Clinical Science and Molecular Medicine (1975) 48,49s42s.
The role of the renin-angiotensin-aldosterone system in
cardiovascular homeostasis in normal man
E. H A B E R , J . S A N C H O , R . R E , J . B U R T O N A N D A. C. B A R G E R
Cardiac Unit, Massachusetts General Hospital and Departments of Medicine and Physiology,
Harvard Medical School, Boston, Massachusetts, U.S.A.
enzyme and of the action of angiotensin on its
vascular receptors has permitted a critical examination of this question. Recent experiments in rats,
rabbits and in trained, conscious dogs (Gavras,
Brunner, Vaughan & Laragh, 1973; Samuels,
Miller, Fray & Haber, 1973; Mimran, Guiod &
Hollenberg, 1974) have demonstrated that angiotensin I1 is essential in the maintenance of normal
blood pressure in the sodium-depleted but not in the
sodium-replete animal. In the present experiments
the role of renin in the maintenance of blood pressure
and in the regulation of aldosterone in relation to
posture is examined in normal man.
s-ry
1. To examine the role of angiotensin I1 in the
maintenance of blood pressure and control of
aldosterone secretion, eight normal human subjects
were studied on a tilt table in sodium-replete and
sodium-depleted states, before and after the administration of an angiotensin converting-enzyme
inhibitor (CEI).
2. Administration of CEI was followed by a
marked fall in blood pressure on tilting in sodiumdepleted, but not in sodium-replete, subjects. CEI
administration also resulted in a rise in plasma renin
activity in the supine position, in the absence of
haemodynamic change. The rise in plasma aldosterone observed both in response to tilting and sodium
depletion did not occur after CEI, even though
plasma renin activities were higher.
3. These results indicate that: (a) angiotensin I1 is
essential for blood pressure control in the sodiumdepleted individual ; (b) angiotensin I1 exerts direct
feedback control on renin secretion; (c) angiotensin
I1 is the primary stimulus to aldosterone secretion
in response to both sodium depletion and posture.
Methods
Human subjects
Eight normal subjects ranging in age from 19 to
27 years, including seven men and one woman, were
studied. Subjects gave informed consent and the
protocol of the investigation was approved by the
institution's human studies committee.
Group 1. Four subjects were maintained for 3
days on a 110 mmol Na-100 mmol K diet. On the
subsequent day, subjects remained supine on a tilt
table for 30 min, were tilted upright to 70" for 30 min
and then permitted to remain supine for an additional 30 min. Heart rate and blood pressure were
monitored. Blood samples were obtained at frequent
intervals.
A single injection of converting-enzyme inhibitor
(25 pmollkg) was given intravenously 30 min after
the first tilt and the earlier protocol was repeated.
Subsequently, the subjects were either maintained
on a 10 mmol Na-100 mmol K diet for 3 days (two
subjects) or were given 80 mg of frusemide orally
Key words : aldosterone, angiotensin, blood pressure,
converting-enzyme inhibitor, renin, tilt table.
Introduction
The role of the renin-angiotensin system in the
maintenance of normal blood pressure has been
uncertain. The recent availability of effective
competitive inhibitors of angiotensin-converting
Correspondence: Dr Edgar Haber, Cardiac Unit, Massachusetts General Hospital, Boston, Massachusetts 021 14,
U.S.A.
49s
50s
E. Haber et al.
12 h before the study. Their mean weight loss was
2.67 1.18 kg. The same experimental protocol as
described above was then repeated.
Group 2. Four subjects were maintained first on a
110 mmol Na-100 mmol K diet for 5 days and then
o n a 10 mmol Na-100 mmol K diet. Before the
experiment, 24 h urine sodium excretion was 138 f24
mmol on the high sodium diet and 15 1 11 mmol on
the low-sodium diet. Average weight loss was
2.16 f0.39 kg on sodium restriction. Each subject
was studied on four separate experimental days, on
110 mmol Na diet, on 10 mmol Na diet, with and
without CEI. In each study, after a supine equilibration period of 30 min, an injection of either
CEI") (25 mmolikg) or diluent (placebo) was given.
Fifteen minutes after the injection subjects were
tilted to 70"for 7 rnin or until they felt faint.
Group 3. Five subjects were examined on a free
diet and 12 h after the oral administration of 80 mg
of frusemide (weight loss 1.54 f0.37 kg). After a 30
rnin period of blood pressure equilibration in the
supine position, 12.7 pmol of CEI or diluent was
administered, followed by a continuous infusion of
CEI (12.7 pmol/min) or diluent. At 150 rnin the
subjects were tilted upright for 7 min or until they
fainted. The subjects were studied during four
experimental sessions on separate days on a free
diet with and without CEI and subsequent to
frusemide with and without converting-enzyme
inhibitor.
Plasma bradykinin concentrations were measured
in two subjects in group 1 before and 5, 30 and 60
rnin after CEI, and in one subject in group 3 before
and 15 and 150 min after CEI.
Analytical techniques
Plasma renin activities (PRA) were assayed by
methods previously described (Haber, Koerner,
Page, Kliman & Purnode, 1969). Plasma aldosterone
determinations were done by a direct radioimmunoassay on plasma extract (Poulsen, Vetter,
Sancho & Haber, 1974). Plasma bradykinin was
determined by the method of Talamo, Haber &
Austin (1969).
Converting-enzyme inhibitor
The converting-enzyme inhibitor utilized was the
( l ) Abbreviations:
CEI, converting-enzyme inhibitor;
PRA, plasma renin activity.
nonapeptide originally isolated from Bothrips
venom having the sequence Tyr-Trp-Pro-Arg-ProGln-Ile-Pro-Pro. Early experiments were performed
with samples of this material kindly donated by
Squibb (SQ 20,881). Later experiments were carried
out with peptide synthesized in our laboratory,
utilizing solid-phase synthetic techniques.
Results
Group 1
As is apparent from examination of Table I ,
sodium-replete subjects underwent a modest narrowing of pulse pressure associated with tachycardia
after 2 min of tilting. Identical changes on tilting
were observed after administration of CEI, indicating that CEI did not have an effect on the
haemodynamic response to tilting in the sodiumreplete subject. After sodium depletion, these
haemodynamic changes were exaggerated. After the
administration of CEI in the sodium-depleted
subject tilting resulted in a dramatic and significant
fall in blood pressure (P<0.05) accompanied by a
marked tachycardia.
The sodium-replete subjects showed a significant
rise in PRA (P<0.05) and plasma aldosterone
(P<O.Ol) during tilting. After CEI, PRA rose
significantly higher on tilting (P<0.05),though there
was no rise in plasma aldosterone. Sodium-depleted
subjects had more dramatic rises in PRA and plasma
aldosterone during control tilting studies. PRA was
still further elevated on the tilt after CEI, though
plasma aldosterone concentrations fell to base-line.
These studies indicate that CEI administration
results in a marked augmentation of the response of
PRA to tilting, while completely blocking the
response of plasma aldosterone.
Group 2
In order to exclude effects of diuresis independent
of sodium depletion, haemodynamic studies were
carried out in an additional group of four subjects
who were sodium-depleted by diet alone. In this
group, each tilting experiment was carried out on a
separate day to exclude the effects of one experiment
on a subsequent one. Table 1 confirms the haemodynamic observations made in group 1 . Sodiumdepleted subjects had a significantly greater fall in
blood pressure (P<0.05)on tilting after CEI than
did sodium-replete subjects.
Renin in cardiovascular homeostasis
51s
TABLE
1. Effects of changes in posture of sodium-replete and sodium-depleied subjects on blood pressure, heari rate, plasma renin
aciiviiy and plasma aldosierone concentration
Results are mean values f SEM. Group 1 : blood pressure, heart rate, PRA, plasma aldosterone: supine, 30 min; upright, maximal
values. Group 2: supine blood presure, heart rate before tilt; upright blood pressure, heart rate 2-3 min after tilt. Group 3:
all supine blood pressure, heart rate, PRA, plasma aldosterone: control, 180 min; CEI or placebo, 150 min; upright blood
pressure, pulse: 2-3 min.
Na-depleted
Na-replete
Control
Blood pressure (mmHg)
Group 1 Systolic
Diastolic
Group 2 Systolic
Diastolic
Group 3 Systolic
Diastolic
Heart rate (beatslmin)
Group 1
Group 2
Group 3
PRA (ng h - ' ml-')
Group 1
Group 3
Plasma aldosterone (pglrnl)
Group 1
Group 3
CEI
CEI
Control
Supine
Upright
Supine
Upright
Supine
Upright
112+5
70f3
121+5
73+3
10424
70f5
113+6
76f3
129+7
87+4
100+7
80f4
111f6
64+4
116+6
70f5
104+8
69+6
109+7
7 8 +5
11626
8657
106+5
7 9 +2
109+3
70f4
114f4
72+4
110f7
69f4
98+2
78+1
101+6
83f3
lOl+lO
7 2 +6
106+5
6 9 +3
108f3
68f3
106+10
67+2
7 5 +6
6 9 +3
6227
105+15
7 9 +6
68f2
6 3 +7
67+5
72f7
59+2
85+12
90+8
77+12
65+5
70+7
60+3
3.2k0.9
6.7+ 1.1
6.2+ 1.7 10.8+ 1.7
3.45 1 . 1
7 . 8 k 2 . 4 18.6k5.2
3.9+ 1.2
349f91
145+25
38+ 6
233f90
98+ 17
1.1+0.3
156f55
42+ 2
Group 3
In order to examine the persistence of the haemodynamic and hormonal effects of CEI, an infusion of
CEI was continued for 150 min and subjects were
tilted at the end of that period. Results in Table 1
confirm observations made in group 1 and group 2
at shorter intervals. As shown in the previous groups,
there is no significant difference in upright blood
pressure or heart rate in sodium-replete subjects
before and after CEI. However, in sodium-depleted
subjects a dramatic fall in blood pressure (P<0.05)
was again observed on tilting after CEI administration. In the sodium-depleted subjects supine
PRA was significantly higher than in control
subjects after CEI (P<0.02), whereas plasma
aldosterone concentrations were significantly lower
(P<O.Ol). These results indicate that the dissociation
of PRA and aldosterone seen on tilting in group 1 in
response to CEI could also be observed in the supine
position in group 3, suggesting that the rise in
aldosterone in response to sodium depletion is also
blocked by CEI.
8 0 +9
98+12
81+4
154+50
10229
89+9
402+68
Supine
Upright
6 5 +9
32+10
8026
32217
56+13
18+13
110f9
100f2
98+6
2 0 . 8 2 4 . 9 23,952.1
21.5+8
154+18
50+ 9
170+32
No rise in bradykinin concentration was observed
in any of the samples analysed.
Discussion
CEI previously has been demonstrated to block
conversion of angiotensin 1 into 11 in man at doses
similar to those used in this study (Collier, Robinson
& Vane, 1973). Because of the short half-life of
angiotensin 11, within minutes after administration
of CEI, the circulating amounts of this hormone
should be negligible. From the data presented, it
appears that angiotensin I1 is needed for the haemodynamic adjustment to upright tilting in sodiumdepleted man; in its absence the sympathetic
nervous system and other homeostatic mechanisms
are inadequate to maintain blood pressure. Appropriate adrenergic response to hypotension is indicated
by the invariable tachycardia observed when blood
pressure falls. In the sodium-replete individual, other
homeostatic mechanisms appear sufficient. It is
unlikely that the other effect of CEI, inhibition of
5 2s
E. Haber et al.
bradykinin breakdown, is responsible for these
observations since increase of plasma bradykinin
concentration was not observed.
We have previously demonstrated that PRA rises
rapidly o n tilting (Oparil, Vassaux, Sanders &
Haber, 1970). The data in these experiments show
that plasma aldosterone follows with similar kinetics.
CEI administration is associated with a significant
increase in PRA in the supine position, more marked
in sodium-depleted than in sodium-replete subjects
at times when no significant haemodynamic change
can be observed. This observation indicates that
angiotensin I 1 exerts negative feedback control on
renin secretion.
After CEI administration, plasma aldosterone no
longer follows the rise in PRA and remains either
unchanged or falls either upon sodium depletion or
tilting. These observations indicate that the major
stimulus to aldosterone secretion in response to
tilting o r sodium depletion is angiotensin 11. The
earlier suggestion that angiotensin I may stimulate
aldosterone secretion in airro (Saruta, Cook &
Kaplan, 1972) does not seem to be confirmed if7 i’ico.
Acknowledgments
The skilful technical assistance of Virginia Lucas
and Elizabeth Dimock is acknowledged. We also
wish to thank D r Richard Talamo for performing
plasma bradykinin determinations. This work was
supported by grant HL-14150 (SCOR) from the
National Institutes of Health.
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