Intracellular Ca2+ and delay of ischemia-induced electrical uncoupling in preconditioned rabbit ventricular myocardium
Intracellular Ca2+ and delay of ischemia-induced electrical uncoupling in preconditioned rabbit ventricular myocardium
复制标题
DOI：
10.1016/s0008-6363(99)00179-0
复制
发表时间：
1999-10-01
影响因子：
10.8
通讯作者：
Opthof, T
中科院分区：
文献类型：
--
作者：
Dekker, LRC;Coronel, R;Opthof, T
目的：短时缺血再灌流改变心肌细胞内钙离子浓度，引起心肌细胞内钙离子浓度轻度升高。我们推测，这些改变与缺血预适应的心脏保护机制有关，可能是通过钙依赖的蛋白激酶C(PKC)激活。方法和结果：在动脉灌流的兔乳头状肌上，我们测定了钙瞬变(Indo 1)和不可逆性缺血损伤开始的指标，包括[Ca~(2+)](I)升高、电脱偶联和收缩。我们测试了三种缺血预适应方案(1-3)。此外，还分析了PKC阻断剂星形孢子素(4)或K-ATP(+)通道阻断剂格列本脲(5)的作用。此外，我们还检测了PKC激活剂佛波酯(PMA)或肌质网钙泵抑制剂环匹亚硝酸(CPA)的预处理效果。在预适应方案的再灌注期，钙瞬变的持续时间和舒张期钙水平暂时增加。只有在这些瞬变过程中诱发持续的缺血，才有心脏保护作用。PMA和CPA均可引起伴随心肌保护的钙瞬变的类似改变。星形孢菌素和格列本脲可拮抗再灌流引起的钙瞬变和心肌保护作用。如果再灌流时间延长，直到钙离子瞬变恢复正常，心脏保护也会消失。在所有受试条件下，持续缺血前舒张期钙升高或一过性钙延长与缺血损伤的延缓有关。结论：缺血前[Ca~(2+)](I)轻度升高是预适应的常见效应因素。我们的数据提示，PKC的激活或K-ATP(+)通道的开放可能启动了导致钙代谢改变和心肌保护状态的通路。(C)1999 Elsevier Science B.V.保留所有权利。
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. (C) 1999 Elsevier Science B.V. All rights reserved.