Effect of Endogenous Adenosine Augmentation by Dipyridamole on Ischemia and Reperfusion Injury of the Liver.

298 Background: Liver ischemia causes progressive degeneration of adenosine triphosphate (ATP), leading to an immense accumulation of purine catabolites in ischemic tissues. Adenosine, one of the intermediary products of the degradation cascade, has been known to improve the microcirculatory disturbance after reperfusion such as increased blood flow, vasodilation, and prevention of platelet aggregation. Upon reoxygenation, adenosine becomes an important substrate for ATP resynthesis. However, adenosine is rapidly deaminated into inosine during ischemia and transported out of the ischemic tissues after reperfusion, thereby depriving ischemic tissues of adenosine's beneficial effects. In the previous study, we reported beneficial effect of endogenous adenosine augmentation by nucleotide transport inhibitor, R-75231, (Transplantation, 1996) but, unfortunately, the agent became unavailable clinically due to withdrawal from future development. In the present study, we tested dipyridamole which was commercially available and had similar mechanisms of action as R-75231, to determine if this agent exert protection against ischemia and reperfusion injury of the liver. Methods Adult female beagle dogs underwent 2-hr hepatic vascular exclusion with venovenous bypass. Dipyridamole was given to dogs by continuous intravenous infusion for one hour before ischemia at a dose of 0.25mg/kg (high-DYP, n=6), 0.1mg/kg (best-DYP, n=6), or 0.05mg/kg (low-DYP, n=6). Nontreated animals were used as the control (CT, n=12). Two-week survival, systemic hemodynamics, hepatic tissue blood flow (HTBF), liver function tests, energy metabolism, and histopathology were analyzed. Results:(Table)TableConclusions: Our data demonstrated that dipyridamole could augment the endogenous adenosine dose-dependently. Dipyridamole, at the dose of 0.1mg/kg, exerted alleviating effects on the liver injury caused by ischemia and reperfusion. It is a promising agent for hepatic surgery and liver preservation.