Menadione mimics the infarct-limiting effect of preconditioning in isolated rat hearts

The role of mitochondrial free radicals in the cardioprotective effect of ischemic preconditioning was examined in isolated buffer-perfused rat hearts. Infarct size in control rat hearts subjected to 30 min of regional ischemia and 120 rain of reperfusion was 32.6 [+ or -] 3.4% of the risk zone. Ischemic preconditioning (3 cycles of 5-min global ischemia/5-min reperfusion) before the same regional ischemia and reperfusion protocol significantly reduced infarct size to 2.6 [+ or -] 0.8% of the risk zone. Perfusion with menadione (3.0 [micro]M), a generator of mitochondrial free radicals, in lieu of preconditioning ischemia significantly reduced infarction to 10.9 [+ or -] 2.7%. N-2-mercaptopropionylglycine (1.0 mM), a free radical scavenger, blocked the protection of menadione, significantly increasing infarction to 23.5 [+ or -] 1.1%. Myxothiazol (0.6 [micro]M), a site III mitochondrial inhibitor, blocked the protection of menadione and significantly increased infarction to 25.2 [+ or -] 3.8%. The infarct-limiting effect of menadione was attenuated to 19.7 [+ or -] 1.5% of the risk zone by 10 [micro]M SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Furthermore, menadione significantly increased p38 MAPK phosphorylation to a level 5.6-fold over basal. These results indicate that free radicals that originate within mitochondria can activate p38 MAPK and protect hearts against infarction. myocardial infarction; ischemia; mitochondria; p38 MAPK