MECHANISMS OF ARRHYTHMOGENIC DELAYED AND EARLY AFTERDEPOLARIZATIONS IN FERRET VENTRICULAR MUSCLE
MECHANISMS OF ARRHYTHMOGENIC DELAYED AND EARLY AFTERDEPOLARIZATIONS IN FERRET VENTRICULAR MUSCLE
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DOI：
10.1172/jci112701
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发表时间：
1986-11-01
影响因子：
15.9
通讯作者：
WIER, WG
中科院分区：
文献类型：
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作者：
MARBAN, E;ROBINSON, SW;WIER, WG
心肌中药物诱发的触发性心律失常涉及膜电位的振荡，称为延迟后除极或早期后除极（DADs或EADs）。我们研究了雪貂心室肌中DADs和EADs的机制。在暴露于高浓度[Ca²⁺]ₒ、毒毛花苷和/或异丙肾上腺素（以诱导DADs）或氯化铯（以诱导EADs）期间，测量膜电位、张力和水母发光蛋白发光情况。兰尼碱（10⁻⁹ - 10⁻⁶ M），一种肌浆网Ca²⁺释放抑制剂，迅速抑制DADs和触发性心律失常。当通过向细胞内加载Ca²⁺螯合剂BAPTA或喹啉-2来增强细胞质Ca²⁺缓冲能力时，DADs同样受到抑制，收缩力和水母发光蛋白发光情况也是如此。与DADs相反，氯化铯诱导的EADs不受兰尼碱或细胞内加载Ca²⁺螯合剂的抑制。通过高度特异性的二氢吡啶Ca²⁺通道激动剂和拮抗剂评估了跨肌膜Ca²⁺内流可能产生EADs的可能性。贝亚K8644（100 - 300 nM）增强EADs，而尼群地平（3 - 20 μM）消除EADs。我们得出结论，DADs和与DAD相关的触发性心律失常是由细胞内游离Ca²⁺浓度升高所激活，而EADs不需要升高的[Ca²⁺]ᵢ，而是作为Ca²⁺通过肌膜慢Ca²⁺通道内流的直接结果而产生。
Drug-induced triggered arrhythmias in heart muscle involve oscillations of membrane potential known as delayed or early afterdepolarizations (DADs or EADs). We examined the mechanism of DADs and EADs in ferret ventricular muscle. Membrane potential, tension and aequorin luminescence were measured during exposure to elevated [Ca2+]o, strophanthidin and/or isoproterenol (to induce DADs), or cesium chloride (to induce EADs). Ryanodine (10-9-10-6 M), an inhibitor of Ca2+ release from the sarcoplasmic reticulum, rapidly suppressed DADs and triggered arrhythmias. When cytoplasmic Ca2+-buffering capacity was enhanced by loading cells with the Ca2+ chelators BAPTA or quin2, DADs were similarly inhibited, as were contractile force and aequorin luminescence. In contrast to DADs, EADs induced by Cs were not suppressed by ryanodine or by loading with intracellular Ca2+ chelators. The possibility that transsarcolemmal Ca2+ entry might produce EADs was evaluated with highly specific dihydropyridine Ca channel agonists and antagonists. Bay K8644 (100-300 nM) potentiated EADs, whereas nitrendipine (3-20 .mu.M) abolished EADs. We conclude that DADs and DAD-related triggered arrhythmias are activated by an increase in intracellular free Ca2+ concentration, whereas EADs do not require elevated [Ca2+]i but rather arise as a direct consequence of Ca2+ entry through sarcolemmal slow Ca channels.