Beneficial effects of inducible nitric oxide synthase inhibitor on reperfusion injury in the pig liver

Background, Although inhibition of endothelial nitric oxide synthase (eNOS) has been reported to aggravate hepatic ischemia-reperfusion (I/R) injury, the role of inducible nitric oxide synthase (iNOS) has been still unknown, We investigated the role of NO produced by iNOS, and evaluated the effect o f an iNOS inhibitor on prolonged warm YR injury in the pig liver. Methods. Pigs were subjected to 120 min of hepatic warm I/R under the extra corporeal circulation. We investigated the time course of changes in serum and hepatic microdialysate NO2- + NO3- (NOx) and the cellular distribution of eNOS and iNOS by immunohistochemistry, including a double-immunofluoresc ence technique in combination with confocal laser scanning microscopy. The effect of iNOS inhibitor was also investigated. Results. Hepatic VR induced new nitric oxide production in serum and hepati c microdialysate NOx after reperfusion and severe hepatic damage in the cen trilobular region where nitrotyrosine was strongly expressed. Diffuse eNOS expression in sinusoidal endothelium did not differ before and after reperf usion. In contrast, strong iNOS expression in Kupffer cells and neutrophils appeared strongly in the centrilobular region after reperfusion. Pigs with intraportal administration of N-G-nitro-L-arginine (10 mg/kg) died during the period of ischemia or early in the period of reperfusion with a high mo rtality rate (80.0%). Intraportal administration of aminoguanidine hemisulf ate (10 mg/kg) significantly suppressed nitric oxide production and serum a spartate aminotransferase after reperfusion, inhibited nitrotyrosine expres sion, and attenuated hepatic damage. Conclusions. These results indicate that hepatic VR injury is triggered by centrilobular iNOS expression; and attenuated by inhibition of iNOS.