MITOCHONDRIAL KATP 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 A T P channel openers have an effect on myocardial protection via a pharmacological preconditioning action. However, it remains unclear as to whether K A T P channel openers can reduce ischemia-reperfusion injury in the liver. The aim of this study was to determine the effects of the mitochondrial K A T P 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.