillary pressures in the
lower body rise to produce edema and ascites.
An initial disturbance to the R-A-A system is a
decrease in arterial pressure (block 9) as a
result of reduced cardiac output (parameter
in block 9) secondary to reduced venous
return to the heart. The decrease in arterial
726
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pressure will presumably activate both receptor pathways to give increased renin secretion,
which subsequently induces high levels of
circulating aldosterone (block 5) to enhance
sodium reabsorption and expand the extracellular fluid volume. At this point, however, the
system fails to provide compensation. The
expansion of the extracellular fluid volume
does not signal the kidneys to decrease renin
secretion, because the increase in extracellular
fluid volume is not distributed throughout the
entire vascular system but is sequestered as
edema and ascites or as blood in the veins of
the lower body. Therefore, the system functions as an open-loop system, since the loop is
opened between blocks 8 and 9, and extracellular fluid volume and vascular volume are no
longer transduced into arterial pressure. Thus,
the kidneys do not perceive the increased
extracellular fluid volume and continue to
respond with increased renin secretion. This
interpretation is supported by the findings of
Robb et al. (79), who could not demonstrate
a reduction in plasma renin activity in dogs
with constricted thoracic inferior vena cavas
after administration of large doses of DOCA.
The normal animal will not continuously
increase sodium reabsorption under excess
mineralocorticoid stimulation (76, 80) but
"escapes" from the sodium-retaining action of
aldosterone. In dogs with constricted thoracic
inferior vena cavas, some other factor prevents
the proximal rejection of sodium that is
characteristic of the escape phenomenon in
the normal animal. It has been suggested (81)
that this factor is a natriuretic hormone.
Several parameters also function in caval
constriction to elevate further the plasma
aldosterone concentration. The metabolism of
aldosterone is decreased (block 5) because of
hepatic congestion (33) and decreased hepatic flow (34). The Starling forces (block 8) are
altered in favor of increased sequestration of
fluid as edema and ascites, because of
increased capillary pressure and decreased
colloid osmotic pressure. The latter is particularly important where paracentesis produces
loss of protein and reduction of plasma
protein concentration. Increased renal vein
BLAINE, DAVIS, HARRIS
pressure induces afferent arteriolar dilation in
addition to the dilation secondary to decreased arterial pressure (51). Increased renal
vein pressure might also have a significant
effect on glomerular filtration rate through
increased intratubular pressure (block 12).
Therefore, in constriction of the thoracic
inferior vena cava, the secretion of aldosterone
is markedly increased due to opening of the
feedback loop at a point where increases in
extracellular fluid volume cannot be perceived
by the receptors controlling the system.
Congestive Heart Failure.—This is another
pathological condition in which renin and
aldosterone are elevated (82). A consistent
finding early in congestive heart failure and
frequently before the onset of failure is a
reduction in renal blood flow which might be
the result of an increase in sympathetic
nervous outflow to provide cardiovascular
compensation. Initially this would represent a
parametric stimulus (blocks 10, 21, 24) to
increase renin secretion either by a direct
action on the release mechanism or by
decreasing glomerular filtration rate and
stretch of the afferent arteriole. However,
congestive heart failure is primarily characterized by a decrease in cardiac output, since the
heart fails as a pump. This acts as a reduction
in overall gain of the R-A-A system by
depression of the curve in block 9. Thus, the
volume of blood in the arterial tree is reduced
and subsequently afferent arteriolar pressure
and macula densa sodium load are reduced to
increase renin and, consequently, aldosterone
secretion. Also, there is a tendency for venous
pooling and development of edema which
reduce the gain in blocks 9 and 10 and further
reduce the overall gain of the system.
Metabolism of aldosterone and renin are
reduced since hepatic blood flow is frequently
very low in congestive heart failure, and
increased physical activity probably increases
sympathetic nerve activity and reduces hepatic blood flow.
Thus, in contrast to constriction of the
thoracic inferior vena cava, which opens the
feedback loop, the R-A-A system is activated
to differing degrees in congestive heart failure
Circulation Research, Vol. XXX, June 1972
727
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
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depending on the reduction in gain of
component 9, which is dependent on the
severity of cardiac compromise.
Hemorrhage.—In this condition, increased
activity of the R-A-A system (83) results from
a decrease in blood volume (block 8);
however, depending on the severity of hemorrhage, different mechanisms are probably
involved. Since a small nonhypotensive hemorrhage does not stimulate renin secretion in
denervated kidneys (84), the renal nerves are
a significant factor in activation of the R-A-A
system. The renal sympathetic nerves could
affect either the renin-releasing mechanism
directly (block 24) or the tension in the
afferent arteriole (block 21). In animals with
innervated kidneys, small hemorrhages could
increase tension in the afferent arteriole
through an increase in sympathetic discharge
or an increase in circulating catecholamines.
With relatively constant perfusion pressure, a
slight decrease in arteriolar lumen diameter
would decrease the stretch of a vascular
receptor (block 21) to signal for an increase
in renin secretion. In the denervated kidney,
there might be no change in arteriolar tension
and diameter, and thus the vascular receptor
would not be affected.
A large hypotensive hemorrhage will activate both receptor limbs in the system,
especially if autoregulation of glomerular
filtration rate is lost. There will be increased
renin and aldosterone secretion to increase
sodium reabsorption. In contrast to constriction of the thoracic inferior vena cava,
hemorrhage does not open the system loop,
and therefore the increase in sodium reabsorption will expand the extracellular fluid volume
toward normal to raise arterial pressure as a
compensatory mechanism. There are also
alterations in system parameters which increase the response of the R-A-A system to
hemorrhage. For example, decreased hepatic
plasma flow will also increase the plasma
concentration of renin and aldosterone (22).
The Steady-State Approach.—The development of a steady-state block diagram
for the renin-angiotensin-aldosterone system serves to emphasize functional relationCircuUtion Research, Vol. XXX, June 1972
ships. The concept of a double intrarenal
receptor system focuses attention on parallel
feedback pathways; these may conceivably
function independently or in an additive
manner. Analysis of the special situations
considered here by this approach calls attention to certain unique features which might
otherwise be overlooked. For example, the
difference between the pathophysiological
mechanisms of sodium retention in cirrhosis of
the liver (exemplified in the model of caval
constriction) and in congestive heart failure is
evident by the opening of the feedback loop
in the former situation and by a decrease in
gain of a crucial component in the system in
the latter. Finally, this type of analysis calls
attention to the missing gaps in our knowledge of the renin-angiotensin-aldosterone system. So little information is available on how
hyperkalemia decreases renin secretion that no
attempt was made to include this relationship
in the diagram; instead, the relationship was
considered in the text. And, the necessity for
postulation of a renin-releasing factor became
clearly evident from the analysis. Thus,
control system analysis not only emphasizes
certain important functional relationships, but
it focuses attention on specific problems for
future research.
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Circulation Research, Vol. XXX, June 1972
A Steady-State Control Analysis of the Renin-Angiotensin-Aldosterone System
EDWARD H. BLAINE, JAMES O. DAVIS and PATRICK D. HARRIS
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Circ Res. 1972;30:713-730
doi: 10.1161/01.RES.30.6.713
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