Attenuation of Ischemic Liver Injury by Augmentation of Endogenous Adenosine1,2

Abstract

Hepatic grafts from non-heartbeating donors may alleviate the organ shortage, but they inherently suffer from warm ischemia. In the present study, we tested our hypothesis that augmentation of endogenous 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 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. Postreperfusion hepatic tissue blood flow was markedly improved by the treatment. Treatment significantly attenuated liver enzyme release, lipid peroxidation, 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 neutrophil 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.

The Effect of Antagonism of Adenosine A1 Receptor Against Ischemia and Reperfusion Injury of the Liver

“…Rapid metabolism by adenosine deaminase and adenosine kinase (2,3,27) serves to reduce the cytoprotective benefits of adenosine. In earlier work, however, we have shown that use of R-75231 and dipyridamole, nucleoside transport inhibitors, augments endogenous adenosine and attenuates ischemia and reperfusion injury of the liver (7,8).…”

“…Previously, we demonstrated that augmentation of endogenous adenosine improves postreperfusion hepatic blood flow and energy metabolism, attenuates liver enzyme release, augments cyclic AMP levels, and consequently improves animal survival in canine models (7,8). In those reports, we showed the beneficial effect of endogenous adenosine against ischemia and reperfusion injury.…”

“…Pump-driven veno-venous bypass (Biomedics 520D, Minetonka, MN) was used to decompress the splanchnic venous bed and infra-hepatic inferior vena cava (8). The bypass circuit connected the left femoral vein and the splenic vein to the left jugular vein (Ishikawa Co., Tochigi, Japan).…”

Attenuation of Ischemic Liver Injury by Monoclonal Anti-Endothelin Antibody, AwETN40

“…Total hepatic vascular exclusion was initiated by cross-clamping the portal vein, hepatic artery, and infra-and supra-hepatic inferior vena cava. Pump-driven venovenous bypass (Biomedics, Minetonka, MN) was used to decompress the splanchnic venous bed and infrahepatic inferior vena cava (8). The bypass circuit connected the left femoral vein and the splenic vein to the left jugular vein.…”

Attenuation of Ischemic Liver Injury by Monoclonal Anti-Endothelin Antibody, AwETN40

“…Total hepatic vascular exclusion was initiated by cross-clamping the portal vein, hepatic artery, and infra-and suprahepatic inferior vena cava. Pump-driven venavenous bypass (Biomedics, Minetonka, MN) was used to decompress the splanchnic venous bed and infrahepatic inferior vena cava (8). The bypass circuit connected the left femoral vein and the splenic vein to the left jugular vein.…”