Cytoprotective function of tetrahydrobiopterin in rat liver ischemia/reperfusion injury

BackgroundTetrahydrobiopterin (BH4) is a key coenzyme of nitric oxide synthase (NOS), which is associated with a cytoprotective function in various ischemia-reperfusion (I/R) injury models. There have been a few reports on the efficacy of BH4 in the treatment of I/R injury in other organs; therefore, the aim of this study was to investigate the effect of BH4 related with NOS reaction in hepatic I/R injury.MethodsA model of 70% liver I/R injury with a 100-minute ischemic time was created in rats, and the non–ischemic lobes were then resected. The rats were given BH4 (BH4 group) or saline solution (saline group) before reperfusion. The specific inducible NOS blocker 1400W was used to evaluate the effect of endogenous inducible NOS in the I/R hepatic injury. Survival, nitric oxide products (nitrate and nitrite), NOS expression, and nitrotyrosine (ie, the peroxynitrite product) were measured after reperfusion.ResultsOn day 7, the survival rate was 62.5% in the BH4 group, as opposed to 14.3% in the saline group (P = .0004); 1400W administration to the BH4 group decreased the survival rate to 0% (P = .003). BH4 prevented the significant increase in total bilirubin levels (P < .01) after 12-hour reperfusion. The increases in serum alanine transaminase levels (after 3 hours and 12 hours of reperfusion) were significantly (P < .01) attenuated in the BH4 group. BH4 increased the nitrate/nitrite concentrations in liver tissue (P < .05) and reduced nitrotyrosine production, and the protein assay showed that BH4 increased inducible NOS and endothelial NOS expression. Histologic examination of the liver revealed that BH4 mitigated the damage that was caused by liver I/R.ConclusionExogenous BH4 increased nitric oxide production, which attenuated the hepatic I/R injury.