Ischemic preconditioning improves mitochondrial tolerance to experimental calcium overload

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

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Background. Ca2+ overload leads to mitochondrial uncoupling, decreased ATP synthesis, and myocardial dysfunction. Pharmacologically opening of mitochondrial KATP channels decreases mitochondrial Ca2+ uptake, improving mitochondrial function during Ca2+ overload. Ischemic preconditioning (IPC), by activating mitochondrial KATP channels, may attenuate mitochondrial Ca2+ overload and improve mitochondrial function during reperfusion. The purpose of these experiments was to study the effect of IPC (1) on mitochondrial function and (2) on mitochondrial tolerance to experimental Ca2+ overload. Methods. Rat hearts (n = 6/group) were subjected to (a) 30 min of equilibration, 25 min of ischemia, and 30 min of reperfusion (Control) or (b) two 5-min episodes of ischemic preconditioning, 25 min of ischemia, and 30 min of reperfusion (IPC). Developed pressure (DP) was measured. Heart mitochondria were isolated at end-Equilibration (end-EQ) and at end-Reperfusion (end-RP). Mitochondrial respiratory function (state 2, 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, state 3/state 4); rate of oxidative phosphorylation (ADP/Δt), and ADP:O ratio) was measured with polarography using α-ketoglutarate as a substrate in the presence of different Ca2+ concentrations (0 to 5 × 10-7 M) to simulate Ca2+ overload. Results. IPC improved DP at end-RP. IPC did not improve preischemic mitochondrial respiratory function or preischemic mitochondrial response to Ca2+ loading. IPC improved state 3, ADP/Δt, and RCI during RP. Low Ca2+ levels (0.5 and 1 × 10-7 M) stimulated mitochondrial function in both groups predominantly in IPC. The Control group showed evidence of mitochondrial uncoupling at lower Ca2+ concentrations (1 × 10-7 M). IPC preserved state 3 at high Ca2+ concentrations. Conclusions. The cardioprotective effect of IPC results, in part, from preserving mitochondrial function during reperfusion and increasing mitochondrial tolerance to Ca2+ loading at end-RP. Activation of mitochondrial KATP channels by IPC and their improvement in Ca2+ homeostasis during RP may be the mechanism underlying this protection.

Original languageEnglish (US)
Pages (from-to)243-251
Number of pages9
JournalJournal of Surgical Research
Issue number2
StatePublished - 2002
Externally publishedYes


  • Calcium
  • Hearts
  • Ischemic preconditioning
  • Mitochondria
  • Potassium channels
  • Rat
  • Reperfusion injury

ASJC Scopus subject areas

  • Surgery


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