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.
Yagnik
Gautam P
GP
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Takahashi
Yoshihito
Y
Tsoulfas
George
G
Reid
Kaye
K
Murase
Noriko
N
Geller
David A
DA
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