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)
Bird
J E
JE
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Moreland
S
S
Waldron
T L
TL
Powell
J R
JR
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003619:Dansyl Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology
D000959:Antihypertensive Agents; D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide