Cytoprotective function of tetrahydrobiopterin in rat liver ischemia/reperfusion injury.
BACKGROUND
Tetrahydrobiopterin (BH(4)) is a key coenzyme of nitric oxide synthase (NOS), which is associated with a cytoprotective function in various ischemia-reperfusion (I/R) injury models. There have been a few reports on the efficacy of BH(4) in the treatment of I/R injury in other organs; therefore, the aim of this study was to investigate the effect of BH(4) related with NOS reaction in hepatic I/R injury.


METHODS
A model of 70% liver I/R injury with a 100-minute ischemic time was created in rats, and the non-ischemic lobes were then resected. The rats were given BH(4) (BH(4) group) or saline solution (saline group) before reperfusion. The specific inducible NOS blocker 1400W was used to evaluate the effect of endogenous inducible NOS in the I/R hepatic injury. Survival, nitric oxide products (nitrate and nitrite), NOS expression, and nitrotyrosine (ie, the peroxynitrite product) were measured after reperfusion.


RESULTS
On day 7, the survival rate was 62.5% in the BH(4) group, as opposed to 14.3% in the saline group (P = .0004); 1400W administration to the BH(4) group decreased the survival rate to 0% (P = .003). BH(4) prevented the significant increase in total bilirubin levels (P < .01) after 12-hour reperfusion. The increases in serum alanine transaminase levels (after 3 hours and 12 hours of reperfusion) were significantly (P < .01) attenuated in the BH(4) group. BH(4) increased the nitrate/nitrite concentrations in liver tissue (P < .05) and reduced nitrotyrosine production, and the protein assay showed that BH(4) increased inducible NOS and endothelial NOS expression. Histologic examination of the liver revealed that BH(4) mitigated the damage that was caused by liver I/R.


CONCLUSIONS
Exogenous BH(4) increased nitric oxide production, which attenuated the hepatic I/R injury.
Department of Surgery, School of Medicine, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Yuzuru
Y
Hara
Kenichi
K
Teramoto
Kozo
K
Ishidate
Shigeki
S
Arii
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000098:blood supply / Q000473:pathology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D016019:Survival Analysis
D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin