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Clinical Science and Molecular Medicine (1915) 48,51s-60s.
The use of angiotensin-converting enzyme inhibitor in
the diagnosis and treatment of hypertension
H. G A V R A S , H . R . B R U N N E R , " ) J. H. L A R A G H , I. G A V R A S
AND
R. A. VUKOVICH
Columbia Presbyterian Medical Center, New York, U S A .
Squibb Laboratories). This, along with a competitive inhibitor of angiotensin 11, has provided a
new approach in assessing the role of the reninangiotensin system and its interaction with the
sodium ion in the pathogenesis and maintenance of
hypertension. In the present work, we investigate
the effects of this compound on the blood pressure of
patients with different types of hypertensive disease.
Summary
1 . The anti-hypertensive effect of converting
enzyme inhibition was evaluated in twenty-three
hypertensive patients (seven renovascular, four
essential, four malignant, one scleroderma, three
chronic renal failure, four primary or idiopathic
aldosteronism).
2. In sixteen patients a single injection (1-4
mglkg) of the inhibitor produced an immediate
anti-hypertensive effect, which lasted up to 16 h.
In six patients the anti-hypertensive effect of the
inhibitor was significantly improved after sodium
depletion.
3. Plasma renin activities increased and plasma
aldosterone concentrations decreased consistently
except in idiopathic aldosteronism.
4. Converting enzyme inhibition provides a
direct way of defining the degree of renin-dependency
of the hypertension. Accordingly, it can be used
diagnostically and for planning appropriate therapy.
Therapeutically, it could be advantageous in
hypertensive emergencies because of its safety,
specificity and capacity to reduce aldosterone
secretion.
Method
Twenty-three hypertensive patients, aged 14-59
years, were studied. All had been off anti-hypertensive medication for at least 3 weeks before the
study and were maintained on a constant salt intake
of 87 mequiv./day. The diagnostic work-up included
measurement of plasma and urine electrolytes,
blood urea nitrogen concentration, creatinine
clearance, screening for phaeochromocytoma, rapidsequence intravenous pyelogram and renal
arteriography .
Renin activity and aldosterone were measured by
radioimmunoassay in plasma obtained with the
patient upright for the initial classification and
supine, immediately before and 4-6 h after administration of the inhibitor SQ 20881. Blood
pressures were monitored at 2 or 5 min intervals
with an automatic blood pressure recorder (Arteriosonde 1216, Roche).
The nonapaptide was diluted in 5 % dextrose to
12.5 mg/ml and slowly injected into the antecubital
vein over a period of 5 min at increasing doses of
0.25, 0.5, 1 .O 2.0 and 4 mg/kg. It was readministered
only after the blood pressure had returned to control
values or had remained unchanged for a period of at
least 2 h.
In six patients who showed only partial response,
sodium depletion was then induced by low sodium
diet (10 mequiv./day) for 48 h and the administration
Key words : angiotensin, converting enzyme, hypertension, inhibitor.
Introduction
Recently, a nonapeptide inhibitor of the enzyme
converting angiotensin I into angiotensin I1 was
discovered (Ondetti, Williams, Sabo, Flusced,
Weaver & Kocy, 1971) and synthesized (SQ 20881,
(I)
Present address: HBpital Cantonal Universitaire,
Department de MCdecine, 101 1 Lausanne, Switzerland.
Correspondence: Dr H. Gavras, Columbia-Presbyterian
Medical Center, 630 West 168th Street, New York, N.Y.
10032, U.S.A.
51s
Diagnosis
Renovascular
Hypertension
Essential
hypertension
Malignant
hypertension
Scleroderma
Hypertension,
chronic renal
failure
Primary or
idiopathic
hyperaldosteronism
Control
Inhibitor
Total sodium loss
on diuretics and
low salt diet
(mequiv.)
180/125
160/100
135/95
125/85
I20/85
5
6
7
8
12
13
14
10
II
9
38 F
47 F
40 F
56 M
50
14.1
49.9
40
12.1
Control
26
4.4
13.8
35
2.3
Inhibitor
Plasma aldosterone
(ng/100 ml)
41
Control Inhibitor"'
11
17
21
8
44
113
49
25
33
18
6.5
74
5.2
4.5
3.9
11
5.8
1.8
330
41
173
29
19
10
19
2.8
55
-
284
77
125
25
5.3
16
8.4
3.0
1.7
16
2.1
51
2.0
7.3
0.19
I .7
0.3I
056
3.5
1.7
4.2
0.17
0.32
0.56
0.81
6.6
Supine plasma renin
activity (ng h-' rnl-l)
TABLE
1. Collectioe data of conoerting enzyme inhibition on twenty-three patients with hypertension of various origins
Creatinine
clearance
(ml/min)
- 303
210/130
180/130
185/135
Blood pressure
(after sodium depletion) (mmHg)
Renin
classification"'
130/80
135/85
140/90
120/85
125/88
170/120
1451100
- 112
- 120
-135
Blood pressure
(normal salt intake)
(mmHg)
Age,
sex
165/115
180/120
180/118
170/105
175/120
1951155
1951130
170/108
165/115
145/100
l85/lOO
140/100
125/90
High
Normal
High
Normal
15
185/115
Inhibitor
Patient
no.
99
106
65
108
91
110
1 I5
2001122
180/130
180/135
185/lOO
185/140
190/135
Normal
1 87/I 20
1SO/130
160/100
145/90
165/105
l55/85
Control
1
High
High
High
High
Normal
High
High
107
66
56
104
-224
- 174
2
3
4
25 F
37 F
40 F
40 M
25 F
19 F
45 M
Normal
High
High
Normal
91
63
25
32 M
37 F
46 M'3'
50 M
35 F
54 M
Normal
High
16
17
15
M
18
95
Based on nomogram relating upright renin activity to concomitant urinary sodium excretion rate.
During administration of SQ 20881 converting-enzyme inhibitor.
Negro patients; other patients were Caucasians.
Low
Low
Low
Low
38
40
15
20
97
64
45 FC3'
40 F
47 F
59 F
54 F
l85/l10
205/145
225/145
230/150
230/165
180/120
160/I00
160/110
190/110
155/85
190/115
160/115
190/122
160/105
135/90
170/105
150/85
19
20
21
22
23
('I
(')
(3)
Converting enzyme inhibition in hypertension
of a diuretic. Urinary sodium excretion was measured
daily and cumulative losses were calculated. Subsequently, a single dose (2 or 4 mglkg) of the nonapeptide was injected. This latter dose was always
equivalent to the highest dose administered before
sodium depletion.
Results
Blood pressure
In sixteen of the twenty-three patients, inhibition of
converting enzyme induced a reduction in blood
pressure (see Table 1). Blood pressure fall started
within minutes after administration of the inhibitor
intravenously and was complete within 1-2 h.
Maximal blood pressure reduction was always
achieved with a dose of 1 mg/kg and further increase up to 4 mg/kg only prolonged the duration of
the blood pressure response.
In all seven patients with renovascular hypertension converting-enzyme inhibition induced a
substantial fall in blood pressure from a mean of
180/123 ( f 4/6) to 137/92 ( & 6/5) mmHg (mean f SE)
(P<O.oOl).
The four patients with malignant hypertension all
exhibited striking blood pressure reductions from
222/151 ( + 6 / 5 ) to 172/107 ( + 7 / 5 ) mmHg (P<0.05).
Three patients with essential hypertension responded partially to the drug with a decrease from
186/121 ( + 5 / 7 ) to 166/105 ( f 8 / 4 ) mmHg.
Of the three patients with chronic renal failure and
hypertension, only one exhibited some reduction
from 180/130 to 1601115 mmHg. None of the
patients with idiopathic aldosteronism showed a
blood pressure response.
Potentiation of the anti-hypertensive response to
converting enzyme blockade by sodium depletion
Six patients were studied twice, first while on a
regular sodium intake and again during sodium
depletion. Administration of the inhibitor (2-4
mglkg) initially produced a mean fall in blood pressure to only 161/107 (&6/4) mmHg. Subsequent
sodium depletion resulted in a negative sodium
balance of 178.6 2 35.4 mequiv. of Na .Despite this,
blood pressure did not change significantly (from
198/135 + 7 / 4 to 188/133 f 5/2). However, readministration of the inhibitor at exactly the same dose
as before now produced a significantly greater fall in
+
59s
blood pressure, to a mean value of 134/93 ( &6/3)
mmHg.
Eflect of drug on plasma renin activity and plusina
aldosterone
Out of nineteen patients studied, plasma renin
activity values were increased by the drug in sixteen.
In two patients with pseudoprimary aldosteronism
renin activities fell and in one they remained
unaltered. In contrast, plasma aldosterone concentrations, which were measured in eight patients,
were found to be reduced in all but the two patients
with idiopathic aldosteronism, in whom they were
increased (Table 1).
Discussion
The present study indicates that blockade of angiotensin I-converting enzyme had a potent antihypertensive effect in sixteen of twenty-three hypertensive patients. This effect was noticed mainly in
renovascular, essential and malignant hypertension
and that due to generalized scleroderma with kidney
involvement. Little or no response was seen in
hypertension associated with chronic renal failure.
No response at all was recorded in primary or idiopathic hyperaldosteronism. This blood pressurelowering effect of the blocking agent is in close
agreement with earlier findings in animals and man
with use of a competitive inhibitor of angiotensin 11
(Gavras, Brunner, Vaughan & Laragh, 1973 ;
Brunner, Gavras, Laragh & Keenan, 1973), the
main difference being that the latter was only
effective in patients with high renin activities whereas
in the present study five out of eight patients with
normal renin had also a significant response. None
of the low-renin-activity patients showed any
response. Plasma renin activity increased during
converting enzyme blockade in all but three patients
with pseudoprimary aldosteronism. In contrast,
plasma aldosterone concentration decreased in all
but two patients with idiopathic aldosteronism
and one patient with essential hypzrtension. In six
patients with a partial response of blood pressure,
readministration of the inhibitor after sodium
depletion (which in itself did not affect blood pressure, perhaps because of compensatory renin release)
produced a significantly greater response. Thus a
relatively small change in total body sodium was
associated with a marked increase in the anti-
60s
H . Gavras et 01.
hypertensive effectiveness. It appears therefore that
in patients in whom both volume and vasoconstrictor factors are operative in sustaining the
hypertension (Laragh, 1973), elimination of one
factor may not be sufficient.
In this context the converting-enzyme blockade
can be a guide for the choice of more specific drug
therapy (renin suppressing, or salt-eliminating or a
combination thereof). Its prolonged action, ease of
administration and lack of toxicity make it suitable
for treating hypertensive emergencies in which a high
renin activity is expected. I t can also be useful for
evaluating surgical curability of renovascular hypertension since the nonapeptide-induced blood pressure response may be able to predict the fall expected with successful vascular repair. Indeed one
patient whose blood pressure was returned to
normal by the drug was subsequently cured by renal
artery repair.
In conclusion, these studies indicate that con-
verting-enzyme inhibition can provide diagnostic
and therapeutic information for a given hypertensive
state and can be valuable for safely and efficiently
treating certain hypertensive emergencies.
References
ONDETTI,
A.M., WILLIAMS, N.J., SAHO.E.F., FLUSCED,
J..
WEAVER,E.R. & KOCY, 0. (1971) Angiotensin-converting
enzyme inhibitor from the venom of Borthrops joracoca.
Isolation, elucidation o f structure and synthesis. Biochemistry, 10, 4033-4039.
CAVKAS,
H . , BRUNNER,
H.R., VAUCHAN.E.D., J R & L A R A G H ,
J.H. (1973) Angiotensin-sodium
interaction i n blood
pressure maintenance o f renal hypertensive and normotensive rats. Science, 180, 1369-1372.
B R U N N E R H.R..
,
GAVRAS.
H.. L A R A G HJ.H.
,
& KEENAN,R.
(1973) Angiotensin 11 blockade in man by Sarl-Alasangiotensin 11 for understanding and treatment of high
blood pressure. Lanwt, ii, 1045-1048.
LARAGH,
J.H. (1973) Vasoconstriction-volume analysis for
understanding and treating hypertension: the use o f renin
and aldosterone profiles. American Joilrtial of Medicine,
55, 26 1-274.