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

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.

• Authors: L R Dekker, R Coronel, E VanBavel, J A Spaan, T Opthof
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 44 Issue 1 Pg. 101-12 (Oct 1999) ISSN: 0008-6363 [Print] England
• PMID: 10615394 (Publication Type: Journal Article)

Chemical References

• Calcium Channel Blockers
• Enzyme Inhibitors
• Indoles
• Potassium Channels
• Adenosine Triphosphate
• Protein Kinase C
• Staurosporine
• Tetradecanoylphorbol Acetate
• Glyburide
• Calcium
• cyclopiazonic acid

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Female
• Glyburide (pharmacology)
• In Vitro Techniques
• Indoles (pharmacology)
• Intracellular Fluid (metabolism)
• Ischemic Preconditioning, Myocardial
• Male
• Myocardial Ischemia (physiopathology, prevention & control)
• Myocardium (metabolism)
• Papillary Muscles (drug effects, physiopathology)
• Potassium Channels (drug effects, metabolism)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Rabbits
• Staurosporine (pharmacology)
• Tetradecanoylphorbol Acetate (pharmacology)