PROTECTIVE ROLE OF NITRIC OXIDE IN ISCHEMIA AND REPERFUSION INJURY OF THE LIVER

Abstract

70 In the liver, nitric oxide (NO) has various actions such as hepatic sinusoidal dilatation and the inhibition of endothelium-neutrophil interaction. Suppressed production of endogenous NO elicited by endothelial injury could be one reason for microcirculatory disturbance and neutrophil-related tissue injury in the liver subjected to ischemia and reperfusion (I/R). Using a two-hour total hepatic vascular exclusion model in dogs, we tested our hypothesis that NO enhancement by administrating the substrate of NO, L-arginine or a novel NO donor, FK409, would attenuate vascular dysfunction and reduce I/R injury of the liver. We also evaluated which sort of enhancement would be more favorable strategy. After skeletonization, the liver was made totally ischemic for two hours by cross-clamping the portal vein, the hepatic artery, and the vena cava(above and below the liver). Veno-venous bypass was used to decompress splanchnic and inferior systemic venous congestion during the procedure. Twenty beagle dogs were assigned into 3 groups Group CT, untreated control(n=10); Group LA, treated with L-arginine (n=5); Group FK, treated with FK409 (n=5). In treated animals, each drug was continuously given for 30 minutes before ischemia and 60 minutes after reperfusion. In total, L-arginine of 200mg/kg was administered intravenously, while FK409 of 600µg/kg was given through a mesenteric vein. Animal survival rate, hepatic tissue blood flow (HTBF), tissue ATP level, and liver enzymes levels in the peripheral venous blood, were determined. Histopathologically, the severity of liver injury and the number of infiltrated polymorphonuclear cells (PMN) in the postischemic tissue were analyzed. Systemic hemodynamics was also assessed using mean arterial pressure (MAP).Table 1Compared to the control, treatments with L-arginine or FK409 significantly improved animal survivals, augmented hepatic tissue blood flow, increased high energy phosphate restoration, lessened hepatocyte damage. Histopathologically, liver injury and PNM infiltration were remarkably reduced in the treated groups. Although any adverse effects were not noticed in the dogs treated with L-arginine, considerable hypotension was observed in Group FK. NO enhancement with L-arginine or FK409 markedly attenuated microcurculatory disturbance and ameliorated ischemia and reperfusion injury of the liver. Due to the adverse effect of FK409, supplementation of L-arginine is considered to be more favorable strategy.