. Effects of natural drugs in hepatic ischemic reperfusion damage.

Hepatic ischemia-reperfusion (I/R) injury is a common consequence of hepatic surgery, particularly following hepatectomies and liver transplantation, and is complicated by microcirculatory failure, followed by necrosis and cell death. In this context, oxidative damage is thought to play an important role, including the outcome of organ transplantation. The present study reports the combined effects of two antioxidant agents, rutin and L-arginine, in rat liver ischemia-reperfusion (I/R) injury. Male Wistar rats were divided into five groups: a) sham operated, b) I/R, c) I/R + rutin, d) I/R + L-arginine, e) I/R + rutin + L-arginine. Several plasmatic and hepatic markers of liver damage, including DNA fragmentation and liver histopathology, were examined. Furthermore, in order to elucidate the mechanism of action of rutin and L-arginine we assessed the expression of nitric oxide synthase isoforms (iNOS and eNOS) and heme-oxygenase-1 (HO-1), both playing key roles in the biochemical cascade of liver injury. Significant increase in plasmatic ALT and AST activities were observed in untreated I/R rats when compared to sham-operated animals whereas the treatment with rutin or L-arginine in the I/R rats reduces hepatic damage. Interestingly, combined therapy with rutin and L-arginine resulted in a further reduction of plasmatic ALT and AST activities when compared to rutin or L-arginine alone. These results were further confirmed by the analysis of DNA fragmentation, LOOH, RSH groups and liver histopathology which showed the highest protective effects following the coadministration of rutin and L-arginine. Finally, the combined therapy protocol resulted in a significant induction of liver HO-1 and in a concomitant reduction of iNOS expression which may be both responsible for the beneficial effects of the proposed pharmacological protocol. In conclusion, our data demonstrated that molecules endowed with free radical scavenger, antioxidant and HO-1 up-regulation activities may provide potent protection against I/R hepatic injury; in addition, this study documented the potential utility of HO-1 inducing agents to prevent I/R injury, suggesting that L-arginine and rutin may be used as potential therapeutic agents against I/R induced oxidative remote organ damage.