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Reperfusion following liver ischemia results in oxidative stress leading to liver injury. The aim of this study was to investigate the combined effects of two antioxidant agents, rutin and L-arginine, in rat liver ischemia-reperfusion (I/R). Male Wistar rats were divided into five groups: 1) sham operated, 2) I/R, 3) I/R+rutin, 4) I/R+L-arginine, and 5) I/R+rutin+L-arginine. Plasmatic and hepatic levels of alanine transaminase (ALT), aspartate transaminase (AST), lipid peroxides (LOOH), and thiol groups (RSH) were examined, as well as DNA fragmentation and liver histopathology. Furthermore, to elucidate the pathophysiological processes involved in the antioxidant mechanism(s) of rutin and L-arginine, we assessed the expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) isoforms 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 compared with sham-operated animals, whereas treatment with rutin or L-arginine in I/R rats reduced hepatic damage. Interestingly, combined therapy with rutin and L-arginine resulted in a further reduction of plasmatic ALT and AST activities compared with 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 a concomitant reduction of iNOS expression that may both be responsible for the beneficial effects of the proposed pharmacological protocol.

Ischemia/reperfusion (I/R) injury is a multifactorial process that affects liver function after transplantation and resectional surgery. Alterations in hepatic microcirculation and decreased hepatic flow can cause local hypoxia and consequently liver damage, which is worsened by reperfusion. The aim of this study was to evaluate if treatment with L-arginine improved hepatic function in rats with I/R injury. Animals were treated with L-arginine, ischemized for 30 min, and reperfused for 3 h. Plasmatic levels of GOT, GPT, lipid hydroperoxides (LOOH), and total thiol groups (RSH) were evaluated. In addition, we analyzed hepatic LOOH and RSH levels, DNA fragmentation, heme oxygenase 1 (HO-1) expression, and histological modifications. Our results demonstrate a significant improvement in hepatic function of I/R rats compared to the control group. Treatment with L-arginine increased the expression of HO-1. These data suggest that L-arginine could be useful in preventing oxidative damage during hepatic surgery., (Copyright 2006 Wiley-Liss, Inc.)