Mitochondrial ATP-sensitive K(+) (mitoK(ATP)) and Ca(2+)-activated K(+) (mitoK(Ca)) channels exist in cardiac myocytes, and they play key roles in cardioprotection. We have recently reported that K(+) influx through mitoK(ATP) or mitoK(Ca) channels occurs independently of each other and confers cardioprotection in a similar manner. Activation of mitoK(ATP) channel is augmented by protein kinase C (PKC), whereas mitoK(Ca) channel is activated by protein kinase A (PKA). However, phosphatidylinositol 3-kinase (PI3-K) is linked to neither mitoK(ATP) nor mitoK(Ca) channels. We have demonstrated that bioactive substances modulate the opening of mitoK(ATP) channels via a PKC-dependent pathway or opening of mitoK(Ca) channels via a PKA-dependent pathway and thereby protecting the heart from ischemia/reperfusion injury. Several endogenous substances such as adenosine and bradykinin can reduce infarct size by activation of mitoK(ATP) channels in a PKC-dependent manner. Adrenomedullin, a potent vasodilator peptide, potentiates the opening of mitoK(Ca) channels by PKA activation. Treatment with adrenomedullin prior to ischemia results in the reduction of infarct size via a PKA-mediated activation of mitoK(Ca) channels. Thus, some endogenous substances confer cardioprotection via PKA- or PKC-mediated activation of mitoK(ATP) or mitoK(Ca) channels.