ATTENUATION OF ISCHEMIC LIVER-INJURY BY AUGMENTATION OF ENDOGENOUS ADENOSINE

Hepatic grafts from non-heartbeating donors may alleviate the organ sh ortage, but they inherently suffer from warm ischemia. In the present study, we tested our hypothesis that augmentation of endogenous adenos ine by inhibition of nucleoside transport with R15231 attenuates ische mic liver injury. Adult female beagle dogs underwent 2-hr hepatic vasc ular exclusion with venovenous bypass. R75231 was given to the animals by continuous intravenous infusion for 30 min before ischemia at a do se of 0.1 mg/kg (Group 2, n=6), 0.05 mg/kg (Group 3, n=6), or 0.025 mg /kg (Group 4, n=6). Nontreated animals were used as the control (Group 1, n=10). Animal survival, hepatic tissue blood flow, liver function, and histopathology were analyzed. Two week animal survival was 30% in Group 1, 83% in Group 2, 100% in Group 3, and 100% in Group 4. Postre perfusion hepatic tissue blood flow was markedly improved by the treat ment. Treatment significantly attenuated liver enzyme release, lipid p eroxidation, and changes in adenine nucleotides and purine catabolites . Structural abnormality of the liver after reperfusion was markedly i mproved by R75231 treatment, showing better architecture and less neut rophil infiltration. Preischemic administration of a nucleoside transp ort inhibitor ameliorated ischemic liver injury due to the positive ef fects of augmented endogenous adenosine, and is applicable clinically when the liver is procured from a controlled nonheartbeating donor.