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)