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Opening of Potassium Channels Protects Mitochondrial Function from Calcium Overload,☆☆

https://doi.org/10.1006/jsre.2000.5979Get rights and content

Abstract

Ischemic preconditioning (IPC) protects myocardium from ischemia reperfusion injury by activating mitochondrial KATP channels. However, the mechanism underlying the protective effect of KATP channel activation has not been elucidated. It has been suggested that activation of mitochondrial KATP channels may prevent mitochondrial dysfunction associated with Ca2+ overload during reperfusion. The purpose of this experiment was to study, in an isolated mitochondrial preparation, the effects of mitochondrial KATP channel opening on mitochondrial function and to determine whether it protects mitochondria form Ca2+ overload. Mitochondria (mito) were isolated from rat hearts by differential centrifugation (n = 5/group). Mito respiratory function was measured by polarography without (CONTROL) or with a potassium channel opener (PINACIDIL, 100 μM). Different Ca2+ concentrations (0 to 5 × 10−7 M) were used to simulate the effect of Ca2+ overload; state 2, mito oxygen consumption with substrate only; state 3, oxygen consumption stimulated by ADP; state 4, oxygen consumption after cessation of ADP phosphorylation; respiratory control index (RCI: ratio of state 3 to state 4); rate of oxidative phosphorylation (ADP/Δt); and ADP:O ratio were measured. PINACIDIL increased state 2 respiration and decreased RCI compared to CONTROL. Low Ca2+ concentrations stimulated state 2 and state 4 respiration and decreased RCI and ADP:O ratios. High Ca2+ concentrations increased state 2 and state 4 respiration and further decreased RCI, state 3, and ADP/Δt. PINACIDIL improved state 3, ADP/Δt, and RCI at high Ca2+ concentrations compared to CONTROL. Pinacidil depolarized inner mitochondrial membrane, as evidenced by decreased RCI and increased state 2 at baseline. Depolarization may decrease Ca2+ influx into mito, protecting mito from Ca2+ overload, as evidenced by improved state 3 and RCI at high Ca2+ concentrations. The myocardial protective effects resulting from activating KATP channels either pharmacologically or by IPC may be the result of protecting mito from Ca2+ overload.

References (42)

  • C.S. Lawson et al.

    Preconditioning: State of the art myocardial protection

    Cardiovasc. Res.

    (1993)
  • R.A. Kloner et al.

    Medical and cellular implications of stunning, hibernation and preconditioning. An NHLBI workshop

    Circulation

    (1998)
  • C.E. Murry et al.

    Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium

    Circulation

    (1986)
  • K.A. Reimer et al.

    Ischemic preconditioning slows ischemic metabolism and limits myocardial infarct size

    Ann. NY Acad. Sci.

    (1994)
  • D.M. Yellon et al.

    Ischemic preconditioning limits infarct size in the rat heart

    Cardiovasc. Res.

    (1992)
  • M. Lazdunski

    ATP sensitive potassium channel: An overview

    J. Cardiovasc. Pharmacol.

    (1994)
  • T. Sato et al.

    Modulation of mitochondrial ATP dependent K channels by protein kinase C

    Circ. Res.

    (1998)
  • G.J. Grover

    Pharmacology of ATP sensitive potassium channel openers in models of myocardial ischemia reperfusion

    Can. J. Physiol. Pharmacol.

    (1997)
  • T. Mizumura et al.

    Bimakalin, an ATP sensitive potassium channel opener mimics the effect of ischemic preconditioning to reduce infarct size, adenosine release and neutrophils function in dogs

    Circulation

    (1995)
  • G.J. Grover

    Protective effects of ATP sensitive potassium channel openers in experimental myocardial ischemia

    J. Cardiovasc. Pharmacol.

    (1994)
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    Presented at the 33rd Annual Meeting of the Association for Academic Surgery, Philadelphia, Pennsylvania, November 1999.

    ☆☆

    This work was partially supported by NIH Grant RO 1-HL39208 (M.D.O.).

    2

    To whom reprint requests should be addressed at University of Maryland Medical System, Department of Surgery, 22 South Greene St., Baltimore, MD 21201.

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