Acta Med Scand 205: 207-212, 1979
The Influence of Sar' Alas Angiotensin I1 (Saralasin) on Plasma Aldosterone in Hypertensive Patients A. J. M . Donker, P. van Hoogdalem, J . J. Pratt and F. H. H. Leenen Froni the Depurtment clflnternul Medicine, Division qf Nephrology, the Centrtrl Isotope Luborutoq, Stute Univcwity. Groningen. und the Department of Cardiology, Medicul Fucnlty, University q f Utrecht, Utrecht, The Netherlunds
ABSTRACT. The effect of a 4-hour infusion of the angiotensin I1 analogue sar' ala" angiotensin I1 (saralasin) on plasma aldosterone concentration (PAC) was assessed in relation to plasma renin activity (PRA) in 12 patients, both on normal sodium intake and after marked sodium depletion. On normal sodium intake the response of PAC to saralasin was variable; following sodium depletion saralasin induced a marked decrease in PAC in 11 of 12 patients. The extent of the change in PAC induced by saralasin correlated closely with log PRA. The data indicate that saralasin is also a competitive antagonist of the effect of the endogenous renin-angiotensin system (RAS) on the adrenal cortex, with agonistic activity appearing at low levels of PRA. The effect of sodium depletion on PAC appears to be mediated to a major degree by the RAS. Key \i*ords: hypertension, plasma renin activity, plasma
aldosterone concentration, renin-angiotensin system, saralasin, sodium depletion. Acta Med Scand 205: 207. 1979.
Gradually, it has become apparent that angiotensin I I exerts many influences besides its pressor activity. For several of these there is still discussion about the extent to which the actions have (patho)physiological relevance or are solely pharmacological effects. Recently, more or less specific blockers of the renin-angiotensin system (RAS) have become available. Studies with these blockers have made it obvious that the RAS plays a major role in the maintenance of blood pressure (BP) in both normo- and hypertensive individuals, especially during sodium restriction and ambulation (9, 10, 13, 21). The role of the RAS in the regulation of aldosterone secretion is also becoming clearer. Several animal studies showed that angiotensin I 1 blockade by the competitive angiotensin I1
antagonist sar' alaH angiotensin I1 (saralasin) induces marked decreases in aldosterone secretion stimulated by e.g. aortic or thoracic caval constriction, or by sodium depletion (8, 12, 18, 19). Studies on the influence of saralasin or a converting enzyme inhibitor indicate a role of the RAS in the increase in plasma aldosterone concentration (PAC) during sodium restriction in normotensive men (14, 17). As yet, the effect of angiotensin I1 blockade on PAC of hypertensive patients before and after sodium depletion has not been evaluated. This was the purpose of the present study. In view of the half-life of plasma aldosterone (about 20-30 min) (3), saralasin was infused for 4 hours in order to assess fully the role of the RAS in the maintenance of a given PAC. PATIENTS AND METHODS The present results were obtained as part of a larger study on the effects of saralasin on BP and renal function in hypertensive patients. The details of this study have been outlined previously (10). Combined data on plasma renin activity (PRA) and PAC were obtained in 12 patients: 5 with unilateral and 3 with bilateral renal artery stenosis and 4 with essential hypertension. Hypertension was characterized by standard procedures, including aortography and selective renal angiography. The relevant patient data are summarized in Table I . All patients were studied twice. For the first study a normal sodium intake (100 mmol Na+ daily) for at least 7 days had been used. The second study was performed after sodium depletion by furosemide, 40 rng twice daily orally, and a daily dietary sodium intake of 20 rnrnol durAddress f o r reprint requests: A. J. M. Donker. State University Hospital, Department of Internal Medicine, Oostersingel 59, Groningen, The Netherlands. Abbreviations: RAS=renin-angiotensin system, PAC= plasma aldosterone concentration, PRA=plasrna renin activity, BP=blood pressure.
A . .I. M . Donker
Table 1. Individircil BP,supine PRA rind PAC in pritients ridhering to (I diet contciining 100 mmol sodium/ duy, and renal vein PRA rcitici Case no.
d d d
24 31 46
Diagnosis Atherosclerotic stenosis of the left renal artery Fibromuscular dysplasia of the right renal artery Fibromuscular dyspkdsia of the right renal artery Fibromuscular dysplasia of the right renal artery Fibromuscular dysplasia of the right renal artery Fibromuscular dysplasia of the right and left renal artery Atherosclerotic stenosis of the right and left renal artery Atherosclerotic stenosis of the right and left renal artery Essential hypertension Essential hypertension Essential hypertension Essential hypertension
ing three days. During each study the patient remained semisupine from 7 a.m. until 8 p.m. Saralasin (Eaton Laboratories, Norwich Benelux, Utrecht, The Netherlands), dissolved in 5 % glucose, was administered i.v. during 4 hours from noon until 4 p.m. On normal sodium intake, saralasin was started at 2 pg min-' kg-', the final dose of 10 pg being reached within 30 min. After sodium depletion the infusion was started at 0.2 pg min-' kg-' and the dose was increased until no further decrease in BP occurred (the final dose reached was 0.8 pg in one study, 2 pg in three studies, 4 pg in two and 10 pg in six), the maximal dose being reached within 60 min. PRA and PAC were estimated by rddioimmunoassay as described previously ( 7 , 16). Serum electrolytes were measured according to standard hospital procedures. Results are expressed as mean values 2S.E.M. Statisti-
PRA (ng A1 ml-' h-I)
1.7 0.7 6.7 1 .s 5
163 96 I74 91 406
cal analysis of the data was performed with Wilcoxon's test for paired comparison. Correlation coefficients were calculated by the method of least squares. Correlations with PRA were calculated using log PRA.
RESULTS Effects of sarulasin on normal sodium intuke
(Table 11, Fig. I ) Values of PRA and PAC, obtained at 8 a.m., noon and 8 p.m., did not differ significantly from each other. Infusion of saralasin during 4 hours resulted in a non-significant increase in PRA. This rise was
Table 11. Eifects of sodium depletion rind a 4-hour i . v . injusion lfrorn noon
4 p . m . ) o f s(irrilasiri on
rind serum e1cctroIyte.s (meun If: S . E . M . )
Normal sodium intake
PRA (ng A1 ml-' h-I) PAC (pglml) Serum Na+ (mmol/l) Serum K + (mmol/l)
After sodium depletion
l 4 3 i 1.82
Angiotensin II blockade and plusma aldosterone
ng A 1 ml-’hr-’
Fig. I . PRA and plasma aldosterone at 8 a.m., noon, 4 p.m. and 8 p.m. in patients with unilateral ( 0 )or bilateral (A) renovascular hypertension, or essential hypertension ( 0 ) . Saralasin was infused from 12 to 4 p m .
Effects of sodium depletion (Table 11, Fig. 2) Cumulative negative sodium and potassium balances amounted to 286518 and 319+23 mmol K’ (n=7); body weight decreased by 2.5k0.3 kg. Serum sodium and potassium decreased significantly @