Abstracts
2000 Digestive Disease Week

# 2265 Bosentan, an Endothelin Receptor Antagonist, Augments Graft Function by Reducing Graft Circulatory Impairment Following Ischemia Reperfusion.
Rocco Ricciardi, Bradley K. Schaffer, Shimul A. Shah, Steven H. Quarfordt, Barbara F. Banner, Ravi S. Chari, William C. Meyers, Worcester, MA

Introduction: Endothelin is a potent hepatic vasoconstrictor. The role of endothelin in hepatic cold ischemia reperfusion (I/R) injury is not completely understood. We evaluated the effect of Bosentan, a novel endothelin receptor antagonist, on hepatic circulatory impairment, cellular damage, and graft function following I/R. Methods: Bosentan was infused directly into the portal vein @ 30mg/kg for 15 minutes prior to cold ischemia and immediately upon reperfusion, in five porcine livers. Five other pigs underwent routine liver harvest and reperfusion without Bosentan pretreatment (Control). Graft circulatory impairment was determined through hepatic vascular resistance (HVR) and liver tissue blood flow (LQB) as measured by thermistor flow probes. Hepatocellular damage was determined through hepatic venous levels of sorbitol dehydrogenase (SDH) and lactate dehydrogenase (LDH). Endothelial cell damage was determined in sections immunostained for Factor VIII and scored by a pathologist (from 0, no endothelial staining to 2, preserved staining). Graft function was determined through O2 consumption, bile flow, and bile acid stimulation with taurocholate. Data were analyzed with t tests. Results: Organs pretreated with Bosentan demonstrated lower HVR (0.0015 vs. 0.021 mmHg min/mL, p < 0.005) and enhanced LQB (59.0 ± 5.7 vs. 25.0 ± 4.6mL/100g/min, p < 0.001) as compared to controls. Portal vein inflow to hepatic tissue was significantly enhanced (4.4 fold) in Bosentan pretreated livers (p < 0.05). No difference was observed in hepatocellular damage as determined by LDH and SDH. Pathology scores for Factor VIII immunohistochemistry stain were improved by 2.3 fold in the Bosentan pretreated group as compared to controls (p < 0.05). The Bosentan pretreated livers also demonstrated enhanced O2 consumption (0.9 ± 0.1 vs. 0.5 ± 0.1mL/100g/min, p < 0.05), increased bile flows (1.7 ± 0.2 vs. 1.0 ± 0.1mL/ 15min, p < 0.05), and augmented taurocholate responses (7.4 ± 0.4 vs. 3.5 ± 0.6mL/15min, p < 0.005). Conclusions: These results indicate that administration of Bosentan prior to and following I/R minimizes hepatic circulatory disturbances, reduces endothelial cell damage, and augments hepatic graft function. Administration of agents aimed at reducing graft circulatory impairment and improving portal venous in-flow may augment post preservation liver function following transplantation.