CONSEQUENCES OF UNCONTROLLED CALCIUM ENTRY AND ITS PREVENTION WITH CALCIUM-ANTAGONISTS
CONSEQUENCES OF UNCONTROLLED CALCIUM ENTRY AND ITS PREVENTION WITH CALCIUM-ANTAGONISTS
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DOI：
10.1093/eurheartj/4.suppl_h.43
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发表时间：
1983-01-01
影响因子：
39.3
通讯作者：
FLECKENSTEINGRUN, G
中科院分区：
文献类型：
--
作者：
FLECKENSTEIN, A;FREY, M;FLECKENSTEINGRUN, G
如果游离的细胞外Ca2+离子大量穿过肌膜进入肌质，从而使Ca2+结合或挤出过程的能力变得过强，心肌纤维总是会经历严重的功能和结构改变，最终导致坏死。关键反应包括高能磷酸盐耗竭，这是由 (a) Ca2+ 依赖性细胞内 ATP 酶过度激活和 (b) Ca2+ 诱导的线粒体损伤引起的。细胞内Ca2+超载被证明是以下情况下产生的严重心肌纤维损伤和死亡发病机制的共同点：过量服用β-肾上腺素儿茶酚胺、二氢速甾醇或维生素D3、营养K+或Mg2+缺乏、叙利亚仓鼠遗传性心肌病。此外，在心肌缺氧或缺血过程中会发生细胞内Ca2+超载，从而导致线粒体的额外急剧损伤。我们在 1968 年进行首次观察后发现，在所有这些情况下，Ca2+ 拮抗剂都能够保护心肌细胞的完整性，因为它们可以防止过度的跨膜 Ca2+ 摄取。 Ca2+ 悖论也是如此：Ca2+ 拮抗剂可能抑制 Ca2+ 缺乏的心肌中肌膜渗漏的发展。然而，当 Ca2+ 心肌纤维返回到正常的 Ca2+ 介质时，Ca2+ 拮抗剂更有可能限制 Ca2+ 通过这些渗漏的过度流入。
Heart muscle fibres always undergo severe functional and structural alterations, finally resulting in necrotization, if free extracellular Ca2+ions penetrate abundantly through the sarcolemma membrane into the myoplasm, so that the capacities of the Ca2+binding or extrusion processes become overpowered. The crucial reaction consists of high-energy phosphate exhaustion which is brought about (a) by excessive activation of Ca2+-dependent intracellular ATPases, and (b) by Ca2+induced impairment of the mitochondria. Intracellular Ca2+overload proved to the common denominator in the pathogenesis of severe myocardial fibre injury and death produced under the following circumstances: Overdoses of β-adrenergic catecholamines, dihydrotachysterol or vitamin D3alimentary K+or Mg2+deficiency, hereditary cardiomyopathy of Syrian hamsters. Moreover, intracellular Ca2+overload develops in the course of myocardial hypoxia or ischaemia thus causing additional precipitous damage of the mitochrondria. Following our first observations made in 1968, it has turned out that in all these cases, Ca2+antagonists are capable of protecting myocardial cell integrity in that they prevent excessive transmembrane Ca2+uptake. This is also true of the Ca2+paradox: Ca2+antagonists possibly inhibit the development of sarcolemmal leaks in the Ca2+deprived myocardium. However, it is more likely that Ca2+antagonists restrict the exaggerated influx of Ca2+through these leaks, when the Ca2+myocardial fibres return to a normal Ca2+medium.