A novel inhibitor of inducible nitric oxide synthase (ONO-1714) prevents critical warm ischemia-reperfusion injury in the pig liver.
BACKGROUND
Recently, a novel inhibitor of inducible nitric oxide synthase, ONO-1714, was developed. We evaluated the effect of ONO-1714 on a critical warm I/R model of the pig liver.


METHODS
Pigs were subjected to 180 min of hepatic warm I/R under the extracorporeal circulation. We investigated the time course of changes in the serum NO2- + NO3- (NOx), the cellular distribution of endothelial and inducible nitric oxide synthase, thrombocyte-thrombi, and nitrotyrosine by immunohistochemistry. The hepatic tissue blood flow (HTBF) was measured continuously using a laser-Doppler blood flowmeter.


RESULTS
ONO-1714 at 0.05 mg/kg improved the survival rate from 54 (control group) to 100%. The serum NOx levels in the ONO-1714 group were significantly lower than those in the control group at 1, 1.5, 2, 3, and 6 hr after reperfusion. The serum aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels of the ONO-1714 group were significantly lower than the control group, and the HTBF of the ONO-1714 group was significantly higher than the control group. The formation of thrombocyte-thrombi and nitrotyrosine after reperfusion was significantly lower in the ONO-1714 group.


CONCLUSIONS
These results indicated that ONO-1714 improved the survival rates and attenuated I/R injury in a critical hepatic warm I/R model of the pig. ONO-1714 will be beneficial for hepatectomy or liver transplantation in the clinical field.
Meguro
Makoto
M
Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Katsuramaki
Tadashi
T
Nagayama
Minoru
M
Kimura
Hitoshi
H
Isobe
Masato
M
Kimura
Yasutoshi
Y
Matsuno
Takashi
T
Nui
Akihiro
A
Hirata
Koichi
K
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006358:Hot Temperature; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D015427:Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology; D016019:Survival Analysis; D013552:Swine; D013927:Thrombosis / Q000517:prevention & control; D014018:Tissue Distribution; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D009566:Nitrates; D009573:Nitrites; C002744:3-nitrotyrosine; D014443:Tyrosine; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D001219:Aspartate Aminotransferases