ATTENUATION OF ISCHEMIC LIVER INJURY BY AUGMENTATION OF ENDOGENOUS ADENOSINE1,2

Hepatic grafts from non-heartbeating donors may alleviate the organ shortage, but they inherently suf­ fer from warm ischemia. In the present study, we tested our hypothesis that augmentation of endoge­ nous adenosine by inhibition of nucleoside transport with R75231 attenuates ischemic liver injury. Adult female beagle dogs underwent 2·hr hepatic vascular exclusion with venovenous bypass. R75231 was given to the animals by continuous intravenous infusion for 30 min before ischemia at a dose 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 tlow, liver function, and histopathology were ana­ lyzed. Two-week animal survival was 300/0 in Group 1, 88% in Group 2, 100% in Group 3, and 100% in Group 4. Postreperfusion hepatic tissue blood tlow was mark· edly improved by the treatment. Treatment signifi. cantly attenuated liver enzyme release, lipid peron­ dation, and changes in adenine nucleotides and purine catabolites. Structural abnormality of the liver after reperfusion was markedly improved by R75231 treatment, showing better architecture and less neu· trophil infiltration. Preischemic administration of a nucleoside transport inhibitor ameliorated ischemic liver injury due to the positive effects of augmented endogenous adenosine, and is applicable clinically when the liver is procured from a controlled non­ heartbeating donor. Liver ischemia causes progressive degradation of adeno­ sine triphosphate (ATP),* leading to an immense accumula­ tion of purine catabolites in ischemic tissues_ Adenosine, one of the intermediary products of the degradation cascade, has been known to exert various biological actions (5-10) such as increased blood flow, vasodilation, inhibition of free radical production, suppression of neutrophil activation, and preven­ tion of platelet aggregation. Upon reoxygenation, adenosine becomes an important substrate for ATP resynthesis. How­ ever, adenosine is rapidly deaminated into inosine during ischemia and transported out of the ischemic tissues after reperfusion, thereby depriving ischemic tissues of ade­ nosine's beneficial effects. In this study, in an attempt to establish a strategy for the use of livers from non-heartbea.t­ ing donors, we first tested our hypothesis that augmentation of endogenous adenosine by inhibiting its transport with a nucleoside transport inhibitor, R75231, attenuates warm ischemic liver injury, using a 2-hr total hepatic vascular exclusion model.