Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia.
METHODS
Nitric oxide synthesis occurs both in vitro and in vivo in response to inflammatory stimuli and can have profound effects on the local cellular environment. Hepatocytes, Kupffer cells, and endothelial cells produce nitric oxide in vitro, but the in vivo role of this reactive mediator in the liver is unknown. We assessed the role of nitric oxide synthesis during endotoxemia in mice by inhibiting its synthesis with NG-monomethyl-L-arginine after lipopolysaccharide injection and by determining the effects of this inhibition on hepatic damage.


RESULTS
Injection of lipopolysaccharide in mice increased plasma nitrite and nitrate concentrations, the stable end products of nitric oxide metabolism, and caused mild hepatic damage as measured by increased circulating hepatocellular enzyme levels. NG-monomethyl-L-arginine decreased plasma nitrite and nitrate values, but increased the lipopolysaccharide-induced hepatic injury. NG-monomethyl-L-arginine caused no hepatic damage when given without lipopolysaccharide. The extent of hepatic damage with NG-monomethyl-L-arginine was proportional to the dose of lipopolysaccharide used and could be reduced with concurrent administration of L-arginine but not D-arginine.


CONCLUSIONS
Nitric oxide synthesis provides a protective function against lipopolysaccharide-induced liver injury that increases in importance as the degree of endotoxemia increases. The production of nitric oxide is, therefore, an important part of the liver's response to a systemic inflammatory stimulus.
Harbrecht
B G
BG
Department of Surgery, University of Pittsburgh, PA.
Billiar
T R
TR
Stadler
J
J
Demetris
A J
AJ
Ochoa
J B
JB
Curran
R D
RD
Simmons
R L
RL
D000208:Acute Disease; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D016470:Bacteremia / Q000150:complications*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D007249:Inflammation; D008070:Lipopolysaccharides; D008107:Liver Diseases / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D008111:Liver Function Tests; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D019323:omega-N-Methylarginine
D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine