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，心肌细胞凋亡的机制在很大程度上仍然未知。本研究旨在阐明心肌缺血/再灌注损伤诱发心律失常的机制。本研究结果总结如下：(1)在培养的新生大鼠游离肌细胞中，环己亚胺（CHX）抑制新生蛋白合成本身可引起肌细胞特异性凋亡样细胞死亡。用细胞可渗透的特异性caspase-3抑制剂（CPP32）处理可减少chx诱导的心肌细胞死亡。活性氧（ROS）似乎参与了chx诱导的心肌细胞死亡，因为这种细胞死亡可以通过Mn（III）四苯甲酸卟啉（mntpap）（一种细胞渗透性超氧化物歧化酶模拟物）的共同处理来防止。我们的结果提示心肌细胞凋亡可能不需要从头合成蛋白质，而蛋白质合成抑制本身会导致心肌细胞凋亡。(2)在培养的新生大鼠离体肌细胞中，缺氧和葡萄糖剥夺（体外缺血）导致收缩间隔时间延长和搏动节律波动增加。然而，在体外缺血期间，肌细胞之间的同步保持不变。这一结果提示在缺氧/缺血时，肌细胞间的间隙连接可能保持开放。(3)在成年大鼠langendorff灌注心脏中，全身缺血导致心脏周期延长，心脏最终在10 min左右停止跳动。然而，大多数Langendorff制剂在再灌注后心跳节律恢复到对照组。在某些情况下，再灌注引起心律失常样的不规则搏动。

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.