Mechanism of Oxygen Free Radical-Induced Cellular Damage in Myocardium

我们验证了氧自由基引起的肌浆网(SR)和肌膜功能的破坏可能是细胞内钙超载的来源的假说，这与在缺血心肌中看到的相似，并将体外结果外推到缺血心肌。结果表明：1)氧自由基能抑制肌浆网钙离子的积累，表现为钙负荷的降低和钙通透性的增加，而氧自由基生成系统对钙离子蓄积的抑制可能不是钙泵抑制的主要原因。2)SR囊泡钙离子通量的钙调素依赖组分直接被氧自由基修饰，氧自由基能通过钙调素抑制钙外流途径增加钙释放，从而减少稳态钙蓄积。3)氧自由基对肌原纤维…无影响更多的Pca-ATPase曲线。4)氧自由基降低肌膜Na~+，K~+-ATPase活性，刺激Na~+-Ca~(2+)&Gt~(2+)交换活性。5)氧自由基致左回旋支冠状动脉内皮依赖性收缩和超氧化物歧化酶抑制收缩。6)上述所有这些效应似乎都与氧自由基和/或密切相关的氧自由基有关，可能是氧自由基的作用。氧自由基的缺乏可能表明收缩蛋白的结构没有发生变化。因此，我们假设，在缺血过程中产生的氧自由基攻击的主要靶细胞器是兴奋-收缩耦合系统的一部分，该系统调节钙向收缩蛋白的输送(SR和肌膜)，而不是收缩蛋白本身。缺血心肌细胞内钙超载的发生在心功能不全中起重要作用，氧自由基可改变参与Na~+-Ca~(2+)&Gt~(2+)交换活性的肌浆网钙离子外流途径和肌膜Na~(++)，K~+-ATPase活性。此外，还推测氧自由基参与了冠状动脉痉挛的发生。较少

We tested the hypothesis that oxygen free radical-induced breakdown in the function of sarcoplasmic reticulum (SR) and sarcolemma may serve as the source of intracellular calcium overload analogous to that seen in the ischemic myocardium, and extrapolated the in vitro results to the ischemic myocardium. The following results were obtained:1) Oxygen free radicals can produce a dininished level of accumulated calcium of SR, which is reflected by the decreased calcium load and an increase in calcium permeability, and the decreased calcium accumulation in the presence of oxygen free radical generating system may not be mainly due to an inhibited calcium pump. 2) Calmodulin-dependent component of calcium fluxes in SR vesicles is modified directly by oxygen free radicals, and oxygen free radicals can reduce steady-state calcium accumulation due to increased calcium release through a calcium efflux pathway which is inhibited by calmodulin. 3) Oxygen free radicals have no effect on myofibrilla … More r pCa-ATPase curve. 4) Oxygen free radicals reduce sarcolemmal Na^+, K^+ -ATPase activity and stimulate Na^+-Ca^<2+> exchange activity. 5) Oxygen free radicals produce endothelium-dependent and SOD inhibitable contraction of isolated left circumflex coronary arteries. 6) All these effects described above seem to be responsible for ^.O^-_ and/or closely related species of oxygen free radical, possibly ^.OH.The lack of an effect of oxygen free radicals may suggest that no structural alterations of contractile proteins have occurred. Thus, we would hypothesize that a major target organelles attacked by oxygen free radicals generated during the ischemic process is the portion of the excitation-contraction coupling system that regulates calcium delivery (the SR and sarcolemmal membrane) to the contractile proteins and not the contractile proteins per se. The SR calcium efflux pathways and sarcolemmal Na^+,K^+-ATPase involving Na^+-Ca^<2+> exchange activity may be altered by oxygen free radicals in ischemic myocardium where the occurrence of intracellular calcium overload plays an important role in cardiac dysfunction. Furthermore, it is postulated that oxygen free radicals participate in spasmogenesis in coronary vessels. Less