THE EFFECT OF ENDOTHELIN AND ITS ANTAGONIST BOSENTAN ON HEMODYNAMICS AND MICROVASCULAR EXCHANGE IN CIRRHOTIC RAT-LIVER

Background/Aims: To characterize the effects of endothelin-1 and of Bo sentan, a mixed endothelin antagonist, on hepatic hemodynamics in cirr hotic animals in vivo and on hepatic microvascular exchange in the per fused rat liver. Methods: Biliary cirrhosis was induced by bile duct l igation, and micronodular cirrhosis by chronic exposure to phenobarbit al/CCl4 in male rats. Hepatic hemodynamics were studied under basal co nditions and after administration of Bosentan (3-30 mg/kg) by the micr osphere technique. Microvascular exchange was assessed in the in situ perfused rat liver by the multiple indicator dilution technique. Resul ts: Bosentan lowered portal pressure in a dose-dependent fashion; at t he highest dose tested, this decrease averaged -29+/-11 and -26+/-8% i n biliary and micronodular cirrhosis, respectively (p<0.01). This was achieved mainly pin a marked decrease in hepatic arterial flow. In the perfused liver, endothelin-1 induced a dose-dependent vasoconstrictio n; up to 10(-9) mol/l; this was not associated with any effect on viab ility, At this dose, endothelin-1 markedly decreased extravascular alb umin space in both controls and micronodular cirrhosis; this could be antagonized by Bosentan 10(-5) mol/l. Conclusions: Endothelin-1 affect s hepatic microvascular exchange, presumably by a direct effect on hep atic sinusoidal endothelial cells. A mixed endothelin antagonist lower s portal pressure in vivo presumably by acting on hepatic stellate cel ls, and counteracts the microvascular effects of endothelin-1 in vitro . These properties could prove useful in treatment of portal hypertens ion.