Blockade of the L-arginine/NO synthase pathway worsens hepatic apoptosis and liver transplant preservation injury.
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.
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Gautam P
GP
Yagnik
Yoshihito
Y
Takahashi
George
G
Tsoulfas
Kaye
K
Reid
Noriko
N
Murase
David A
DA
Geller
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000097:blood* / Q000172:deficiency / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000473:pathology*; D016031:Liver Transplantation; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009336:Necrosis; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew; D015854:Up-Regulation / Q000502:physiology
D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001119:Arginase; D019331:NG-Nitroarginine Methyl Ester