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, S 9490, and MK421 decreased, in a dose-dependent manner, the pressor response to angiotensin I. The rabbit and the rat were the most sensitive species, with ID50 values, respectively, of 2.7 +/- 0.4 and 5.9 +/- 0.3 micrograms/kg i.v. for S 9490 and 1.2 +/- 0.2 and 2.6 +/- 0.8 micrograms/kg i.v. for S 9780. S 9490 induced a dose-dependent decrease in serum ACE activity in rabbits (0.6-20 micrograms/kg i.v.) and guinea pigs (10-100 micrograms/kg i.v.). In conscious rats and dogs S 9490 (0.03-1 mg/kg p.o.) 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 sodium restriction, but the cardiac output was markedly decreased. S 9490 (0.1-1 mg/kg i.v.) decreased mean blood pressure both in sodium-restricted and sodium-repleted pentobarbital-anesthetized dogs. However, the lowering effect was more pronounced in sodium-restricted dogs. S 9490 (3 mg/kg p.o.) did not change mean blood pressure in conscious dogs maintained on normal-sodium diet but decreased mean blood pressure in conscious sodium-restricted dogs. Plasma renin activity (PRA) and plasma aldosterone concentration were strongly enhanced in conscious dogs maintained on low-sodium diet.(ABSTRACT TRUNCATED AT 250 WORDS)