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 ETA 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 ETA 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.