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

304 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
Publication statusPublished - 2001 Nov 9
Externally publishedYes

Fingerprint

KATP Channels
Reperfusion
Ischemia
Diazoxide
Permeability
Fluorescence
Bongkrekic Acid
Ischemic Preconditioning
Mitochondrial Membrane Potential
Mitochondrial Membranes
Calcium Channels
Cardiac Myocytes
Confocal Microscopy
Muscle Cells
Cyclosporine
mitochondrial K(ATP) channel
Homeostasis
Rabbits
Calcium
rhod-2

Keywords

  • Cardioprotection
  • Ischemia
  • Mitochondrial calcium overload

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca2+ overload during simulated ischemia and reperfusion : Possible mechanism of cardioprotection. / Murata, Mitsushige; Akao, Masaharu; O'Rourke, Brian; Marbán, Eduardo.

In: Circulation Research, Vol. 89, No. 10, 09.11.2001, p. 891-898.

Research output: Contribution to journalArticle

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