© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Intracellular Ca2+ and delay of ischemia-induced electrical uncoupling in preconditioned rabbit ventricular myocardium
Department of Clinical and Experimental Cardiology (L.R.C.D., R.C., T.O.) and the Department of Medical Physics (E.V., J.A.E.S.), Academic Medical Center, Amsterdam, The Netherlands
* Corresponding author. Tel.: +31-20-566-3266; fax:+31-20-697-5458 L.R.Dekker{at}AMC.UVA.NL
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 Ca2+-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.
KEYWORDS Experimental; Heart; Pathophysiology; Preconditioning; Calcium; Ischemia; Reperfusion
For this paper Dr. K. Sipido (Leuven, Belgium) acted as guest editor.
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