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(Hypertension. 1995;25:1191-1195.)
© 1995 American Heart Association, Inc.

Articles

Antihypertensive Effects of a Novel Endothelin-A Receptor Antagonist in Rats

J. Eileen Bird; Suzanne Moreland; Thomas L. Waldron; James R. Powell

From the Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

Correspondence to Eileen Bird, DVM, PhD, Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000. E-mail bird@ bms.com.

Abstract Endothelin is a potent pressor agent mediated primarily through activation of endothelin-A receptors on vascular smooth muscle. Surprisingly, there is no consensus in the literature regarding the role of endothelin itself or endothelin-A receptors in hypertension. The goal of this study was to compare the effects of the novel, selective endothelin-A receptor antagonist BMS-182874 in various models of hypertension. BMS-182874 specifically inhibited the pressor response to endothelin-1 (0.3 nmol/kg IV) in Sprague-Dawley rats in a dose-dependent manner (ED₂₅=8 µmol/kg IV) but had no effect on changes in mean arterial pressure brought about by other vasoactive agents. The antihypertensive effects of BMS-182874 were evaluated in conscious deoxycorticosterone acetate (DOCA)–salt hypertensive rats, spontaneously hypertensive rats (SHR), and sodium-deplete SHR. BMS-182874 reduced blood pressure in DOCA-salt hypertensive rats when administered at a dose of 30, 100, or 300 µmol/kg IV. A maximal decrease of approximately 45 mm Hg was observed after treatment with 100 µmol/kg IV. Three days of oral or intravenous treatment with BMS-182874 (100 µmol/kg) elicited a sustained decrease in blood pressure in the DOCA-salt hypertensive rats. In SHR, BMS-182874 decreased blood pressure by approximately 30 mm Hg, but the antihypertensive effects were similar at doses of 75, 150, and 450 µmol/kg PO. In sodium-deplete SHR, BMS-182874 did not significantly reduce blood pressure. In summary, BMS-182874 is a specific, orally active endothelin-A receptor antagonist that is efficacious in mineralocorticoid hypertension in rats but has less effect in sodium-replete and sodium-deplete SHR. Thus, endothelin-A receptor activation may play a role in volume-dependent or low-renin hypertension but is unlikely to be important in all hypertensive states.

Key Words: hypertension, experimental • hypertension, mineralocorticoid • receptors, endothelin • endothelins

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