Antihypertensive effects of a novel endothelin-A receptor antagonist in rats

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 mumol/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 mumol/kg IV. A maximal decrease of approximately 45 mm Hg was observed after treatment with 100 mumol/kg IV. Three days of oral or intravenous treatment with BMS-182874 (100 mumol/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 mumol/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.(ABSTRACT TRUNCATED AT 250 WORDS)