Protective role of the L-arginine-nitric oxide synthase pathway on preservation injury after rat liver transplantation.
BACKGROUND
A major problem complicating liver transplantation is the preservation injury that results from cold storage and subsequent ischemia/reperfusion injury after organ revascularization. The L-arginine-nitric oxide (NO) pathway has been recognized to play critical roles during infection, inflammation, organ injury, and transplant rejection. Recent data indicates that NO synthesis has beneficial effects in several models of liver injury. The purpose of this study is to examine the role of the L-arginine-NO pathway on preservation injury in an experimental model of rat liver transplantation.


METHODS
Orthotopic liver transplantation was performed in syngeneic (LEW to LEW) rats. Liver preservation injury was determined by measuring serum liver function tests 6 to 48 hours after transplantation. In some experiments, rats received L-arginine supplementation 0 to 24 hours after transplantation. In other experiments, NO synthase inhibitors (L-NAME or L-NIL) were injected at the time of isograft revascularization.


RESULTS
L-Arginine supplementation decreased hepatic transaminase levels at all time points examined (6-48 hours). L-Arginine produced a significant improvement in liver preservation injury by 12 hours after reperfusion. The NO synthase inhibitor L-NAME caused a significant increase in liver injury 24 hours after injection. The inducible NO synthase (iNOS)-specific inhibitor L-NIL had no significant effect on liver injury.


CONCLUSIONS
The results show that L-arginine supplementation and NO synthesis improve hepatic injury and have a protective role in the transplanted liver graft. The protective effect may be mediated by low-level cNOS-derived NO.
Geller
D A
DA
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA. gellerda@msx.upmc.edu.edu
Chia
S H
SH
Takahashi
Y
Y
Yagnik
G P
GP
Tsoulfas
G
G
Murase
N
N
D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000378:metabolism*; D001123:Argininosuccinate Lyase / Q000378:metabolism*; D001124:Argininosuccinate Synthase / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000502:physiology*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D013047:Specific Pathogen-Free Organisms
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009097:Multienzyme Complexes; C090663:N(6)-(1-iminoethyl)lysine; C019726:arginine synthetase system; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester