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Pretreatment with tumor necrosis factor-α (TNF-α) is known to trigger cardioprotection and it can activate multiple downstream signaling cascades. However, it is not known whether the mitochondrial permeability transition pore and the Ca2+-activated K+ channel (KCa channel) are involved in the TNF-α-induced cardioprotection. In the present study, we examined whether TNF-α inhibits pore opening and activates the KCa channel in the cardioprotection. In isolated rat hearts subjected to 30 min of regional ischemia and 120 min of reperfusion, pretreatment with 10 U/ml TNF-α for 7 min followed by 10 min washout improved the recovery of rate-pressure product (RPP = left ventricular developed pressure × heart rate) and coronary flow (CF) during reperfusion, and reduced the infarct size and release of lactate dehydrogenase (LDH). Administration of 20 μmol/L atractyloside, a pore opener, for the last 5 min of ischemia and first 15 min of reperfusion, and pretreatment with 1 μmol/L paxilline, an inhibitor of the KCa channel, for 5 min before ischemia, attenuated the recovery of RPP and CF, and the reductions of infarct size and release of LDH induced by TNF-α. On the other hand, administration of 10 μmol/L NS 1619, an opener of the KCa channel, for 10 min before ischemia, decreased the infarct size and LDH release, and improved contractile functions and CF; these effects were attenuated by atractyloside. Pretreatment with 0.2 μmol/L cyclosporin A for the last 5 min of ischemia and first 15 min of reperfusion showed similar effects to those of TNF-α, and they were not attenuated by paxilline. In mitochondria isolated from hearts pretreated with 10 U/ml TNF-α for 7 min, a significant inhibition of Ca2+-induced swelling was observed. Furthermore, paxilline attenuated the inhibition of Ca2+-induced mitochondrial swelling by TNF-α. These findings indicate that TNF-α protects the myocardium against ischemia and reperfusion injury by inhibiting mitochondrial permeability transition pore opening as well as activating KCa channels, probably the mitochondrial KCa channel, which is upstream from the pore.