Endotoxin-stimulated nitric oxide production increases injury and reduces rat liver chemiluminescence during reperfusion.
OBJECTIVE
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.
Ma
T T
TT
Division of Gastroenterology, University of Pennsylvania, Philadelphia.
Ischiropoulos
H
H
Brass
C A
CA
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008107:Liver Diseases / Q000378:metabolism*; D008163:Luminescent Measurements; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism*
D008070:Lipopolysaccharides; D009569:Nitric Oxide; D001120:Arginine; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D019331:NG-Nitroarginine Methyl Ester