Nitric oxide synthase inhibitor increases hepatic injury with formation of oxidative DNA damage and microcirculatory disturbance in endotoxemic rats.
OBJECTIVE
Nitric oxide plays important roles in the pathogenesis of endotoxin shock and multiple organ failure. Nitric oxide synthase inhibitors are used in patients to improve hemodynamics in endotoxin shock. However, the role of nitric oxide is controversial in hepatic injury with oxidative DNA damage in endotoxemia. This report investigated the role of nitric oxide on hepatic blood flow and liver injury in endotoxemic rats.


METHODS
Under light ether anesthesia, male Wistar rats were given lipopolysaccharide (10 mg/kg) intravenously. Several hours (0-24 hr) later, the animals were used for experiments. In some experiments, NG-[1-iminoethyl]-L-ornithine, a potent inhibitor of nitric oxide synthase, was administered 5 mg/kg intraperitoneally every 3 hour after lipopolysaccharide injection. Hemodynamic changes, biochemical and histological analysis were determined.


RESULTS
Lipopolysaccharide increased the activity of inducible nitric oxide synthase in the liver, lungs and spleen. Significant amounts of nitric oxide-hemoglobin complexes and nitrite plus nitrate appearing in the blood peaked at 8 hr after treatment. NG-[1-iminoethyl]-L-ornithine completely inhibited the generation of nitric oxide metabolites, but hardly affected formation of urinary 8-hydroxydeoxyguanosine and the systemic blood pressure in normal rats. NG-[1-iminoethyl]-L-ornithine increased 8-hydroxydeoxyguanosine formation and decreased the blood flow more in the superior mesenteric artery and hepatic microvascular blood flow in endotoxemic rats. Inhibition of nitric oxide synthase markedly caused deterioration of the lipopolysaccharide-induced liver injury indicated by hepatic enzymes and histological findings.


CONCLUSIONS
These results suggested that suppresion of endogenous nitric oxide might aggravate hepatic injury, partly caused by decrease in hepatic blood flow accompanied with oxidative stress in endotoxemia.
Takemura
S
S
Department of Surgery II, Osaka City University Medical School, Japan. takemura@med.osaka-cu.ac.jp
Minamiyama
Y
Y
Inoue
M
M
Kubo
S
S
Hirohashi
K
K
Kinoshita
H
H
D000818:Animals; D004249:DNA Damage / Q000187:drug effects*; D019446:Endotoxemia / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019331:NG-Nitroarginine Methyl Ester