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

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Mitochondrial ATP-sensitive K+ (mitoKATP) and Ca2+-activated K+ (mitoKCa) channels exist in cardiac myocytes, and they play key roles in cardioprotection. We have recently reported that K+ influx through mitoKATP or mitoKCa channels occurs independently of each other and confers cardioprotection in a similar manner. Activation of mitoKATP channel is augmented by protein kinase C (PKC), whereas mitoKCa channel is activated by protein kinase A (PKA). However, phosphatidylinositol 3-kinase (PI3-K) is linked to neither mitoKATP nor mitoKCa channels. We have demonstrated that bioactive substances modulate the opening of mitoKATP channels via a PKC-dependent pathway or opening of mitoKCa 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 mitoKATP channels in a PKC-dependent manner. Adrenomedullin, a potent vasodilator peptide, potentiates the opening of mitoKCa channels by PKA activation. Treatment with adrenomedullin prior to ischemia results in the reduction of infarct size via a PKA-mediated activation of mitoKCa channels. Thus, some endogenous substances confer cardioprotection via PKA- or PKC-mediated activation of mitoKATP or mitoKCa channels.
社団法人日本薬理学会の論文
2009-03-20