Antihypertensive effects of CI-907 (indolapril): a novel nonsulfhydryl angiotensin converting enzyme inhibitor.
CI-907 is a new orally active nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor. Monoester (prodrug) and diacid forms produced concentration related ACE inhibition in guinea-pig serum (IC50 for monoester, 1.7 X 10(-7) M and for diacid, 2.6 X 10(-9) M). In isolated rabbit aortic rings and in rat and dog autonomic studies, CI-907 is highly specific in suppressing the contractile or pressor responses to angiotensin I. In two-kidney, one-clip Goldblatt hypertensive rats, single daily doses (0.03-30 mg/kg p.o.) produced dose-dependent decreases in blood pressure; 3 mg/kg lowered blood pressure to normotensive levels. In the spontaneously hypertensive rat, subacute administration of CI-907 (30 mg/kg/day for 5 days) produced the same decrease in blood pressure as that obtained in the renal hypertensive rat. In diuretic-pretreated renal hypertensive dogs, 10 mg/kg normalized blood pressure. For equivalent drops in blood pressure, heart rate increases were less in CI-907 than in enalapril-treated renal hypertensive dogs. No side effects were observed with CI-907 in any of the conscious animals. The antihypertensive response to CI-907 (0.03-1.0 mg/kg p.o.) was found to correlate with inhibition of vascular tissue ACE, but not plasma or brain ACE in two-kidney, one-clip renal hypertensive rats. These studies indicate that CI-907 is a potent antihypertensive agent with a heart rate profile different from enalapril.
D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004656:Enalapril; D006339:Heart Rate / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000188:drug therapy; D007211:Indoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004151:Dipeptides; D007211:Indoles; D004656:Enalapril; C038812:Indolapril