Antihypertensive mechanism of captopril in renal hypertensive rats: studies with a nonpeptide angiotensin II receptor antagonist and an angiotensin II monoclonal antibody

PC Wong, WA Price, TM Reilly, JV Duncia and PB Timmermans

Medical Products Department, E.I. du Pont de Nemours & Company, Inc., Wilmington, Delaware.

The validity of using EXP6803, a nonpeptide angiotensin II (AII) receptor antagonist, and KAA8, an AII monoclonal antibody, as specific tools for studying the physiology of AII has been established previously. In this study, we used these specific probes to examine the role of blocking AII formation in the antihypertensive effect of captopril in conscious renal artery-ligated rats (RALRs), a high renin, renal hypertensive model. Mean arterial pressure and plasma renin activity in a typical group of RALRs averaged 175 +/- 5 mm Hg and 28.2 +/- 6.2 ng of angiotensin 1 per ml/hr (n = 6), respectively. The antihypertensive effect of captopril (3 mg/kg i.v.) was determined in RALRs given either EXP6803 (30 mg/kg + 2 mg/kg/min i.v.) or KAA8 (10 mg + 1 mg/min i.v. per rat) with the corresponding vehicle-treated RALRs. These doses of EXP6803 and KAA8 were very effective in blocking the pressor response to AII but not to norepinephrine or vasopressin in RALRs. Captopril decreased mean arterial pressure by 44 +/- 2 and 53 +/- 8 mm Hg in the groups treated with the vehicles of EXP6803 (n = 5) and KAA8 (n = 5), respectively. In the presence of EXP6803 (n = 5) or KAA8 (n = 5), the antihypertensive effect of captopril was almost or totally abolished. Indomethacin did not alter the antihypertensive effect of captopril. These results suggest that the antihypertensive effect of captopril in conscious RALRs is due mainly to the blockade of AII formation. Furthermore, circulating AII rather than locally formed AII appears to play a major role in maintaining hypertension in hypertension in RALRs.

Volume 250, Issue 2, pp. 515-522, 08/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics

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