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Blockade of the L ‐arginine/NO synthase pathway worsens hepatic apoptosis and liver transplant preservation injury
Author(s) -
Yagnik Gautam P.,
Takahashi Yoshihito,
Tsoulfas George,
Reid Kaye,
Murase Noriko,
Geller David A.
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.35058
Subject(s) - blockade , arginine , liver injury , atp synthase , apoptosis , medicine , liver transplantation , pharmacology , chemistry , transplantation , biochemistry , enzyme , receptor , amino acid
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 N G ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME), or iNOS selective inhibitor L ‐ N 6 ‐(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.