angiotensin blockade: its clinical significance

Angiotensin Blockade: Its Clinical Significance

DAVID H. P. STREETEN, MB., D.Phil.,

GUNNAR H. ANDERSON, Jr., M.D.

THEODORE G. DALAKOS, M.D.

Syracuse, New York

From the Section of Endocrinology, State Uni- versity of New York, Upstate Medical Center, Syracuse, New York. This study was supported by a Graduate Training Grant in Endocrinology (AM 07146) from the National Institute of Arthritis, Metabolism and Digestive Diseases, a Clinical Research Center Grant, (RR-00229) from the Di- vision of Research Facilities and Resources; a grant from the Central New York Regional Medical Program and a grant from Eaton Laboratories, Norwich, New York. Requests for reprints should be addressed to Dr. David H. P. Streeten, State University of New York Upstate Medical Center, 766 Irving Avenue, Syracuse, New York 13210.

An understanding of the possible role of excessive angiotensin II activity in the pathogenesis of hypertension in every patient is therapeutically desirable, but it is frustrated by the lack of complete reliability of peripheral plasma measurements of renin activity. Observation of a clear-cut, supranormal decrease in btood pressure during the intravenous infusion of the angiotensin II antagonist, saralasin, has provided a far more reliable indication of the presence of an angiotensinogenic component in the hypertension. There is convincing evidence, however, that the presence of sodium-overload may prevent a decrease in blood pressure during saralasln infusion in persons known to have angiotensinogenic hypertension and that saralasin may cause a slight decrease in the blood pressure of normal subjects after natriuresis. For these reasons, it is important to study hypotensive responses to saralasin under standardized conditions after the admlnistration of a potent diuretic and to com- pare the observations with those made on normal subjects under identical circumstances. This angiotensin antagonist may be used in the therapy of malignant or advanced hypertension and as an aid to therapeutic decisions in hypertensive patients who have known renal diseases, are taking oral contraceptives or have had severe trauma to the area of the kidneys. Side effects of saralasin are limited to excessive fails in blood pressure levels, mainly when vasodilators or ganglioplegic drugs are being taken at the time of the saralasin infusion, and excessive rises in blood pressure levels, especially in hypertensive subjects with “low renin” activity during high rates of saralasin infusion or after intravenous injections of large boluses. This safe and reliable drug is a valuable tool in the inves- tigation and therapy of hypertension.

The classic investigations of Goldblatt et al. [l] led physicians to look

for the clinical counterpart of the dog with a clip on one renal artery and to show that surgical correction of unilateral renal arterial stenosis by arterial bypass or unilateral nephrectomy would sometimes dra- matically reduce or “cure” hypertension [2,3].

These findings and improvements in the safety and ease of arteriography have stimulated the widespread use of selective renal arte- riograms for the detection of potentially curable hypertension resulting

from renal arterial stenosis. However, routine surgical correction of such lesions before measurements of renal vein renin levels were available, reduced the hypertension in a disappointingly low per- centage of cases [4]. In a more recent series of 46 consecutive hypertensive patients who had arteriographically obvious renal arterial stenosis, we found that the renal vein plasma renin activity ratio was below 1.5 in 26 patients, and concluded from the observations of others [5-81 that excessive renin release was probably not respon-

May 31, 1976 The American Journal of Medicine Volume 60 617

ANGIOTENSIN BLOCKADE: ITS CLINICAL SIGNIFICANCE-STREETEN ET AL.

sible for the hypertension in these 26 patients (i.e., 56 per cent of the patients) (Streeten et al., unpublished).

The introduction of relatively simple and reliable methods of measuring plasma renin activity by bioassay [9, lo] and radioimmunoassay [ 11,121 stimulated the widespread use of these determinations in patients with hypertension. Several investigators employed such measurements to classify the condition in patients into “high renin,” “ normal renin” and “low renin” types of hypertension [ 131. However, the implied relationship between “high renin” levels and the pathogenesis of the hypertension was frequently found not to be valid. Thus, many patients whose hypertension was associated not only with renal arterial stenosis, but also with elevated renal vein renin ratios (greater than 1.5) and a subsequent cure of the hypertension by renal or renovascular surgery, had normal levels of plasma renin in their peripheral blood [7,8].

In 15 patients studied by us, peripheral plasma renin activity levels were normal in 40 per cent, yet elevated renal vein plasma renin activity ratios correctly pre- dicted surgical “cure” of renovascular hypertension in all 15 patients. On the other hand, it is clear that raised levels of plasma renin activity in the peripheral blood may be found in many normotensive subjects (such as most patients with cirrhosis and ascites, with the ne- phrotic syndrome, or with ingestion of estrogen-progestogen combinations for contraceptive purposes).

For these reasons, it became evident that in order to attribute hypertension to excessive angiotensin activity, it was necessary to show (1) some evidence that renin production or circulating angiotensin levels are excessive as reflected by elevated plasma angiotensin II or plasma renin activity in peripheral blood and/or renal vein plasma renin activity ratios above 1.5; and (2) that blood pressure would be reduced to the normal range by preventing or overcoming excessive angiotensin activity via (a) renal or renovascular surgery, (b) drug inhibition of renin release, (c) inhibition of the conver- sion of angiotensin I to angiotensin II or (d) blocking the action of the circulating angiotensin II with a specific antagonist. Use of Drugs to Inhibit the Renin-Angiotensin System. As implied, drugs acting at three different sites have been employed to reduce the activity of angiotensin II at its arteriolar receptors. The first of these sites is the juxtaglomerular apparatus where renin release may be reduced by drugs which block sympathetic beta-activity. Propranolol is a potent agent of this type [ 171, but plasma renin activity may frequently also be reduced by the administration of clonidine, reserpine, methyl- dopa and ganglionic blocking drugs [ 131. A second site of inhibition of angiotensin II production is the enzyme responsible for converting the decapeptide angiotensin

I to the octapeptide, angiotensin II. Angiotensin converting enzyme can be antagonized by a group of components originally isolated from the venom of Bothrops jararaca, of which the most active is a nonapeptide, B.P.P.9, or SQ 20,881 [18]. This substance was found to reduce the pressor action of injected angiotensin I tenfold, without having any effect on the pressor action of angiotensin II in human subjects [ 191, and to be an effective hypotensive agent in patients with “high renin” hypertension [20]. The third site at which the activity of angiotensin II may be reduced is at the angiotensin II receptors where the action of angiotensin II may be competitively antagonized by angiotensin II analogues, of which saralasin (1-sar-8-ala-angiotensin II or P-l 13) appears to be the most promising [21]. Pharmacologic Actions of Saralasin. Saralasin has been shown consistently to block the actions of angiotensin II on the function of a variety of tissues in vitro, including the angiotensin II induced contractions of rabbit aortic strips [21-231, the positive inotropic action on rabbit atria [24] and the aldosterone release from isolated adrenal glomerulosa cells [23]. That these effects of saralasin result from specific antagonism of angiotensin II is indicated by failure of saralasin to block the effects of norepinephrine or serotonin on the aorta [21] or of tyramine on rabbit atria [24] or of ACTH on adrenal glomerulosa cells [23].

In vivo, saralasin has been shown invariably to block the pressor actions of infused angiotensin II both in animals [21,25-271 and in man [ 151. The experimental hypertension of the recent and long-term two-kidney Goldblatt types was reversed by saralasin [25,27-291, but one-kidney Goldblatt hypertension (renal artery constriction with contralateral nephrectomy) was not affected by the angiotensin antagonist [25] unless the rats were subjected to sodium restriction for four weeks [30]. Saralasin has had no effect on the blood pressure elevations seen in spontaneously hypertensive rats [21] or in animals made hypertensive by the administration of norepinephrine [21,25], tyramine, vasopressin, phenylephrine or deoxycorticosterone [21]. In man, too, the increase in blood pressure resulting from norepinephrine infusion [ 151 and from hyperaldosteronism [31] is not reduced by the administration of saralasin. Thus, there is a large body of experimental evidence to show that saralasin will reduce elevated blood pressure levels only when, and to the extent that, the elevation results from the effects of angiotensin II. It is reasonable to conclude therefore, that when hypertension is cor- rected by the infusion of saralasin, the hypertension must have been caused by angiotensin excess or angiotensinogenic. Effects of Sodium on Responses to Saralesin. Gavras et al. [30,32] investigated the possibility that the hy-

616 May 31, 1976 The American Journal of Medicine Volume 60


Figure 1. Automatic blood pressure measurements showing the hypotensive effect of an infusion of saralasin when this was pmceded by an intravenous injection of tiosemkje, 40 mg, 3 hours before, and prevention of this effect by intravenous infusion of 500 ml 0.9 per cent sodium chloride.

potensive efficacy of saralasin in recently induced “two-kidney” Goldblatt hypertension and its lack of effectiveness in the more long-standing “two-kidney” and the “one-kidney” models might have resulted from the high total body sodium content of the unresponsive rats, which had previously been demonstrated to exist in “one-kidney” Gcldblatt hypertension [33]. By vig- orously reducing sodium intake for four weeks and by diuretic therapy, Gavras et al. failed to overcome the hypertension of “two-kidney” and of “one-kidney” Goldblatt rats but succeeded in converting the hypertension to a saralasin-responsive form from its previous unresponsiveness to saralasin.

This experimental evidence has been confirmed in observations on normal subjects and in patients with hypertension. When saralasin was administered by intravenous infusion to a group of healthy volunteer subjects on their customary diets, there was no significant change in blood pressure. After intake of a 10 meq sodium diet for three days the subjects experienced a slight but significant decrease in mean blood pressure, i.e., diastolic i- one-third pulse pressure (mean level falling from 83.1 f 3.4 to 74.95 f 1.8 mm Hg), whereas after ingestir,, a high sodium diet (regular diet + 102 meq added sodium chloride/day) for four days, they showed a slight increase in blood pressure (mean increase from 82.3 f 3.1 to 88.4 f 4.5 mm Hg, p <0.05) during intravenous infusions of saralasin at a rate of 10 wg/kg/min.

Similarly, in patients with renovascular hypertension associated with elevated levels of plasma renin activity, the hypotensive effect of saralasin infusion is often blunted or completely prevented by salt overload. Figure 1 shows the blood pressure record obtained in a hypertensive patient who had high levels of peripheral plasma renin activity. The blood pressure level fell from a mean of 148192 to 118/70 mm Hg during saralasin infusion administered 3 hours after an intravenous in-

1500 1600 1700 I800

TIME

jection of furosemide, 40 mg. When the infusion was repeated a few hours later, after the intravenous administration of 500 ml 0.9 per cent sodium chloride solution, the previous response to saralasin was abol- ished.

It is known that in states of extreme sodium depletion normal blood pressures may be maintained by, and be dependent upon, hyperactivity of the renin-angiotensin system, so that severe hypotension will result from saralasin administration [34]. It is not known whether or not a similar phenomenon might occur in hypertensive patients whose elevated blood pressure level, previously maintained by neurogenic or volume factors, would become dependent upon hyperangiotensinemia after diuresis and who would then experience a fall in blood pressure levels to or below normal during saralasin infusion. In the absence of the concomitant administration of other drugs, saralasin has never been recognized to have this effect in our experience of its infusion into several hundred patients. In hypertensive patients with pitting edema due to congestive heart failure or renal insufficiency, it is probably necessary to overcome the excessive sodium and water accu- mulation completely by the administration of diuretics before the absence of a hypotensive response to saralasin can be taken to exclude a possible role of angiotensin in the pathogenesis of the hypertension. Blood Pressure Responses to the Infusion of Saralasin in Hypertensive Patients. In an unselected group of 300 patients with hypertension, an intravenous injection of furosemide was given at 8 A.M., followed by leisurely ambulation from 9 to 11 A.M., measurement of peripheral plasma renin activity at 11 A.M., and intravenous infusion of saralasin, usually at rates of 0.05, 0.5 and 5.0 pg/kg/min, each for 15 minutes in recumbency, starting at about 1 I:30 A.M. In 26 normal subjects treated identically, blood pressure levels never fell by more than 1018 mm Hg during the infusion of saralasin.

May 31, 1976 The American Journal of Medicine Volume 60 619

ANGIOTENSIN BLOCKADE: ITS CLINICAL SIGNIFICANCE-STREETEN

High PRA 0

Normal PRA Low PRA

50 4

1

0 Estrogen Therapy q

Saralasin

Response :

Fall in B.P. 0

No Fall in 9.P. .

n= 54 n=l49 n= 97 ( I8 %/.) (50%) ( 3 2 % )

Figure 2. Measurements of plasma renin activity (PRA) in blood from a peripheral vein ati& the administration of furosemide (40 mg given intravenously 3 hours before) and standing for 2 hours in 300 patients with hypertension. It is ev&nt that only 23 of 54 patients with elevated plasma renin activity levels experienced a fall in blood pressure levels of trwre than lo/8 mm Hg during sat-a&sin infusion and that four “saralasin responders” had normal plasma renin acti\iity levels. Five patients who were receiving estrogen-progestogen combinations for contraceptive purposes had increased plasma renin activity concentratrbns but were unresponsive to saralasin.

Among the 300 hypertensive patients, (a) the blood pressure level fel,l by more than IO/8 mm Hg in 31 patients, all of whom were found to have elevated peripheral plasma renin levels and/or renal vein plasma renin activity ratios greater than 1.5, as had been found in previous studies [ 15,161. Independent collateral evidence of renal or renovascular disease was subse- quently obtained in most of these patients (20 of the 31) by intravenous pyelography, isotopic renal flow studies or renal arteriography. In these 31 patients whose responses to saralasin indicated that their hypertension was, at least partly, angiotensinogenic, the following renal lesions were finally recognized [35]: (1) 11 patients (36 per cent) had unilateral renal arterial stenosis; (2) three patients (10 per cent) had unilateral renal arterial stenosis together with renal insufficiency (azo- temia and creatinine clearance below 40 ml/min); (3) three patients (10 per cent) had bilateral renal arterial stenosis: (4) three patients (10 per cent) had bilateral renal parenchymal disease; and (5) 11 patients (36 per cent) had no renal abnormality (apart from the renin measurements) detectable by the studies performed. Renal arterial bypass surgery or nephrectomy was performed in seven of the 11 patients with uncompli- cated, unilateral renal arterial stenosis (in all of whom this diagnosis had been suspected prior to the saralasin

AL.

infusion). More than eight months after the surgery, the diastolic blood pressure level was normal (below 90 mm Hg) in six, and had fallen to 100 mm Hg in the seventh patient, without drug therapy. (b) Blood pressure levels neither rose nor fell by more than 10/8 mm Hg in 149 of the 300 patients, most of whom were classified as having “normal renin” essential hypertension. (c) In 97 of the 300 patients, saralasin administration induced a rise in blood pressure levels of >10/8 mm Hg. This agonistic response to the angiotensin analogue was commonly, but not exclusively, seen in patients with “low renin hypertension.”

Measurements of peripheral plasma renin activity in this group of hypertensive patients are shown in Figure 2. It is evident that plasma renin activity was below normal limits under the conditions of study in 97 patients (32 per cent), was normal in 149 patients (50 per cent) and was increased in 54 patients (18 per cent). These percentages are similar to those reported by Laragh et al. [ 131 from observations made under somewhat different conditions.

It is evident that only half of the patients with high levels of plasma renin activity showed a fall in blood pressure levels during saralasin infusion. In several of these “high renin” nonresponders to saralasin, measurements of renal vein plasma renin activity ratios, isotopic renal flow studies and renal arteriography were undertaken. In only one of them did the nonresponse to saralasin appear to constitute a false negative result in that fibromuscular dysplasia of one renal artery was present, together with an increased renal vein plasma renin activity ratio. In this patient the blood pressure level had fallen to normal after the furosemide injection and before the saralasin infusion. Thus, it seems reasonable to conclude that a hypotensive response to saralasin correctly indicates the presence of angiotensinogenic hypertension and that lack of a hypotensive response reliably excludes this type of hypertension, as long as the blood pressure level is elevated when the saralasin is administered and as long as salt overload has been eliminated. Use of Saralasin Bolus as a Screening Procedure for Hypertensive Subjects. It would clearly be difficult for physicians to use infusions of saralasin as a method of screening for angiotensinogenic hypertension in their daily office practices. The attractive possibility of using injections of a bolus of saralasin (10 mg) has, therefore, been proposed as a more practicable off ice procedure [36]. Marks et al. showed that 11 patients with renovascular stenosis and two with “high renin” essential hypertension experienced a striking fall in blood pressure levels for up to half an hour after an intravenous injection of 10 mg saralasin, preceded by the administration of an oral diuretic (furosemide) at 5 P.M. the day


240 I” 1

SARALASIN SARALASIN

2 mg I.V 2 mg I.V.

E 0 0 - t 200-

:

2 v) 160-

: a

D 120-

8

I

I

TIME (hours)

1

2

F&w-e 3. Blood pressure recordings to show (lefl) the fall in blood pressure after intravenous injections of saralasin (2 mg) in a patient with high peripheral blood levels of plasma renin activity and (rtght) an increase in blood pressure in a patient with low renin hypertension.

before. In contrast, eight patients with essential hypertension associated with normal or low plasma renin activity experienced no fall in blood pressure levels after the saralasin injection. Both the responders and the nonresponders showed a transient increase in blood pressure for 4 to 6 minutes to values which never ex- ceeded 230/130 mm Hg. We have had similar experi- ences in injecting 2 mg or 10 mg boluses of saralasin in hypertensive patients, and have confirmed the findings of Marks et al. [36] (Figure 3, left). Two aspects of this procedure are unattractive in our opinion, however, and led us to warn against the use of injections of large boluses of the drug despite the striking responses to saralasin injections in some patients [ 141. The first is that, although the increase in blood pressure in small groups of carefully selected patients may not be for- bidding, one occasionally encounters more striking increases in blood pressure, even with the 2 mg dose of saralasin, which we believe are dangerous and will, sooner or later, result in a vascular catastrophe. One such response, with an increase in blood pressure to 210/160 mm Hg, is shown in Figure 3, right. This was an agonistic response to saralasin, seen, as is usually the case, in a “low renin” hypertensive subject. Since low renin hypertensive subjects constitute approxi- mately 30 per cent of the hypertensive population, the likelihood of observing these severe agonistic responses will be greater if unselected hypertensive subjects are studied than in the small group studied by Marks et al. [36], which included only three patients with low plasma renin activity. Secondly, it has been our experience that when large groups of hypertensive

w

2

~-_-~~~

0.9 % NoCl Soralasin

:

80 - Iml I.V. 2 mg I.V.

A m I

4Ot


01 12~00 12~15 12~30 l2:45 l3:OO l3:15

TIME

subjects are given saralasin, many show borderline responses which are even more difficult to interpret after injections than during infusions of saralasin which can be continued for longer than originally intended when responses are equivocal. Nonetheless, the con- cept of using saralasin injections as an outpatient screening procedure is still appealing if it can be done with safety. Other Clinical Uses of Saralasin in Hypertensive Pa- tients. In addition to its great value as a means of screening large groups of patients with high blood pressure for angiotensinogenic hypertension, saralasin has several other uses:

(1) In the treatment of malignant or advanced hypertension, saralasin is frequently effective, especially if its use is preceded or accompanied by the administration of a potent diuretic. Brunner et al. [37] reported that when given to seven patients with malignant or advanced hypertension, saralasin lowered blood pressure levels to close to normal in three patients whose peripheral plasma renin activity levels were elevated, and reduced the blood pressure levels slightly or not at all in the remaining four patients who had normal or low levels of plasma renin activity. A similar experience was reported by Streeten et al. [36] in four patients with malignant hypertension associated with high plasma renin activity. In this study, the blood pressure levels fell to normal and remained normal as long as saralasin was infused (for 20 hours in one pad tient) in two of the patients. The other two patients experienced a fall in blood pressure levels during saralasin

May 31,1978 The American Journal of Medicine Volume SO 821


infusion but a greater fall during nitroprusside infusions.

Thus, in the acute emergencies presented by patients

with diastolic blood pressures over 140 mm Hg and

papilledema, saralasin is often a useful drug which will

lower the blood pressure level rapidly without inducing

hypotension or other adverse consequences. However,

it is less reliable in these circumstances than intrave-

nous infusions of nitroprusside.

(2) In hypertensive patients with known renal dis-

ease, the blood pressure response to saralasin, after

natriuresis, is sometimes of great help in clinical

management. Thus, for example, one would be inclined

to recommend nephrectomy in a patient with a non-

functioning kidney on one side if the blood pressure

level came down to or close to normal during saralasin

therapy. In these circumstances, an abnormally in-

creased renal vein plasma renin activity ratio would usually provide additional evidence to support the

probable usefulness of nephrectomy, in the absence

of serious contraindications.

(3) In women who are found to be hypertensive while

taking oral contraceptive preparations of estrogen and

progestogen, it is useful to measure the blood pressure

response to saralasin infusion after natriuresis. Blood

pressure levels will sometimes return to normal as

peripheral plasma renin activity returns to the normal

range in such patients when the intake of the estro-

gen-progestogen combination is stopped 1391. In such

instances, the blood pressure level would be expected

to fall to normal during a saralasin infusion. However,

in many instances women are found to be hypertensive

while they are taking contraceptive pills, but not nec-

essarily because of the pills and not necessarily be-

cause of increased levels of plasma renin activity. In

such cases we have found no hypotensive response to

saralasin, and no improvement in the blood pressure

after stopping the oral contraceptive therapy.

(4) In occasional patients with severe hypertension

associated with emergency circumstances, such as

trauma to one or both kidneys or an enlarging mass (or

aneurysm) apparently impinging on one renal artery, a

good hypotensive response to saralasin infusion is

therapeutically valuable and also helpful in making the

difficult decision as to whether to recommend surgery

or not. We have also found in such patients that a good

response to saralasin usually indicates that propranolol,

in large doses, if necessary, will be useful in lowering

the blood pressure. Side Effects of Saralasin. During or after the admin-

istration of saralasin by intravenous infusion at rates up to 10 or 20 pg/kg/min to over 800 patients with hy-

pertension of all types, no serious toxic effects of any

kind have been observed. No adverse changes have

been found in urinalysis, electrocardiogram or mea-

surements of blood count, blood urea nitrogen or serum

concentrations of electrolytes, creatinine, glucose,

bilirubin, uric acid, glutamic-oxalic transaminase Or

lactic dehydrogenase [3 11. One patient had a nonfatal

myocardial infarct two days after the saralasin infusion,

and in another diabetes mellitus was discovered for the

first time, three weeks after the infusion, but we doubt

whether either of these untoward developments was

attributable to the saralasin.

The only potentially serious side-effects of saralasin

are related to its action on the blood pressure. In the

absence of other drug therapy (except for the ante-

cedent diuretic), saralasin has only reduced blood

pressure excessively in one of 800 hypertensive pa-

tients: in this patient the blood pressure level fell from

115190 to 74/63 mm Hg. However, saralasin may cause

serious hypotension if it is administered to hypertensive

subjects whose other mechanisms of maintenance of

blood pressure have been overpowered by concomitant

administration of drugs such as vasodilators and gan-

glioplegic agents [40,41]. In these circumstances, the

danger of its producing hypotension is identical with that

of any other potent hypotensive drug and its relative

safety vis-a-vis other drugs is lost. Similarly, saralasin

may reduce blood pressure to dangerously low levels

if and when it is given to persons who have pathologic

vasodilatation, low cardiac output or extreme hypovo-

lemia. Special care should be observed if it is given for

any reason to patients with cirrhosis and ascites, low-

output heart failure or severe dehydration. The agonistic hypertensive effect of saralasin may

also constitute an undesirable, potentially dangerous

action of the drug. This effect is seldom of any concern,

however, if the drug is administered by intravenous

infusion, after giving intravenous furosemide, and

starting with a very low rate of infusion such as 0.05 or

0.1 pg/kg/min. Under these circumstances, the basal

pressure is usually lowered by the furosemide and the

severity of the hypertensive response is milder than

when high blood concentrations of saralasin are induced

by starting with rapid rates of infusion or by the injection

of large boluses of the drug.

The experience with saralasin, to date, has shown,

therefore, that it is a highly specific antagonist of angiotensin II, with mild agonistic action in some cir-

cumstances. As a pharmacologic tool for the study of disease processes it has great potential. It is invaluable

as a means of recognizing, rapidly and reliably, the

presence of an angiotensinogenic component in the

hypertension of the individual patient and in removing this component therapeutically when this is desirable. As an aid to the understanding and management of the

822 May 31, 1978 The American Journal of Medfcine Volume 80


overwhelming problem of hypertension it appears to Research Center for their assistance in the clinical hold great promise. studies reported here.

ACKNOWLEDGMENT We also wish to acknowledge our indebtedness to

Terry Walsh, Marjorie Soears, Carol Jones and to We are glad to acknowledge our indebtedness to Mrs. Tom Scullard for technical assistance in the labora- Nancy Blakeman and the other nurses of the Clinical tory.

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angiotensin blockade: its clinical significance

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