Effect of uric acid on liver injury during hemorrhagic shock.
BACKGROUND
It remains unproven whether nitric oxide (NO) exerts a toxic effect on hepatocytes directly or through the formation of a more toxic compound during hemorrhagic shock (HS). NO reacts at a very high rate constant with superoxide to give peroxynitrite, a potentially toxic molecule. In this study, we investigated whether or not peroxynitrite contributed to tissue injury in the liver during HS.


METHODS
Male Sprague-Dawley rats were subjected to decompensated HS followed by resuscitation. In addition to the time course of tissue injury and inducible NO synthase (iNOS) messenger RNA (mRNA) expression in the liver during HS, we investigated the effect of N6-(iminoethyl)-L-lysine(LNIL) (a specific inhibitor of iNOS) and also that of uric acid (a natural scavenger of peroxynitrite) on tissue injury and nitrotyrosine formation (a footprint of peroxynitrite) in the liver.


RESULTS
The liver injury, evaluated by plasma aminotransferase levels and histology, became evident at the end of the shock period and had significantly increased 1 hour after the start of resuscitation (Shock-1 h). There was no iNOS mRNA expression in the liver at baseline, and it had clearly increased by Shock-1 h. Treatment with LNIL or uric acid significantly attenuated the tissue injury with a prominent reduction in nitrotyrosine formation in the liver.


CONCLUSIONS
These lines of evidence suggest that one of the mechanisms by which NO production causes liver injury during HS may be its reaction with superoxide to form peroxynitrite.
Tsukada
K
K
Department of First Surgery, Gunma University School of Medicine, Showamachi Maebashi, Japan.
Hasegawa
T
T
Tsutsumi
S
S
Katoh
H
H
Kuwano
H
H
Miyazaki
T
T
Yamamoto
Y
Y
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000293:injuries / Q000473:pathology*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000201:enzymology / Q000473:pathology*; D013997:Time Factors; D014158:Transcription, Genetic; D014527:Uric Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D012333:RNA, Messenger; D014527:Uric Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine