Myocardial Ischemia and Cell Functions - Characterization of Free Radical-Induced Dysfunction of Sarcoplasmic Reticulum Calcium Transport and Excitation-Contraction Coupling System in Myocardium -

已经证明心肌缺血的发生与细胞内pH的显著降低相关，并且提出在急性缺血过程中兴奋-收缩（E-C）偶联系统的破坏在心肌功能障碍中起关键作用。E-C耦合系统的崩溃可以在亚细胞水平上解释缺血肌肉的行为。最近的研究表明，自由基参与心肌缺血诱导的细胞损伤的病理生理。然而，在缺血过程中，自由基参与导致不可逆细胞损伤的一系列事件的程度尚不清楚，自由基对肌浆网（SR）功能的影响机制，在E-C耦合系统中耦合钙的源和汇，需要澄清。在目前的研究项目中，我们考虑的证据支持的假设，羟基自由基，而不是超氧阴离子，参与的机制，可能会导致增加的钙渗透性的SR膜在pH 6.4，缺血心肌的细胞内pH值，和羟基自由基的影响是钙调素依赖性。还有证据表明，SR功能的这种破坏可能是细胞内钙超载的来源。因此，羟基自由基的产生可能代表了通过SR功能障碍导致心肌缺血组织破坏的最终途径。

It has been demonstrated that the onset of myocardial ischemia is associated with a significant decrease in intracellular pH and proposed that breakdown of the excitation-contraction (E-C) coupling system plays a pivotal role in myocardial dysfunction during the course of acute ischemia. A breakdown of the E-C coupling system can explain the behavior of the ischemic muscle at a subcellular level. Recent studies suggest an involvement of free radicals in the pathophysiology of myocardial ischemia-induced cell damage. However, the extent of free radical involvement in the series of events leading to irreversible cell injury during the course of ischemia is unknown, and the mechanism of the effect of free radicals on function of sarcoplasmic reticulum (SR), the source and sink for coupling calcium in the E-C coupling system, requires clarification. In the present research project we consider the evidence supporting the hypothesis that hydroxyl radical, but not superoxide anion, is involved in a mechanism that may cause an increase in the calcium permeability of the SR membrane at pH 6.4, the intracelluar pH of the ischemic myocardium, and that the effect of hydroxyl radical is calmodulin dependent. There is also evidence that this breakdown in SR function may serve as the source of intracellular calcium overload. Thus it would appear that the generation of hydroxyl radical may represent a final pathway leading to tissue destruction in myocardial ischemia via SR dysfunction.