Opening of potassium channels protects mitochondrial function from calcium overload

Juan A. Crestanello, Nicolai M. Doliba, Andriy M. Babsky, Natalia M. Doliba, Koki Niibori, Mary D. Osbakken, Glenn J.R. Whitman

Research output: Contribution to journalArticlepeer-review

Abstract

Ischemic preconditioning (IPC) protects myocardium from ischemia reperfusion injury by activating mitochondrial K(ATP) channels. However, the mechanism underlying the protective effect of K(ATP) channel activation has not been elucidated. It has been suggested that activation of mitochondrial K(ATP) 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 K(ATP) 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 x 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 K(ATP) channels either pharmacologically or by IPC may be the result of protecting mito from Ca2+ overload. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)116-123
Number of pages8
JournalJournal of Surgical Research
Volume94
Issue number2
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Calcium overload
  • Mitochondria
  • Oxygen
  • Pinacidil
  • Potassium channel opener

ASJC Scopus subject areas

  • Surgery

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