Nonlinear dynamics of heart beat rhythm during ischemia / reperfusion and death of cardiac myocytes.

心肌细胞凋亡已在缺血/再灌注损伤的动物模型以及充血性心力衰竭或急性心肌梗死患者中得到证实。然而，负责心肌细胞凋亡的机制仍然在很大程度上未知。本研究旨在阐明缺血/再灌注心脏损伤诱发心律失常的机制。结果表明：（1）放线菌酮（CHX）抑制新生大鼠心肌细胞蛋白质合成可引起心肌细胞特异性凋亡样细胞死亡。CHX诱导的心肌细胞死亡减少的治疗与细胞渗透性，特异性抑制剂caspase-3（CPP 32）。活性氧物质（ROS）似乎参与CHX诱导的心肌细胞死亡，因为这种细胞死亡是由Mn（III）四（苯甲酸）卟啉（MnTBAP），一种细胞渗透性超氧化物歧化酶模拟物的共同治疗。我们的研究结果表明，心肌细胞凋亡可能不需要从头蛋白质合成，蛋白质合成抑制本身将导致心肌细胞凋亡。(2)在培养的新生大鼠离体心肌细胞中，缺氧缺糖（体外缺血）导致收缩间期延长和搏动节律波动。然而，在体外缺血期间，心肌细胞之间的同步化保持不变。这一结果表明，心肌细胞之间的缝隙连接在缺氧/缺血期间保持开放的可能性。(3)在Langendorff灌流心脏从成年大鼠，全脑缺血导致的心脏周期延长，心脏最终停止跳动，在约10分钟。然而，心脏跳动节律恢复到对照组在大多数Langendorff制剂再灌注后。在某些情况下，再灌注可引起心肌样不规则搏动。

Cardiomyocyte apoptosis has been demonstrated in animal models of ischemia/reperfusion injury as well as patients with congestive heart failure or acute myocardial infarction. However, the mechanism responsible for cardiomyocyte apoptosis remains largely unknown. The present study aimed at elucidating the mechanisms responsible for the induction of cardiac arrhythmia associated with ischemia/reperfusion cardiac injury. The results obtained from this study are summarized as follows:(1) In the cultured dissociated myocytes from neonatal rats, inhibition of de novo protein synthesis itself by cycloheximide (CHX) evoked myocyte-specific apoptosis-like cell death. CHX-induced myocyte death was reduced by a treatment with a cell-permeable, specific inhibitor of caspase-3 (CPP32). Reactive oxygen Species (ROS) appeared to be involved in the CHX-induced myocyte death, because such cell death was prevented by co-treatment of Mn(III) tetrakis(benzoic acid) porphyrin (MnTBAP), a cell-permeable superoxide dismutase mimic. Our results suggest a possibility that cardiomyocyte apoptosis would not require de novo protein synthesis, and that protein synthesis inhibition itself would result in the myocyte apoptosis.(2) In the cultured dissociated myocytes from neonatal rats, hypoxia and glucose deprivation (in vitro ischemia) resulted in the increase of the contraction interval and of the fluctuation of the beating rhythm. However, synchronization between myocytes remained unchanged during in vitro ischemia. This result suggests a possibility that gap-junction among myocytes remained open during hypoxia/ischemla.(3) In the Langendorff-perfused heart from adult rats, global ischemia resulted in the elongation of heart periods, and the heart eventually stopped beating in about 10 min. However, heart beat rhythm recovered to the control one after reperfusion in most of the Langendorff preparations. In some cases, reperfusion induced arrhythmia-like irregular beat.