Electrophysiologic characterization of dronedarone in guinea pig ventricular cells
Electrophysiologic characterization of dronedarone in guinea pig ventricular cells
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DOI：
10.1097/00005344-200302000-00007
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发表时间：
2003-02-01
影响因子：
3
通讯作者：
Nisato, D
中科院分区：
文献类型：
--
作者：
Gautier, P;Guillemare, E;Nisato, D
本文研究了非碘化胺碘酮类药物曲尼达酮(SR33589)对豚鼠心脏乳头肌动作电位(AP)、收缩、膜离子电流、钙瞬变和收缩的电生理特性。在多细胞制剂中，屈尼达酮(3、10和30um)降低AP的最大上升速率(dv/dtmax)，且呈浓度和频率依赖关系；静息电位不变，AP幅度仅在30um时降低。除最高浓度时AP时程(30%)和时程(50%)略有下降外，不同复极百分比的AP时程(APDS)变化不明显。在分离的心室肌细胞上，屈尼达酮抑制快速激活延迟整流钾电流(I-Kr)(半数抑制浓度[IC50]小于或等于3微米；不依赖电压)；缓慢激活延迟整流钾电流(I-Ks)(IC50类似或等于10微米；电压依赖和时间、频率或使用无关)；和内向整流钾电流(I-K1)(IC50大于或等于30微米)。在刺激频率为0.033 Hz时，丹参酮以使用和频率依赖的方式阻断L型钙电流(I-Ca(L))(IC_(50)=0.18+/-0.033微米)。在这些电生理效应的同时，屈尼达酮降低了乳头肌的收缩幅度，减少了心室肌细胞的钙瞬变和缩短。结果表明，曲尼达酮可降低Dv/dtmax(I-Na)、I-Ca(L)、I-Kr、I-Ks和I-Ki，是一种多通道阻滞剂。伴随这些效应的是细胞内游离钙和收缩幅度的降低。无论刺激频率如何，都不会显著改变动作电位时程。我们的数据表明，尽管其分子结构中没有碘，但其急性电生理特性与胺碘酮在心室部的非常相似。
The electrophysiological properties of dronedarone (SR33589), a noniodinated amiodarone-like agent, were studied on action potential (AP) and contraction of papillary muscle and on membrane ionic currents, Ca2+ transient, and shortening of ventricular cells of the guinea pig heart. In multicellular preparations, dronedarone (3, 10, and 30 muM) decreased maximum rate of rise of AP (dV/dt max) with a concentration- and frequency-dependent relationship; resting potential was not modified and AP amplitude was decreased only at 30 muM. The effects of dronedarone on AP durations (APDs) at different percentages of repolarization were not significantly changed, except for a slight decrease in APD(30) and APD(50) at the highest concentration. In isolated ventricular myocytes, dronedarone inhibited rapidly activating delayed-rectifier K+ current (I-Kr) (median inhibitory concentration [IC50] less than or equal to 3 muM; voltage-independent); slowly activating delayed-rectifier K+ current (I-Ks) (IC50 similar or equal to 10 muM; voltage-dependent and time-, frequency-, or use-independent); and inward rectifier potassium current (I-K1) (IC50 greater than or equal to 30 muM). Dronedarone blocked L-type Ca2+ current (I-Ca(L)) (IC50 = 0.18 +/- 0.018 muM at a stimulation frequency of 0.033 Hz) in a use- and frequency-dependent manner. Simultaneously to these electrophysiological effects, dronedarone reduced contraction amplitudes of papillary muscle and decreased Ca2+ transient and shortening of ventricular myocytes. The results show that dronedarone is a multichannel blocker because it decreases dV/dt max (I-Na), I-Ca(L), I-Kr, I-Ks, and I-KI. These effects are accompanied by a reduction in free intracellular calcium and contraction amplitudes. Dronedarone does not significantly change APD whatever the stimulation frequency. Our data demonstrate that the acute electrophysiological characteristics of dronedarone, despite absence of iodine in its molecular structure, are very similar to those of amiodarone in cardiac ventricle.