Mitochondrial K(ATP) channel opener prevents ischemia-reperfusion injury in rat liver.
Ischemia-reperfusion injury is responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. Recently, it has been reported that mitochondrial K(ATP) channel openers have an effect on myocardial protection via a pharmacological preconditioning action. However, it remains unclear as to whether K(ATP) channel openers can reduce ischemia-reperfusion injury in the liver. The aim of this study was to determine the effects of the mitochondrial K(ATP) channel opener, nicorandil, on ischemia-reperfusion injury in the rat liver. Male Wistar rats were subjected to 73% ischemia for 45 minutes followed by 120 minutes of reperfusion. Nicorandil (3 mg/kg) was orally administered 60 minutes before hepatic ischemia. Nicorandil significantly decreased plasma levels of alanine aminotransferase and lactate dehydrogenase by about 50% and inhibited the remarkably increased TUNEL-positive hepatocytes after reperfusion. Some mediators associated with apoptosis were analyzed by Western blotting. Cytochrome-c and caspase-3 levels in the cytosol increased after reperfusion; nicorandil inhibited the release of cytochrome-c and activation of caspase-3. The expression of Bax and Bcl-2 was significantly increased after reperfusion, being slightly inhibited by the administration of nicorandil. These results suggest that the protective effects of nicorandil against hepatic ischemia-reperfusion injury correlate with the inhibition of mitochondrial cytochrome-c release and caspase-3 activation. These findings demonstrate that nicorandil may become a therapeutic drug for ischemia reperfusion-related liver injury.
Hai
S
S
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan. m4011498@msic.med.osaka-cu.ac.jp
Takemura
S
S
Minamiyama
Y
Y
Yamasaki
K
K
Yamamoto
S
S
Kodai
S
S
Tanaka
S
S
Hirohashi
K
K
Suehiro
S
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015640:Ion Channel Gating / Q000502:physiology*; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D020108:Nicorandil / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D014665:Vasodilator Agents / Q000494:pharmacology
D015221:Potassium Channels; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D020108:Nicorandil