DIFFERENTIAL-EFFECTS OF A NOVEL NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONIST (BOSENTAN) IN RAT-LIVER AND VASCULATURE

1. We studied the effects of the non-selective, nonpeptide, orally active endothelin (ET) receptor antagonist bosentan (Ro 47-0203) on rat hepatic and mesenteric vascular membrane I-125-ET-1 binding characteristics in vitro and ex vivo (after bosentan by gavage in vivo). 2. Bosentan caused a concentration-dependent competitive inhibition of I-125-ET-1 binding to female rat mesenteric vascular (predominantly ETA receptors) and hepatic (predominantly ETB receptors) membranes in vitro and ex vivo. 3. The time course of the inhibition of binding ex vivo after administration of bosentan in vivo was 1-4 h for mesenteric vascular (predominantly ETA receptors) binding and 1-16 h for hepatic (predominantly ETB receptors) binding. 4. The time course of displacement of I-125-ET-1 binding from mesenteric vascular and hepatic membranes by bosentan in vitro was similar. 5. Since bosentan is significantly excreted by the liver, the prolonged hepatic I-125-ET-1 binding by bosentan presumably represents hepatic accumulation of bosentan, which may have implications for bosentan antagonizing the actions of ET in the liver.