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

The role of mitochondrial free radicals in the cardioprotective effect of i schemic preconditioning was examined in isolated buffer-perfused rat hearts . Infarct size in control rat hearts subjected to 30 min of regional ischem ia and 120 min of reperfusion was 32.6 +/- 3.4% of the risk zone. Ischemic preconditioning (3 cycles of 5-min global ischemia/5-min reperfusion) befor e the same regional ischemia and reperfusion protocol significantly reduced infarct size to 2.6 +/- 0.8% of the risk zone. Perfusion with menadione (3 .0 muM), a generator of mitochondrial free radicals, in lieu of preconditio ning ischemia significantly reduced infarction to 10.9 +/- 2.7%. N-2-mercap topropionylglycine (1.0 mM), a free radical scavenger, blocked the protecti on of menadione, significantly increasing infarction to 23.5 +/- 1.1%. Myxo thiazol (0.6 muM), a site III mitochondrial inhibitor, blocked the protecti on of menadione and significantly increased infarction to 25.2 +/- 3.8%. Th e infarct-limiting effect of menadione was attenuated to 19.7 +/- 1.5% of t he risk zone by 10 muM SB203580, a p38 mitogen-activated protein kinase (MA PK) inhibitor. Furthermore, menadione significantly increased p38 MAPK phos phorylation to a level 5.6-fold over basal. These results indicate that fre e radicals that originate within mitochondria can activate p38 MAPK and pro tect hearts against infarction.