Blockade of the l-arginine/NO synthase pathway worsens hepatic apoptosis and liver transplant preservation injury

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Abstract
Organ graft preservation injury is a major problem complicating liver transplantation. The l-arginine/nitric oxide pathway has protective effects in several models of liver injury. The purpose of this study was to evaluate the role of the l-arginine/NO synthase (NOS) pathway on liver preservation injury and to characterize endogenous inducible NOS (iNOS) expression. Orthotopic liver transplantation was performed with 18-hour University of Wisconsin preservation solution in syngeneic rats. Recipient rats were either untreated or treated with l-arginine, d-arginine, nonspecific NOS inhibitor NG -nitro-l-arginine methyl ester (l-NAME), or iNOS selective inhibitor l-N6 -(1-imino-ethyl)lysine (l-NIL) after revascularization. As early as 1 hour following reperfusion, circulating arginine levels decreased 10-fold and ornithine levels increased 4-fold. A corresponding increase in arginase I protein was detected in serum. To address the profound arginine deficiency, we supplemented recipients with arginine after transplantation. l-arginine (but not d-arginine) supplementation significantly reduced preservation injury 12 hours after reperfusion, suggesting that the protective effect of l-arginine was mediated through the generation of NO. iNOS protein expression peaked in the liver 6 to 12 hours following reperfusion. Blockade of the l-arginine/NO pathway with l-NAME significantly increased necrotic and apoptotic cell death in the transplanted graft. Addition of the iNOS selective inhibitor l-NIL mildly increased liver transaminase levels and also increased apoptosis in the liver graft. In conclusion, transplant recipients are profoundly arginine deficient postreperfusion due to arginase release. l-Arginine supplementation and NO synthesis decrease necrotic and apoptotic cell death and ameliorate liver transplant preservation injury.

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