Effects of bosentan (Ro 47–0203), an ETA‐, ETB‐receptor antagonist, on regional haemodynamic responses to endothelins in conscious rats

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Abstract
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 ETA-, ETB-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. 3 Bosentan blocked all the effects of big ET-1, and, in a separate group of rats (n = 7), blocked all the haemodynamic effects of a lower dose of ET-1 (50 pmol kg−1), with the exception of a slight mesenteric vasoconstriction. 4 The most straightforward explanation of the results is that the major haemodynamic effects of ET-1, −2 and −3, and all the effects of big ET-1, are mediated through ETA- and/or ETB-receptors that are effectively antagonized by bosentan.

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