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

Objective: Short periods of ischemia and reperfusion alter myocardial Ca2handling and temporarily induce a mild increase of [Ca2+](i). We hypothesiz ed that these alterations are involved in the cardioprotective mechanism of ischemic preconditioning, possibly via a Ca2+-dependent activation of prot ein kinase C (PKC). Methods and Results: In arterially perfused rabbit papi llary muscles, we determined Ca2+ transients (indo 1) and indicators of the onset of irreversible ischemic damage, including [Ca2+](i) rise, electrica l uncoupling and contracture. We tested three protocols of ischemic precond itioning (1-3). In addition, the effects of infusion of staurosporine, a bl ocker of PKC (4), or glibenclamide, a blocker of K-ATP(+) channels (5) were analyzed. Furthermore, pretreatment with phorbol 12-myrisate 13-acetate (P MA), 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 preco nditioning protocols, the duration of the Ca2+ transient and the diastolic Ca2+ level temporarily increased. Only if sustained ischemia was induced du ring these changes of the transients, cardioprotection was present. Similar alterations of the Ca2+ transient concurring with cardioprotection were in duced by pretreatment with PMA as well as CPA. Staurosporine and glibenclam ide antagonized the reperfusion-induced changes of the Ca2+ transients as w ell as cardioprotection. If reperfusion was extended until the Ca2+ transie nt had normalized, cardioprotection was also absent. Under all conditions t ested, the diastolic Ca2+ elevation or the Ca2+ transient prolongation prio r 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 ope ning of K-ATP(+) channels may initiate the pathway leading to an alteration of Ca2+ metabolism and a protected status of the myocardium. (C) 1999 Else vier Science B.V. All rights reserved.