Nonpeptide angiotensin II receptor antagonists. I. Pharmacological characterization of 2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5- acetic acid, sodium salt (S-8307)

PC Wong, AT Chiu, WA Price, MJ Thoolen, DJ Carini, AL Johnson, RI Taber and PB Timmermans

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

2-n-Butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid, sodium salt (S-8307) displaced [3H]angiotensin II (All) from its specific binding sites in rat adrenal cortical membranes with an IC50 of 4 x 10(- 5) M. In rabbit aorta, S-8307 competitively inhibited the contractile response to All with a pA2 value of 5.49 but at 10(-4) M it did not alter the response to norepinephrine or KCI. Similarly, a specific AII antagonism was shown in vivo in the spinal pithed rat model. In anesthetized rats, S-8307 did not potentiate the bradykinin vasodepressor response. In renal artery-ligated rats, a high renin model, S-8307 decreased mean blood pressure at 10 and 30 mg/kg i.v. as well as at 100 mg/kg p.o. In anesthetized rats, furosemide enhanced the hypotensive effect of S-8307. Blockade of the renin-angiotensin system by captopril, saralasin or bilateral nephrectomy inhibited significantly but did not abolish completely the hypotensive effect of S-8307 in furosemide-treated rats. Inhibition of prostaglandin synthesis by indomethacin did not significantly reduce the hypotensive effect of S-8307. Our results identify S-8307 as a selective antagonist of AII receptors. However, at higher doses, mechanisms other than AII receptor blockade may partly account for its acute hypotensive effect.

Volume 247, Issue 1, pp. 1-7, 10/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

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