Evidence for a functional tissue renin-angiotensin system in the rat mesenteric vasculature and its involvement in regulating blood pressure

RE Weishaar, RL Panek, TC Major, J Simmerman, ST Rapundalo and DG Taylor

Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.

Electrical stimulation of the isolated rat mesenteric vascular bed resulted in a frequency-dependent pressor response, which could be potentiated by increasing concentrations of renin substrate (synthetic tetradecapeptide). This potentiating effect appeared to be mediated by tissue conversion of renin substrate to angiotensin II because the response 1) could be mimicked by angiotensin II, 2) was accompanied by an increase in angiotensin II production and 3) was blocked by the angiotensin converting enzyme (ACE) inhibitor quinaprilat and the angiotensin II receptor antagonist saralasin ([Sar1,Ile5,Ala8]angiotensin II). To assess the role of this tissue renin-angiotensin system in contributing to blood pressure regulation, spontaneously hypertensive rats were administered the prodrug ACE inhibitor quinapril at a dose of 10 mg/kg/day for 7 days. Such administration resulted in a reduction in systolic blood pressure of 48 +/- 3 mm Hg, a greater than 95% inhibition of serum ACE activity, and a significant attenuation of the potentiating effect of renin substrate on electrically evoked contractions of isolated mesenteric beds. Significant reductions in blood pressure and the potentiating effect of renin substrate on the isolated mesenteric vasculature were still observed 24 and 48 hr after the last dose of quinapril. In contrast, serum ACE activity returned to normal levels within 48 hr after the last dose of quinapril. These results suggest that the changes in tissue renin-angiotensin system, and not the circulating system, are closely related to the blood pressure lowering effect of the ACE inhibitor, quinapril.

Volume 256, Issue 2, pp. 568-574, 02/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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