PHARMACOLOGICAL STUDY OF SR 47436, A NONPEPTIDE ANGIOTENSIN-II AT1-RECEPTOR ANTAGONIST, IN CONSCIOUS MONKEYS

Objective: The hypotensive and hormonal responses of an AT1-subtype an giotensin II receptor antagonist, SR47436, were investigated and compa red with those of DuP753 (losartan), the leading AT1-receptor antagoni st, and captopril and enalapril, two major angiotensin converting enzy me (ACE) inhibitors, in conscious, sodium-replete and sodium-depleted non-human primates. Design and method: Blood pressure and heart rate w ere measured in conscious, chronically instrumented sodium-replete (n= 3-5) and sodium-depleted (n=4) cynomolgus monkeys (Macaca fascicularis ). Plasma renin activity (PRA), active renin and angiotensin II plasma concentrations were determined. Results: SR47436 induced a dose- and time-related fall in blood pressure in sodium-depleted monkeys; the bl ood pressure-lowering effect was obtained at a range of doses from one -third to one-tenth the equihypotensive dose of DuP 753 after intraven ous and oral administrations. The hypotensive effect obtained with SR4 7436 was similar to that of captopril and was sustained in sodium-repl ete monkeys, although it was weaker and less long-lasting than that of enalaprilat. In both sodium-depleted and sodium-replete monkeys the A T1 antagonist and ACE inhibitors caused similar increases in PRA and a ctive renin. However, although angiotensin II levels increased after S R47436 or DuP753 treatment, they decreased after treatment with enalap rilat. Modest decreases in the heart rate sometimes accompanied the hy potension, irrespective of the compound tested. Conclusion: These data demonstrate that the AT1 antagonist SR47436 is an effective hypotensi ve agent in both sodium-replete and sodium-depleted monkeys, with an i ntrinsic potency three to 10 times that. of DuP 753 and similar to tha t of ACE inhibitors.