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Ischemic preconditionining has been shown to trigger a signaling pathway by potentiating tyrosine kinase phosphorylation leading to the activation of p38 MAP kinase and MAPKAP kinase 2. Recently, the nuclear transcription factor, NFκB, was found to play a role in the signaling process. Since NFκB is a target of oxygen free radicals, we hypothesized that reactive oxygen species might play a role in the signaling process. To test this hypothesis, isolated rat hearts were perfused in the absence or presence of either dimethyl thiourea (DMTU), a OH· radical scavenger, or SN 50 peptide, a NFκB blocker. Hearts were then subjected to ischemic preconditioning by four repeated episodes of 5 min ischemia each followed by 10 min reperfusion. All hearts were then made globally ischemic for 30 min followed by 2 h of reperfusion. The results of our study demonstrated enhanced tyrosine kinase phosphorylation during ischemic preconditioning which was blocked by DMTU. DMTU also inhibited preconditioning mediated increased phosphorylation of p38 MAP kinase and MAPKAP kinase 2 activity. However, DMTU had no effect on the translocation and activation of protein kinase C (PKC) resulting from preconditioning. Preconditioning reduced myocardial infarct size as expected. This cardioprotective effect of preconditioning was abolished by both DMTU and SN 50. Preconditioning resulted in the nuclear translocation and activation of NFκB. Increased NFκB binding was blocked by both DMTU and SN 50. The results of this study demonstrate that reactive oxygen species play a crucial role in signal transduction mediated by preconditioning. This signaling process appears to be potentiated by tyrosine kinase phosphorylation resulting in the activation of p38 MAP kinase and MAPKAP kinase 2 leading to the activation of NFκB suggesting a role of oxygen free radicals as second messenger. Free radical signaling seems to be independent of PKC although PKC is activated during preconditioning process suggesting the role of two separate signaling pathways in ischemic preconditioning.