670
Stimulus-Response Curve of the Renal
Baroreceptor: Effect of Converting Enzyme
Inhibition and Changes in Salt Intake
Eli R. Farhi, James R. Cant, William C. Paganelli, Victor J. Dzau, and A. Clifford Barger
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
We investigated the effect of converting enzyme inhibition (CEI) on the relationship between renal
perfusion pressure (RPP) and steady-state plasma renin activity (PRA) in unlnephrectomlzed
conscious dogs on normal-salt (80 meq NaVday) and low-salt (10 meq NaVday) diets. Stimulusresponse curves for the renal baroreceptor were determined by measuring the steady-state PRA while
the RPP was lowered and then held constant by an inflatable cuff placed around the renal artery. On
each diet the control stimulus-response curve can be described by two lines intersecting at a threshold
pressure; in the higher pressure range PRA is relatively insensitive to changes in RPP, while in the
lower pressure range PRA is very responsive to changes in RPP. On the normal-salt diet CEI
significantly increases the sensitivity of PRA to RPP in the responsive range without affecting the
threshold pressure itself or the values of PRA at pressures greater than the threshold pressure. On
the low-salt diet CEI also increases the sensitivity of PRA to RPP significantly in the responsive range;
we were unable to determine the effect of CEI on PRA at RPPs greater than the threshold pressure
in the low-salt state because CEI causes a significant drop in blood pressure under these circumstances.
The effect of CEI was significantly greater in the dogs on the low-salt diet than in the dogs on the
normal-salt diet. Thus, CEI and salt depletion interact synergistically to increase the sensitivity of
the renal baroreceptor only in the responsive range of the stimulus-response curve, i.e., at renal
perfusion pressures below the threshold pressure. (Circulation Research 1987;61:670-677)
S
ince the classic description of an experimental
model of renovascular hypertension by Goldblatt et al,1 investigators have been trying to
elucidate the mechanisms involved in the control of
plasma renin activity (PRA). There are four types of
stimuli known to affect PRA: 1) renal perfusion
pressure (RPP), 2) salt and volume status, 3) renal
nerve activity, and 4) circulating hormones such as
epinephrine or angiotensin II (All). Most of our
knowledge about these stimuli has come from experiments that have focused on the effects of a single,
isolated input. Although these experiments have provided a great deal of valuable information, their
physiologic implications are limited by the fact that, in
the conscious animal, all of the stimuli mentioned
above are always acting and inter-acting simultaneously to control plasma renin activity. This is
particularly true of angiotensin II. Any stimulus that
increases PRA will almost immediately produce a rapid
and significant increase in AH. This, in turn, will
inhibit the rate of renin secretion through a number of
mechanisms, including an increase in aortic (and hence
renal perfusion) pressure, promotion of salt and water
retention, and a direct intrarenal inhibitory effect of AH
on the cells of the juxtaglomerular apparatus.2"7 Thus,
From the Department of Physiology and Biophysics, Harvard
Medical School, Boston, Mass.
Supported in part by grants from the National Institutes of Health
HL-19467, HL-19259, and HL-33697 and a gift from RJR Nabisco
Inc.
Address for correspondence: Eli R. Farhi, MD, PhD, CC-172,
SUNY at Buffalo-Clinical Center, 462 Grider Street, Buffalo, NY
14215.
Received June 27, 1986; accepted May 29, 1987.
All plays a central role in a number of important
feedback loops that influence renin release, and the
interactions between these various loops are as critical
as the individual mechanisms themselves in the control
of PRA in the intact, conscious animal.
The importance of examining the effect of AH and
renin release within the context of the many interrelated
stimuli that interact to control PRA is demonstrated by
the varying results that investigators have obtained
during blockade of the renin-angiotensin system. For
example, the inhibitory influence of angiotensin II on
plasma renin activity may appear more or less important depending on the renal perfusion pressure; in man
and in animals, blockade of AH formation by converting enzyme inhibitors (CEIs) increases renin secretion during renal hypotension, but not necessarily at
higher blood pressures.'"" In addition, the effect of
angiotensin II on PRA also appears to be influenced by
salt intake; at control blood pressures, converting
enzyme inhibition increases PRA in men and dogs on
low-salt, but not on normal-salt, diets." 12
In each of these situations, the effect of blockade of
the renin-angiotensin system on PRA is modified by the
renal perfusion pressure, salt and volume state, and the
intrarenal effects of angiotensin II. To understand the
renin-angiotensin system properly, as a whole rather
than as a number of disparate mechanisms, one must
find a conceptual framework that will permit analysis
not only of each individual mechanism but also of their
interactions. Recently, we demonstrated the utility of
examining renin secretion in terms of the stimulusresponse curve of the renal baroreceptor.13"15 This
concept allowed us to integrate some of the signals
involved in renin release within a single model, which
Farhi et al
CEI, Salt Intake, and Renal Baroreceptors
describes not only the effects of each individual
stimulus on renin secretion but also the interactions
between various stimuli such as renal perfusion pressure, salt intake, and circulating catecholamines. In
this paper, we report on the results of similar experiments designed to examine the mechanisms of the
inhibitory effects of angiotensin II on PRA and to
include these negative feedback loops into an integrated model of the control of plasma renin activity in
the conscious animal.
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Materials and Methods
Seven male mongrel dogs (25-35 kg) were trained
to lie quietly on a padded table in an experiment room
for 2 to 3 hours. Then, during a sterile procedure under
intravenous pentobarbital anesthesia, catheters were
implanted in the aorta, inferior vena cava (caudal to the
kidney), and one renal artery, using the technique of
Herd and Barger,l6 and an inflatable silastic cuff (Hazen
Everett, Mahwah, N.J.) was placed around the renal
artery proximal to the tip of the renal arterial catheter.
The contralateral kidney was removed. The animals
were given at least 10 days to recover from surgery
before any experiments were performed. The catheters
were flushed daily with isotonic dextrose and then filled
with heparin.
The dogs were housed in individual cages and were
fed either a normal-salt diet (approximately 80 meq
NaVday) or a low-salt diet (approximately 10 meq
NaVday) with the same potassium content. Urinary
collections were analyzed daily to determine the total
urinary sodium excretion, which ranged between 70
and 90 meq Na + /day on the normal-salt diet and
between 2 and 10 meq Na + /day on the low-salt diet.
In addition, dogs beginning the low-salt diet were
given furosemide (40 mg orally twice a day for three
days). The dogs were allowed 10 days to equilibrate,
as documented by urinary sodium excretion, after a
change in salt intake prior to any experiments.
The renal baroreceptor stimulus-response curves
were determined as described in previous papers.1314
Briefly, the dog was brought into an experiment room
where it would lie quietly as the aortic and renal arterial
catheters were connected to Statham P23Dc pressure
transducers. After a 20-minute control period, two
blood samples were drawn at 5-minute intervals for
later determination of PRA. The constrictor cuff around
the renal artery was then inflated to decrease the renal
perfusion pressure by a predetermined amount (15, 20,
or 25 mm Hg); this pressure was then kept constant for
30 minutes by continuous adjustment of the cuff as
needed. At the end of this time, when mean arterial
pressure had stabilized, two blood samples were drawn
5 minutes apart for later analysis of PRA. Then, if the
dog was still relaxed, the cuff was inflated further to
decrease the renal perfusion pressure by another 15 mm
Hg, and the procedure was repeated. The renal perfusion pressure was decreased in this manner in
sequential steps until the dog became restless or the
next constriction would have resulted in a perfusion
pressure of less than 40 mm Hg.
671
To determine the effect of angiotensin converting
enzyme inhibition on the stimulus-response curve of
the renal baroreceptor, the procedure described above
was modified after the control period by giving a 15 mg
intravenous bolus of the converting enzyme inhibitor
teprotide (SQ 20881), followed by an infusion at 5.4
mg/hr. After another 25-minute control period, the
renal perfusion pressure was decreased as described
above. The efficacy of the converting enzyme inhibition was tested by determining the pressor response to
an intravenous bolus of 1 /ig angiotensin I immediately
prior to the bolus of converting enzyme inhibitor and
at the end of the experiment. In all experiments, the
angiotensin I bolus caused the mean aortic pressure to
rise transiently by at least 20 mm Hg prior to converting
enzyme blockade but did not change mean aortic
pressure during CEI infusion.
The blood samples for the PRA assay were drawn
into 5-ml EDTA vacutainer tubes. The tubes were kept
on ice for less than 10 minutes until they could be spun
in a refrigerated centrifuge to remove cells and platelets. Plasma samples were decanted and then frozen
until the assays were performed. At the end of an
experiment, the red blood cells were suspended in
isotonic dextrose and returned to the animal. PRA was
measured by the method of Haber et al17; the results are
expressed as nanograms of angiotensin I generated per
milliliter of plasma per hour at pH 7.4.
Four dogs were examined on the normal-salt diet and
5 on the low-salt diet. Of these, 2 were studied on both
diets. On each diet, 3 or 4 experiments, each consisting of 3 to 5 successive reductions in the renal
perfusion pressure, were performed in every animal
over a two-week period, with and without converting
enzyme inhibition. From a series of such experiments,
we obtained steady-state values of PRA in each dog at
each renal perfusion pressure in the presence and the
absence of angiotensin II. By averaging all values of
PRA obtained within a 5 mm Hg range of RPP and then
plotting this average PRA against the renal perfusion
pressure we obtained stimulus-response curves for the
renal baroreceptor of that dog with and without
converting enzyme blockade. As we have previously
described, the stimulus-response curves consist of two
ranges of renal perfusion pressures separated by a
threshold pressure (Figure 1). In the lower range, below
the threshold pressure, PRA increases steeply in
response to decrements in RPP, while above the
threshold pressure PRA is relatively independent of
RPP. For purposes of analysis, a straight line was fitted
to the data within each range of RPP, and the
intersection of the two lines was defined as the
threshold pressure. Converting enzyme inhibition did
not affect blood pressure during the control period in
the dogs on the normal-salt diet but did cause the
control arterial pressure to fall to or below the threshold
pressure when the dogs were on a low-salt diet; in these
cases the data were fit to a single line.
As in our previous papers, the form of the stimulusresponse curves was similar in all the dogs in each
condition, although the absolute values of PRA and of
Circulation Research
672
~~40
60
80
Vol 61, No 5, November 1987
stimulus-response curves of each dog were normalized, expressing each PRA value as a percent of the
maximum PRA of the control stimulus-response curve.
Composite stimulus-response curves were then ob^
tained by averaging all the normalized PRA values of
each dog (i.e., one value per dog) within each 5 mm
Hg interval of renal perfusion pressure as shown in
Figure 2.
Comparisons between slopes and intercepts of these
lines in the same dog for the different protocols were
performed using the analysis of covariance technique
for comparison, of regression lines described by Snedecor and Cochran." When the normalized curves were
compared, the number of degrees of freedom was
decreased by one. Direct comparisons of PRA values
obtained with and without converting enzyme inhibition at renal perfusion pressures above the threshold
pressure were performed using analysis of variance and
paired t tests.
100
RENAL ARTERY PRESSURE (mm Hg)
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
FIGURE 1. Stimulus-response curves of the renal baroreceptor
in one dog (8 experiments) on a normal-salt diet (80 meq
Na*lday) in the control state (A,
) and during converting
enzyme inhibition (A, —). Plasma renin activity is expressed
as ng Allml plasma/hour. Each point represents the average of
all steady-state values of plasma renin activity within a 5 mm
Hg range of renal artery pressure. In each condition, two
straight lines were fit to the data by standard regression
techniques.
the slopes of the lines above and below the threshold
pressure varied from dog to dog as shown in Tables 1
and 2. In an earlier paper examining the effect of
changes in salt intake on PRA,14 we demonstrated that
some of these differences in absolute values could be
a result of variation in the amplitude of the stimulusresponse curve, such that the percent change in PRA
caused by any change in RPP is the same in the various
dogs even though the absolute values may differ.
Therefore, to allow comparison of animals on the
different salt diets and to reduce interanimal variation
(which may be due to the fact that the salt intake of each
animal was the sameregardlessof its size and age), the
Results
Using the techniques described above, we generated
four sets of stimulus-response curves with and without
CEI for dogs on the normal-salt diet (28 experiments)
and five sets for dogs on the low-salt diet (33
experiments). Stimulus-response curves of a representative dog on a normal-salt diet with and without CEI
are shown in Figure 1, while composite curves,
summarizing the results of all the dogs on the normalsalt diet with and without CEI are shown in Figure 2.
The results of all dogs on the normal-salt diet are
summarized in Table 1. In all of the dogs, the slope of
the stimulus-response curve at RPPs below the threshold pressure was increased during converting enzyme
blockade; this effect was statistically significant
(/7<O.O5) in 3 of the 4 dogs and for the group as a
whole. Infusion of converting enzyme inhibitor did not
change the threshold pressure significantly in the dogs
on a normal-salt diet, nor did it affect the values of PRA
at RPPs above the threshold pressure.
CEI decreased blood pressure to below the threshold
pressure in the dogs on the low-salt diet so that no PRA
Table 1. Analysis of Stimulus-Response Curves in Individual Dogs on Normal Salt Diet
Dog
BO
E
H
X
TP
(mm Hg)
78
90
72
85
81
Control RA constriction
Slope of
Normalized
stimulusslope of
response
stimuluscurve
response
below TP
curve
(ng AI/ml/
below
hr/mm Hg)
TP
-0.12
-2.6
-1.7
-0.08
-0.36
-2.9
-0.13
-2.1
-0.17
-2.1
Average
PRA
above TP
(ng AI/
ml/hr)
0.2
0.3
0.5
0.2
0.3
RA constriction during converting enzyme inhibition
Normalized
Slope of
slope of
stimulusAverage
stimulusresponse
PRA
response
curve
above TP
curve
below TP
(ng AI/
below
TP
(ng AI/mV
ml/hr)
TP
(mm Hg) hr/mm Hg)
0.3
-2.8
93
-0.13
-0.16*
-3.5*
0.1
86
-4.3*
0.4
82
-0.53*
-3.1*
0.2
84
-0.19*
-3.2*
-0.25
0.3
86
Threshold pressures (TP), slopes of regression lines fit to stimulus-response curves below threshold pressure, and
average plasma renin activity (PRA) above threshold pressure during renal artery (RA) constriction in dogs on a normalsalt diet under control conditions and converting enzyme inhibition. Slopes were normalized by expressing each PRA
value as a percent of the maximum PRA of the control stimulus-response curve.
*p<0.05 compared to control.
Farhi et al CEI, Salt Intake, and Renal Baroreceptors
673
Table 2. Analysis of Stimulus-Response Curves in Individual Dogs on Low-Salt Diet
Dog
BO
BR
S
X
Z
Mean
TP
(mm Hg)
80
85
77
81
85
82
Control RA constriction
Normalized
Slope of
slope of
stimulus
stimulusresponse
response
curve
curve
below TP
below
(ng AI/ml/
TP
hr/mm Hg)
-0.35
-0.72
-0.63
-0.25
0.17
-0.42
-2.3
-2.2
-2.5
-2.2
-1.8
-2.1
Average
PRA
above TP
(ng AI/
ml/hr)
1.5
0.7
2.3
0.9
1.6
1.4
RA constriction during
converting enzyme inhibition
Slope of
Normalized
slope of
stimulus
stimulusresponse
response
curve
curve
below TP
below
(ng AI/ml/
TP
mm Hg)
-0.36
-1.6*
-0.79*
-0.53*
-0.46*
-0.75*
-2.3
-4.9*
-3.2*
-4.6*
-5.0*
-4.3*
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Threshold pressures (TP), slopes of regression lines fit to stimulus-response curves below threshold pressure, and
average plasma renin activity (PRA) above threshold pressure during renal artery (RA) constriction in dogs on a low-salt
diet under control conditions and converting enzyme inhibition. Slopes were normalized by expressing each PRA value as
a percent of the maximum PRA of the control stimulus-response curve.
*p<0.05 compared to control.
values could be obtained at renal perfusion pressures
equal to or greater than the threshold pressure. As a
result, the stimulus-response curves obtained during
teprotide infusion could be modeled with one line
rather than two lines intersecting at a threshold pressure. The stimulus-response curve of a typical dog on
the low-salt diet is shown in Figure 3, and the composite curves are shown in Figure 4. The results of the
individual dogs and the combined curves are summarized in Table 2. At RPPs below threshold pressure, the
slopes of the stimulus-response curves increased in
TO
60
S3
100
RENAL ARTERY PRESSURE (mm Hg)
FIGURE 2. Stimulus-response curves of the renal baroreceptor;
average results from 4 dogs on a normal-salt diet (28 experiments). Individual values ofplasma renin activity are expressed
as a percent of the maximum value of the stimulus-response
curve (normalized plasma renin activity), as described in the
text. Points at each renal artery pressure represent the mean of
4 dogs at that pressure in the control state (A,
) and during
converting enzyme inhibition (A, — ) .
each dog; this change was statistically significant (p<
0.05) in 4,of the 5 dogs and for the group as a whole.
The normalized control curves for the dogs on the
low-salt and normal-salt diets are shown in Figure 5.
As in our previous paper,13 the two curves are indistinguishable when expressed as a percentage change in
PRA. The effect of converting enzyme inhibition,
however, is different in dogs on the two salt diets.
Figure 6 shows that during converting enzyme inhibition, the normalized values of PRA at renal perfusion
pressures below the threshold pressure are greater in the
40
60
S3
100
RENAL ARTERY PRESSURE (mm Hg)
FIGURE 3. Stimulus-response curves of the renal baroreceptor
in one dog (7 experiments) on a low-salt diet (10 meq Na*/day)
in the control state (*,
) and during converting enzyme
inhibition (o, •••). Plasma renin activity is expressed as ng Allml
plasmaJhour. Each point represents the average of all steadystate values of plasma renin activity within a 5 mm Hg range of
renal artery pressure. In each condition, two straight lines were
fit to the data by standard regression techniques.
674
Circulation Research
300
JOO
LOW SALT DIET
*
CEI
Normol Salt Die (n-4)
Low Salt Oiet (n-5)
25
1 °
200
^
150
"
~
4 0 6 0 8 0
100
RENAL ARTERY PRESSURE (mm Hg)
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
dogs on the low-salt diet (/?<0.05). As the figure
demonstrates, this effect appears to be due to an
increase in the slope of the stimulus-response curve at
RPPs below the threshold pressure; during CEI infusion, the slope was steeper in the dogs on the low-salt
diet, although the difference in slopes did not reach
statistical significance (p = 0.07).
120
Normol Salt Diet ( n - 4 )
Low Soil Diet ( n - 5 )
s
80
<j
60
I"
4(5
tOO
1 so
Contra*
FIGURE 4. Stimulus-response curves of the renal bororeceptor:
average results from 5 dogs on a low-salt diet (33 experiments).
Individual values of plasma renin activity are expressed as a
percent of the maximum value of the stimulus-response curve
(normalized plasma renin activity), as described in the text.
Points at each renal artery pressure represent the mean of 5 dogs
at that pressure in the control state (•,
) and during
converting enzyme inhibition fo, •••).
^
200
•q 150
100-
50-
Vol 61, No 5, November 1987
60
80
RENAL ARTERY PRESSURE (mm Hg)
FIGURE 5. Stimulus-response curves of the renal baroreceptor
under control conditions; average results from 4 dogs on the
normal-salt diet (A) and 5 dogs on the low-salt diet (*).
Individual values of plasma renin activity are expressed as a
percent of the maximum value of the stimulus-response curve
(normalized plasma renin activity), as described in the text.
"
\
o
\
\
'
\
40
60
8b " 100
RENAL ARTERY PRESSURE (mm Hg)
FIGURE 6. Stimulus-response curves of the renal baroreceptor
in the presence of converting enzyme inhibitor; average results
from 4 dogs on the norma l-salt diet (A, —) and 5 dogs on the
low-salt diet (O, •••). Individual values of plasma renin activity
are expressed as a percent of the maximum value of the
stimulus-response curve (normalized plasma renin activity), as
described in the text.
Discussion
We determined nine sets of stimulus-response curves
with these experiments, showing the effect of converting enzyme inhibition in dogs on normal-salt and
low-salt diets. On both diets, the shape of the control
curves was similar to those seen in our previous
experiments, consisting of two ranges of pressures.
PRA is relatively unresponsive to changes in renal
perfusion pressure at higher pressures, while below a
certain threshold pressure small changes in RPP cause
large changes in systemic PRA. Although the form of
the stimulus-response curve was the same in each dog,
the absolute values (the slope of the curves above and
below the threshold pressure and the threshold pressure) varied from dog to dog as shown in Tables 1 and
2. Because of this, we normalized the stimulusresponse curves, expressing them as a percent change
rather than as absolute values. This decreased the
interanimal variability and also allowed us to compare
the groups of dogs on the different salt diets.
Figures 1 and 2 show that in the dogs on the
normal-salt diet, converting enzyme inhibition increased the slope of the stimulus-response curve at
RPPs below the threshold pressure without changing
the threshold pressure itself or the stimulus-response
curve at RPPs above the threshold pressure. This is
consistent with earlier data from our laboratory, which
demonstrated that CEI does not affect blood pressure
in recumbent man or in dogs on a normal-salt diet at
control blood pressure," 12 while at a decreased RPP
converting enzyme inhibition causes a significant
increase in PRA in the dog.8
As Figures 3 and 4 demonstrate, converting enzyme
inhibition increases the slope of the stimulus-response
Farhi et al
CEI, Salt Intake, and Renal Baroreceptors
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
curve at RPPs below threshold pressure in dogs on the
low-salt diet; this effect is qualitatively similar to that
seen in dogs on the normal-salt diet. Because of the
hypotensive effect of CEI in low-salt dogs, we were
unable to obtain values of PRA at renal perfusion
pressures close to the control blood pressure. Thus, we
could not determine the nature of the stimulus-response
curve at RPPs above threshold pressure, or even the
threshold pressure itself, in low-salt dogs during CEI
infusion. From inspection of Figure 4, it would appear
that the threshold pressure itself is unchanged by
converting enzyme inhibition in the dogs on the
low-salt diet, although we were not able to confirm this
statistically given the nature of our experiments.
Previous work done in our laboratory may be helpful
in determining the nature of the stimulus-response
curve at RPPs above threshold pressure in dogs on a
low-salt diet after converting enzyme inhibition. Sancho et al" found that converting enzyme inhibition
caused an increase in PRA in normal subjects on a
low-salt diet without causing a significant decrease in
blood pressure. Samuels et al12 reported that in conscious, sodium-depleted dogs, CEI caused a significant
increase in PRA associated with a drop in blood
pressure. After CEI, infusions of phenylephrine sufficient to return blood pressure back to control levels
did not prevent the rise in plasma renin activity seen in
the salt-depleted dogs. These data indicate that, in
some salt-depleted animals, CEI increases PRA at
RPPs close to the control blood pressure. One must,
however, be very careful in extrapolating these results
to our stimulus-response curves for at least two
reasons. First, the experimental models were considerably different from ours. Sancho et al" reported that
there was a transient period of hypotension after
converting enzyme inhibition in their experiments; this
may have been a sufficient stimulus for an increase in
renin release. In the experiments of Samuels et al, the
dogs were adrenalectomized and were very saltdepleted, so that the control mean arterial pressure was
approximately 70 mm Hg; this value would be below
the threshold pressure in our dogs. Second, the
interpretation of the results of Samuels et al depends
on the assumption that a-adrenergic agents do not
themselves stimulate renin secretion; this is currently
a subject of some controversy."
Previous experiments from our laboratory14 have
demonstrated that changes in salt intake affect the scale
of the renal baroreceptor, multiplying the PRA at any.
renal perfusion pressure by a constant factor. In that
study, the scaling factor (the ratio of the low-salt PRA
to the normal-salt PRA at any renal perfusion pressure)
was 3.0; the scaling factor for the present study is 2.8.
This scaling factor is independent of the renal perfusion
pressure, so that while the absolute values of PRA at
any renal perfusion pressure are greater on a low-salt
diet than on a normal-salt diet, the percentage change
in PRA produced by any change in RPP is the same in
both salt states. This is demonstrated in Figure 5, which
shows that the control stimulus-response curves, expressed as a percentage change in PRA, are the same
675
in dogs on the normal-salt and the low-salt diets.
The effect of converting enzyme inhibition, however, is different in dogs on the two salt diets. Figure
6 shows that, after CEI, the normalized PRA values at
renal perfusion pressures below the threshold pressure
are greater in the dogs on the low-salt diet than in the
dogs on the normal-salt diet. This effect may be related
to the fact that the aortic pressure fell considerably
when converting enzyme inhibitor was given to the
dogs on the low-salt diet, but did not change when
given to the dogs on the normal-salt diet. Previous work
in our laboratory has demonstrated that decreasing the
pressure sensed by the carotid baroreceptors during
renal hypotension increases PRA.20 Thus, the fall in
blood pressure seen after CEI in the dogs on the low-salt
(but not the normal-salt) diet would be sensed by the
systemic baroreceptors, which could stimulate renin
release when the renal perfusion pressure is decreased.
From inspection of Figure 6, this increase in PRA
seen in the dogs on the low-salt diet when compared
to those on the normal-salt diet appears to be due a
steeper slope of the stimulus-response curve at renal
perfusion pressures below the threshold pressure. The
difference in slopes, however, did not achieve statistical significance (p = 0.07). The lack of statistical
significance could be due to two reasons. One is that
the slopes are, in fact, different but that we were unable
to confirm this statistically because of the small number
of animals, the relatively large interanimal variability,
and our inability, because of the nature of our experiments, to determine the threshold pressure in the
low-salt animals during converting enzyme inhibition.
The other explanation is that the slopes are actually not
significantly different and that the values of PRA are
increased by a different mechanism, such as a shift of
the stimulus-response curve to the right. This last
possibility would be consistent with the hypothesis
raised earlier involving an interaction of carotid and
renal baroreceptors during CEI infusion in low-salt
animals; the effect of systemic baroreceptors on PRA
is likely to involve the sympathetic nervous system,
which is associated with a rightward shift of the
stimulus-response curve.13
These results have a number of physiologic and
pathophysiologic consequences. First, they raise methodologic questions about studies in which renin
secretion rates are measured prior to the attainment of
a steady state; our data indicate that changes in renin
secretion rates in response to an acute stimulus might
well be time dependent, decreasing as circulating levels
of renin and angiotensin II increase (particularly in
response to a hemodynamic stimulus such as decreased
renal perfusion pressure). The data also have some
physiologic implications: for example, the fact that the
stimulus-response curves are increased when the renal
perfusion pressure is decreased suggests that angiotensin II may inhibit renin release by the renal
baroreceptor (i.e., renin released in response to a
lowered renal perfusion pressure) to a greater degree
than it inhibits renin release by other mechanisms (such
as salt depletion at control renal perfusion pressures).
676
Circulation Research
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Most importantly, these results provide a framework
that can be used to analyze the effects of blockade of
the renin-angiotensin system in terms of PRA, salt and
volume status, and renal perfusion pressure. This
model has many potential applications; one example
would be in understanding the effects of various
interventions on the renal vein renin ratio, a clinical
tool commonly used in the evaluation of renal artery
stenosis. First proposed by Judson and Helmer,21 the
renal vein renin ratio is the ratio of the PRA in the renal
vein of the kidney with the stenosed renal artery (S) to
that in the renal vein of the normal kidney (N); higher
ratios often indicate significant renal artery stenosis.
This is demonstrated in Figure 7 where, assuming an
arbitrary gradient of approximately 40 mm Hg across
the renal artery of the stenosed kidney, the renal vein
renin ratio would be S/N; a tighter stenosis would
further reduce the RPP, moving to the left along the
control (solid) stimulus response curve to point S1, and
raising the renal vein renin ratio to S'/N. Because this
test as originally proposed had a relatively high number
of false-positive results,22 a number of investigators
attempted to increase the sensitivity of the technique by
salt depletion or administration of diuretics ,M-24 but this
intervention did not increase the sensitivity of the renal
vein renin ratio when evaluated closely.23 Thereasonfor
this is again shown in Figures 5 and 7; changes in salt
and volume status alone do not affect the normalized
stimulus-response curve, so that the renal vein renin
ratio would remain at S/N. Other investigators attempted to increase the sensitivity of the technique by
decreasing blood pressure, using upright tilt2 or30 vasodilators such as hydralazine or nitroprusside.2*"30 This
intervention had somewhat better results, consistent
with our model. Vasodilators or upright tilt decrease
renal perfusion pressure; this is shown in Figure 7 by
a shift along the control (solid) stimulus-response
—
Contral
—
C E I Nomwl Soil Dlel
• •• CEI UM Soil Diet
Vol 61, No 5, November 1987
curve, from N to N1 for the normal kidney and from
S to S1 for the stenosed kidney. Both kidneys will
therefore increase renin secretion, but the decrease in
pressure will only affect the normal kidney once the
renal perfusion pressure is below the threshold pressure; thus, assuming the same gradient, there is a slight
but definite increase in the renal vein renin ratio (S/N
under control conditions compared to S'/N1 after
vasodilators or upright tilt).
Most recently, a number of investigators have
attempted to increase the sensitivity of the renal vein
renin ratio by using specific antagonists of the reninangiotensin system such as converting enzyme inhibitors or saralasin, often with concommitant salt
depletion.31"3* Blockade of therenin-angiotensinsystem has consistently increased the sensitivity of the
renal vein renin ratio; the mechanism for this is
demonstrated again in Figure 7. In the normal-salt
state, CEI increases the slope of the stimulus-response
curve only at renal perfusion pressures below the
threshold pressure, as shown by the change in the
stimulus-response curve from the solid to the dashed
line. Thus, CEI will increase renin secretion from the
stenosed kidney (S to S2), but not the normal kidney,
causing a larger change in the renal vein renin ratio
(from S/N in the control state to S2/N after CEI). In the
low-salt state, the effect of CEI is even more pronounced because of two factors. First, the slope of the
stimulus-response curve is increased even further (as
shown by the dotted line). In addition, CEI causes a
drop in blood pressure in the low-salt state but not the
normal-salt state. This is associated with a small
increase in renin secretion from the normal kidney (N
to N3) and a dramatic increase in renin secretion from
the stenosed kidney (S to S3), causing a marked increase
in the renal vein renin ratio (from S/N under control
conditions to SVN3 after CEI and salt depletion). Thus,
the change in the slope of the stimulus-response curve
at subthreshold pressures, combined with the decrease
in renal perfusion pressure, may be the mechanism
behind the clinical observation that converting enzyme
inhibition will preferentially increase renin secretion
from the affected kidney in cases of unilateral renal
artery stenosis, and that salt depletion, whether caused
by a low-salt diet, diuretics, or both, accentuates this
effect.
Acknowledgments
We thank Birthe Creutz, Richard R. Pintal, Franklin
W. Smith, and Ronald E. Cotter for their invaluable
assistance. The teprotide used in these studies was a gift
from Dr. Z.P. Horovitz of E.R. Squibb and Sons.
RENAL ARTERY PRESSURE
FIGURE 7. Effects of various interventions on the stimulusresponse curve of the renal baroreceptor and the renal vein renin
ratio in cases of renal artery stenosis. N,S = normal and
stenosed kidneys under control conditions; N',S' = normal and
stenosed kidneys during afterload reduction; S2 = stenosed
kidney during CEI on a normal-salt diet; N',S' = normal and
stenosed kidneys during CEI on a low-salt diet. See text for
explanation.
References
1. Goldblatt H, Lynch J, Hanzal RF, Summerville WW: Studies
on experimental hypertension. I. The production of persistent
elevation of systolic blood pressure by means of renal ischemia.
J Exp Med 1934^9:347-379
2. Skinner SL, McCubbin JW, Page IH: Control ofreninsecretion.
Ore Res 1964;15:64-75
3. Vander AJ, Geelhoed GW: Inhibition of renin secretion by
angiotensin II. Proc Soc Exp Biol Med 1966; 120:399-403
4. Blair-West JR, Coghlan JP, Demon DA, Funder JW, Scoggins
Farhi et al
5.
6.
7.
8.
9.
10.
11.
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
CEI, Salt Intake, and Renal Baroreceptors
BA, Wright RD: Inhibition of renin secretion by systemic and
intrarenal angiotensin infusion. Am J Physiol 1971 ;220:
1309-1315
Michelakis AM: The effect of angiotensin on renin production
and release in vitro. Proc Soc Exp Biol Med 1971; 138:
1106-1108
Shade RE, Davis JO, Johnson J A, Gotshal 1RW, Spielman WS:
Mechanism of action of angiotensin II and antidiuretic hormone on renin secretion. Am J Physiol 1973;224:926-929
VanDongen R, Peart WS, Boyd GW: Effect of angiotensin II
and its nonpressor derivatives on renin secretion. Am J Physiol
1974;226:277-282
Miller ED, Samuels AI, Haber E, Barger AC: Inhibition of
angiotensin conversion in experimental renovascular hypertension. Science 1972;177:1108-1109
Johnson JA, Davis JO: Effects of a specific competitive
antagonist of angiotensin II on arterial pressure and adrenal
steroid secretion in dogs. Circ Res 1973;32(suppl 1):159—168
Ayers CR, Vaughan ED, Yancey MR, Bing KT, Johnson C,
Morton C: Effect of l-sarcosine-8-alanine angiotensin II and
converting enzyme inhibitor on renin release in dog acute
renovascular hypertension. Circ Res 1974;(suppl 1 to vols 34
and 35):27-33
Sancho J, Re R, Burton J, Barger AC, Haber E: The role of
the renin-angiotensin-aldosterone system in cardiovascular
homeostasis in , normal human subjects. Circulation
1976;53:400-405
Samuels AI, Miller ED, Fray JCS, Haber E, Barger AC:
Renin-angiotensin antagonists and the regulation of blood
pressure. Fed Proc 1976;35:2512-2520
Farhi ER, Cant JR, Barger AC: Interactions between intrarenal
epinephrine receptors and the renal baroreceptor in the control
of PRA in conscious dogs. Circ Res 1982;50:477-485
Farhi ER, Cant JR, Barger AC: Alteration of renal baroreceptor
by salt intake in control of plasma renin activity in conscious
dogs. Am J Physiol 1983;245:F119-F122
Gibbons GH, Dzau VJ, Farhi ER, Barger AC: Interactions of
signals influencing renin release. Annu Rev Physiol
1984;46:29I-308
Herd JA, Barger AC: Simplified technique for chronic catheterization of blood vessels. J Appl Physiol 1964; 19:791-792
Haber E, Koerner I, Page LB, Kliman B, Purnode A:
Application of a radioimmunoassay for angiotensin I to the
physiologic measurement of plasma renin activity in normal
human subjects. J Clin Endocrinol Metab 1969;29:1349-1355
Snedecor GW, Cochran WG: Statistical Methods, ed 6. Ames
Iowa, Iowa State University Press, 1967, pp 432-436
Blair ML: Stimulation of renin secretion by alpha-adrenergic
agonists. Am J Physiol 1983;244:E37-E44
Rocchini AP, Barger AC: Renin release with carotid occlusion
in the conscious dog: Role of renal arterial pressure. Am J
Physiol 1979;236:H108-Hlll
Judsori WE, Helmer OM: Diagnostic and prognostic values of
renin activity in renal venous plasma in renovascular hypertension, Hypertension XIII: Proceedings of the Council for
High Blood Pressure Research of the American Heart Association. Cleveland, 1964, pp 79-89
677
22. Marks LS, Maxwell MH: Renal vein renin: Value and limitations in the prediction of operative results. Urol Clin North'
Am 1975;2:311-325
23. Vermillion SE, Sheps SG,Strong CG, Harrison EG, Hunt JC:
Effect of sodium depletion on renin activity of renal venous
plasma in renovascular hypertension. JAMA 1969;208:
2302-2306
24. Strong CG, Hunt JC, Sheps SG, Tucker RM, Bernatz PE: Renal
venous renin activity: Enhancement of sensitivity of lateralization by sodium depletion. Am J Cardiol 1971 ;27:602—611
25. Chuang VP, Ernst CB, Kotchen TA: Effects of furosemide on
renal venous plasma renin activity. Radiology 1979; 130:
613-616
26. Michelakis AM, Simmons J: Effect of posture on renal vein
renin activity in hypertension: Its implication in the management of patients with renovascular hypertension. JAMA
1969;208:659-662
27. Huvos A, Yagi S, Mannick JA, Hollander W: Stimulation of
renin secretion by hydralazine. II. Studies in renovascular
hypertension. Circulation 1965;32(suppl 2):118-128
28. Cohen EL, Rovner DR, Conn JW: Postural augmentation of
plasma renin activity: Importance in diagnosis of renovascular
hypertension. JAMA 1969;197:973-978
29. Norman N, Sundsfjord JA, Stiris G: Effective renal plasma flow
of the individual kidney and renal venous renin activity before
and after the administration of dihydralazine in renovascular
hypertension. Scand J Clin Lab Invest 1975;35:219-229
30. Kaneko Y, Ikeda T, Takeda T, Ueda H: Renin release during
acute reduction of arterial pressure in normotensive subjects
and patients with renovascular hypertension. J Clin Invest
1967;46:705-716
31. Re R, Novelline R, Escourrou M, Athanasoulis C, Burton J,
Haber E: Inhibition of angiotensin-converting enzyme for
diagnosis of renal-artery stenosis. N Engl J Med 1978;298:
582-586
32. Baer L, Parra-Carillo JZ, Radichevich I, Williams GS:
Detection of renovascular hypertension with angiotensin II
blockade. Ann Intern Med 1977;86:257-260
33. Wilson HM, Wilson JP, Slaton PE, Foster JH, Liddle GW,
Hollifield JW: Saralasin infusion in the recognition of renovascular hypertension. Ann Int Med 1977;87:36-42
34. Thibonnier M, Joseph A, Sassano P, Guyenne TT, Corvol P,
Raynaud A, Seurot M, Gaux AC: Improved diagnosis of
unilateral renal artery lesions after captopril administration.
JAMA 1984;251:56-60
35. Lyons DF, Streck WF, Kern DC, Brown RD, Galloway DC,
Williams GR, Chrysant SG, Danisa K, Carollo M: Captopril
stimulation of differential renins in renovascular hypertension.
Hypertension 1983;5:615-622
36. Thind G: Role of renal venous renins in the diagnosis and
management of renovascular hypertension. J Urol 1985;134:
2-5
KEY WORDS • renal baroreceptor • renin •• angiotensin
II • converting enzyme inhibitor
Stimulus-response curve of the renal baroreceptor: effect of converting enzyme inhibition
and changes in salt intake.
E R Farhi, J R Cant, W C Paganelli, V J Dzau and A C Barger
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Circ Res. 1987;61:670-677
doi: 10.1161/01.RES.61.5.670
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1987 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circres.ahajournals.org/content/61/5/670
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further information
about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation Research is online at:
http://circres.ahajournals.org//subscriptions/