Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca2+ overload during simulated ischemia and reperfusion: Possible mechanism of cardioprotection

Mitsushige Murata, Masaharu Akao, Brian O'Rourke, Eduardo Marbán

Research output: Contribution to journalArticle

313 Citations (Scopus)

Abstract

Mitochondrial ATP-sensitive potassium (mitoKATP) channels play a key role in ischemic preconditioning of the heart. However, the mechanism of cardioprotection remains controversial. We measured rhod-2 fluorescence in adult rabbit ventricular cardiomyocytes as an index of mitochondrial matrix Ca2+ concentration ([Ca2+]m), using time-lapse confocal microscopy. To simulate ischemia and reperfusion (I/R), cells were exposed to metabolic inhibition (50 minutes) followed by washout with control solution. Rhod-2 fluorescence gradually increased during simulated ischemia and rose even further with reperfusion. The mitoKATP channel opener diazoxide attenuated the accumulation of [Ca2+]m during simulated I/R (EC50=18 μmol/L). These effects of diazoxide were blocked by the mitoKATP channel antagonist 5-hydroxydecanoate (5HD). In contrast, inhibitors of the mitochondrial permeability transition (MPT), cyclosporin A and bongkrekic acid, did not alter [Ca2+]m accumulation during ischemia, but markedly suppressed the surge in rhod-2 fluorescence during reperfusion. Measurements of mitochondrial membrane potential, ΔΨm, in permeabilized myocytes revealed that diazoxide depolarized ΔΨm (by 12% at 10 μmol/L, P<0.01) in a 5HD-inhibitable manner. Our data support the hypothesis that attenuation of mitochondrial Ca2+ overload, as a consequence of partial mitochondrial membrane depolarization by mitoKATP channels, underlies cardioprotection. Furthermore, mitoKATP channels and the MPT differentially affect mitochondrial calcium homeostasis: mitoKATP channels suppress calcium accumulation during I/R, while the MPT comes into play only upon reperfusion.

Original languageEnglish
Pages (from-to)891-898
Number of pages8
JournalCirculation research
Volume89
Issue number10
DOIs
Publication statusPublished - 2001 Nov 9

Keywords

  • Cardioprotection
  • Ischemia
  • Mitochondrial calcium overload

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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