Bosentan, an endothelin antagonist, augments hepatic graft function by reducing graft circulatory impairment following ischemia/reperfusion injury

Endothelin is a potent hepatic vasoconstrictor. We evaluated the role of an endothelin antagonist in hepatic ischemia/reperfusion injury. Bosentan, a novel endothelin receptor antagonist, was infused directly into the portal vein prior to cold ischemia and immediately on reperfusion, in five porcine livers. Five other pigs underwent routine liver harvest and reperfusion wi thout bosentan treatment. Hepatic vascular resistance and liver tissue bloo d flow, as measured by thermistor flow probes, were determined following re perfusion. Hepatocellular damage was assessed through hepatic venous levels of sorbitol dehydrogenase and lactate dehydrogenase. Endothelial cell dama ge was determined in sections immunostained for factor Vm. Graft function w as determined through oxygen consumption, bile production, and response to bile acid challenge. Organs treated with bosentan demonstrated lower vascul ar resistance and enhanced tissue blood flow (P <0.05) as compared to untre ated organs. Portal vein inflow to hepatic tissue was significantly enhance d (4.4-fold) in the bosentan-treated organs (P <0.05). No difference was ob served in hepatocellular damage. Pathology scores for factor VIII immunohis tochemical staining were 2.3-fold higher in the bosentan-treated livers as compared to untreated livers (P <0.05). The bosentan-treated livers also de monstrated enhanced oxygen consumption, increased bile production, and augm ented biliary response to a bile acid challenge (P <0.05). These results in dicate that administration of bosentan before and after ischemia/reperfusio n reduces hepatic circulatory disturbances, diminishes endothelial fell dam age, and augments hepatic graft function.