MCC-134, a single pharmacophore, opens surface ATP-sensitive potassium channels, blocks mitochondrial ATP-sensitive potassium channels, and suppresses preconditioning

Norihito Sasaki, Mitsushige Murata, Yiru Guo, Su Hyun Jo, Andreas Ohler, Masaharu Akao, Brian O'Rourke, Rui Ping Xiao, Roberto Bolli, Eduardo Marbán

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Abstract

Background - MCC-134 (1-[4-(H-imidazol-1-yl)benzoyl]-N-methylcyclobutane-carbothioamide), a newly developed analog of aprikalim, opens surface smooth muscle-type ATP-sensitive potassium (KATP) channels but inhibits pancreatic KATP channels. However, the effects of MCC-134 on cardiac surface KATP channels and mitochondrial KATP (mitoKATP) channels are unknown. A mixed agonist/blocker with differential effects on the two channel types would help to clarify the role of KATP channels in cardioprotection. Methods and Results - To index mitoKATP channels, we measured mitochondrial flavoprotein fluorescence in rabbit ventricular myocytes. MCC-134 alone had little effect on basal flavoprotein fluorescence. However, MCC-134 inhibited diazoxide-induced flavoprotein oxidation in a dose-dependent manner (EC50=27 μmol/L). When ATP was included in the pipette solution, MCC-134 slowly activated surface KATP currents with some delay (>10 minutes). These results indicate that MCC-134 is a mitoKATP channel inhibitor and a surface KATP channel opener in native cardiac cells. In cell-pelleting ischemia assays, coapplication of MCC-134 with diazoxide abolished the cardioprotective effect of diazoxide, whereas MCC-134 alone did not alter cell death. These results were reproducible in both rabbit and mouse myocytes. MCC-134 also attenuated the effect of ischemic preconditioning against myocardial infarction in mice, consistent with the results of cell-pelleting ischemia assays. Conclusions - A single drug, MCC-134, opens surface KATP channels but blocks mitoKATP channels; the fact that this drug inhibits preconditioning reaffirms the primacy of mitOKATP rather than surface KATP, channels in the mechanism of cardioprotection.

Original languageEnglish
Pages (from-to)1183-1188
Number of pages6
JournalCirculation
Volume107
Issue number8
DOIs
Publication statusPublished - 2003 Mar 4

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Keywords

  • Ischemia
  • Myocardial infarction
  • Potassium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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