EFFECTS OF BOSENTAN (RO-47-0203), AN ET(A)-RECEPTOR, ET(B)-RECEPTOR ANTAGONIST, ON REGIONAL HEMODYNAMIC-RESPONSES TO ENDOTHELINS IN CONSCIOUS RATS

1 Regional haemodynamic responses to endothelin (ET)-1, -2 and -3 and big ET-1 (all at 500 pmol kg(-1)) were assessed in the same conscious Long Evans rats (n = 8) in the absence or presence of the mixed ET(A)-, ET(B)-receptor antagonist, Ro 47-0203 (bosentan; 30 mg kg(-1)). 2 Bosentan blocked the initial depressor, tachycardic and hindquarters hyperaemic vasodilator effects of ET-1, -2 and -3, and substantially curtailed the primary renal and secondary hindquarters vasoconstrictor responses. Bosentan did not inhibit the initial mesenteric vasoconstrictor action of ET-1, but reduced the duration of the later mesenteric vasoconstriction. In contrast, bosentan delayed the rate of onset, and reduced the duration, of the mesenteric vasoconstrictor actions of ET-2 and ET-3. The most likely explanation of this finding is that ET-1, but not ET-2 or ET-3, triggered a covert mesenteric vasodilator mechanism which was antagonized by bosentan.