Differential effects of a novel non-peptide endothelin receptor antagonist (bosentan) in rat liver and vasculature.

1. We studied the effects of the non-selective, non-peptide, orally active endothelin (ET) receptor antagonist bosentan (Ro 47-0203) on rat hepatic and mesenteric vascular membrane 125I-ET-1 binding characteristics in vitro and ex vivo (after bosentan by gavage in vivo). 2. Bosentan caused a concentration-dependent competitive inhibition of 125I-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 1-4h for mesenteric vascular (predominantly ETA receptors) binding and 1-16h for hepatic (predominantly ETB receptors) binding. 4. The time course of displacement of 125I-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 125I-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.