Gastroenterology

Gastroenterology

Volume 108, Issue 2, February 1995, Pages 463-469
Gastroenterology

Endotoxin-stimulated nitric oxide production increases injury and reduces rat liver chemiluminescence during reperfusion,☆☆

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Abstract

Background/Aims: Nitric oxide has many physiological functions and may play an important role in modulating tissue injury. However, the mechanism of NO action in ischemia/reperfusion injury is completely unknown. This report investigates the role of NO in hepatic reperfusion injury. Methods: Rat liver was oxygenated for 30 minutes, followed by 30 minutes of ischemia, and then reperfused for 30 minutes. Perfusate was sampled for aspartate aminotransferase content, as an indication of hepatic injury, and for nitrite, an index of NO production. Spontaneous organ chemiluminescence was continuously monitored as a measure of oxyradical production. Results: NO production by the perfused rat liver was induced in vivo by pretreatment with Escherichia coli lipopolysaccharide. This induction led to an increase in hepatic injury during reperfusion that was partially ameliorated by the NO synthase inhibitor NG-monomethyl-l-arginine. Chemiluminescence during reperfusion, a measure of superoxide production in this system, was also decreased in the lipopolysaccharide-treated animals, and this effect was blunted by NG-monomethyl-l-arginine. Conclusions: These data suggest that NO may combine with superoxide formed during reperfusion to directly cause hepatocellular injury. In vitro work shows that this chemical product is the highly toxic species peroxynitrite.

Abbreviations

CLI
chemiluminescence during ischemia
CLO
chemiluminescence during initial oxygenation
CLR
chemiluminescence during reperfusion
iNOS
inducible nitric oxide synthase
l-NAME
NG-monomethyl-l-arginine
LPS
lipopolysaccharide
RI
reperfusion index
SOD
superoxide dismutase

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Supported in part by a VA Merit Review Award and an American Heart Association Student Fellowship (to T.T.M.). Dr. Brass was the Hans Popper Liver Scholar of the American Liver Foundation.

☆☆

Presented in part at the New York Academy of Science Conference on Cellular, Biochemical, and Molecular Aspects of Reperfusion Injury, New York, in July 1993.