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 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.
Nishida
Hirofumi
H
Department of Pharmacology, Chiba University Graduate School of Medicine, Japan. hinishida@faculty.chiba-u.jp
Sato
Toshiaki
T
Ogura
Takehiko
T
Nakaya
Haruaki
H
D053607:Adrenomedullin / Q000378:metabolism; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism
D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; C117780:mitochondrial K(ATP) channel; D053607:Adrenomedullin; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C