INHIBITION OF ANGIOTENSIN I-CONVERTING ENZYME WITH S-9490-BIOCHEMICAL EFFECTS, INTERSPECIES DIFFERENCES, AND ROLE OF SODIUM DIET IN HEMODYNAMIC-EFFECTS

Abstract

S 9780, the diacid form of S 9490, inhibited guinea pig plasma angiotensin-converting enzyme (ACE) by 50% (IC50) at a concentration of 2.4 .+-. 0.1 nM. A Ki of 1.2 nM was obtained for S 9780 (Dixon-Webb plot) with angiotensin I as a substrate. In rabbits, rats, cats, guinea pigs and dogs, S 9780, MK 422 [enalaprilat], S 9490 and MK421 [enalapril] decreased, in a dose-dependent manner, the pressor response to angiotensin I. The rabbit and the rat were the most sensitive species, with ID50 [median inhibitory dose] values, respectively, of 2.7 .+-. 0.4 and 5.9 .+-. 0.3 .mu.g/kg i.v. for S 9490 and 1.2 .+-. 0.2 and 2.6 .+-. 0.8 .mu.g/kg i.v. for S 9780. S 9490 induced a dose-dependent decrease in serum ACE activity in rabbits (0.6-20 .mu.g/kg i.v.) and guinea pigs (10-100 .mu.g/kg i.v.). In conscious rats and dogs S 9490 (0.03-1 mg/kg p.o. [orally]) induced a long-lasting inhibition of the angiotensin I-induced pressor response; 40% inhibition was recorded in dogs, 24 h after 1 mg/kg p.o. S 9490 (0.03-0.1 mg/kg i.v.) potentiated the increase in femoral blood flow induced by bradykinin injected into the femoral artery of dogs. In anesthetized dogs, mean blood pressure and heart rate were not changed after Na+ restriction, but the cardiac output was markedly decreased. S 9490 (0.1-1 mg/kg i.v.) decreased mean blood pressure both in Na+-restricted and Na+ repleted pentobarbital-anesthetized dogs. The lowering effect was more pronounced in Na+-restricted dogs. S 9490 (3 mg/kg p.o.) did not change mean blood pressure in conscious dogs maintained on normal Na diet but decreased mean blood pressure in conscious Na+-restricted dogs. Plasma renin activity (PRA) and plasma aldosterone concentration were strongly enhanced in conscious dogs maintained on low-Na+ diet. S 9490 (3 mg/kg p.o.) induced a further increase in PRA associated with a decrease in plasma aldosterone concentration. The degree and duration of ACE inhibition appear to exceed those obtained with MK 421 and MK 422.