ANTIHYPERTENSIVE EFFECTS OF A NOVEL ENDOTHELIN-A RECEPTOR ANTAGONIST IN RATS

Endothelin is a potent presser agent mediated primarily through activa tion of endothelin-A receptors on vascular smooth muscle. Surprisingly , there is no consensus in the literature regarding the role of endoth elin itself or endothelin-A receptors in hypertension. The goal of thi s study was to compare the effects of the novel, selective endothelin- A receptor antagonist BMS-182874 in various models of hyper tension. B MS-182874 specifically inhibited the presser response to endothelin-1 (0.3 nmol/kg IV) in Sprague-Dawley rats in a dose-dependent manner (ED (25)=8 mu mol/kg IV) but had no effect on changes in mean arterial pre ssure brought about by other vasoactive agents. The antihypertensive e ffects of BMS-182874 were evaluated in conscious deoxycorticosterone a cetate (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHR), and sodium-deplete SHR. BMS-182874 reduced blood pressure in DO CA-salt hypertensive rats when administered at a dose of 30, 100, or 3 00 mu mol/kg IV. A maximal decrease of approximately 45 mm Hg was obse rved after treatment with 100 mu mol/kg IV. Three days of oral or intr avenous treatment with BMS-182874 (100 mu mol/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 t he antihypertensive effects were similar at doses of 75, 150, and 450 mu mol/kg PO. In sodium-deplete SHR, BMS-182874 did not significantly reduce blood pressure. In summary, BMS-182874 is a specific, orally ac tive endothelin-A receptor antagonist that is efficacious in mineraloc orticoid hypertension in rats but has less effect in sodium-replete an d sodium-deplete SHR. Thus, endothelin-A receptor activation may play a role in volume-dependent or low-renin hypertension but is unlikely t o be important in all hypertensive states.