New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Mitochondrial Ion Channels and Cardioprotection

Mitochondrial ATP-sensitive K⁺ (mitoK_ATP) and Ca²⁺-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.