Intracellular Ca2+ and delay of ischemia-induced electrical uncoupling in preconditioned rabbit ventricular myocardium

L.R.C. Dekker, R. Coronel, E.T. VanBavel, J.A.E. Spaan, T. Opthof

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

OBJECTIVE: Short periods of ischemia and reperfusion alter myocardial Ca2+ handling and temporarily induce a mild increase of [Ca2+]i. We hypothesized that these alterations are involved in the cardioprotective mechanism of ischemic preconditioning, possibly via a Ca(2+)-dependent activation of protein kinase C (PKC).

METHODS AND RESULTS: In arterially perfused rabbit papillary muscles, we determined Ca2+ transients (indo 1) and indicators of the onset of irreversible ischemic damage, including [Ca2+]i rise, electrical uncoupling and contracture. We tested three protocols of ischemic preconditioning (1-3). In addition, the effects of infusion of staurosporine, a blocker of PKC (4), or glibenclamide, a blocker of K+ATP channels (5) were analyzed. Furthermore, pretreatment with phorbol 12-myrisate 13-acetate (PMA), an activator of PKC (6), or cyclopiazonic acid (CPA), an inhibitor of the SR Ca2+ pump (7) was tested. During periods of reperfusion in the preconditioning protocols, the duration of the Ca2+ transient and the diastolic Ca2+ level temporarily increased. Only if sustained ischemia was induced during these changes of the transients, cardioprotection was present. Similar alterations of the Ca2+ transient concurring with cardioprotection were induced by pretreatment with PMA as well as CPA. Staurosporine and glibenclamide antagonized the reperfusion-induced changes of the Ca2+ transients as well as cardioprotection. If reperfusion was extended until the Ca2+ transient had normalized, cardioprotection was also absent. Under all conditions tested, the diastolic Ca2+ elevation or the Ca2+ transient prolongation prior to sustained ischemia correlated with the postponement of ischemic injury.

CONCLUSIONS: A pre-ischemic mild increase of [Ca2-]i presents a common effector of preconditioning. Our data suggest that activation of PKC or opening of K+ATP channels may initiate the pathway leading to an alteration of Ca2+ metabolism and a protected status of the myocardium.

Original languageEnglish
Pages (from-to)101-12
Number of pages12
JournalCardiovascular Research
Volume44
Issue number1
Publication statusPublished - Oct 1999
Externally publishedYes

Keywords

  • Adenosine Triphosphate
  • Animals
  • Calcium
  • Calcium Channel Blockers
  • Enzyme Activation
  • Enzyme Inhibitors
  • Female
  • Glyburide
  • In Vitro Techniques
  • Indoles
  • Intracellular Fluid
  • Ischemic Preconditioning, Myocardial
  • Male
  • Myocardial Ischemia
  • Myocardium
  • Papillary Muscles
  • Potassium Channels
  • Protein Kinase C
  • Rabbits
  • Staurosporine
  • Tetradecanoylphorbol Acetate

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