Azimilide causes reverse rate-dependent block while reducing both components of delayed-rectifier current in canine ventricular myocytes.
Azimilide causes reverse rate-dependent block while reducing both components of delayed-rectifier current in canine ventricular myocytes.
复制标题
阿齐利特引起反向速率依赖性阻滞，同时减少犬心室肌细胞中延迟整流电流的两个分量。
DOI：
10.1097/00005344-199806000-00020
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发表时间：
1998
影响因子：
3
通讯作者：
Gintant,GA
中科院分区：
文献类型：
--
作者：
Gintant,GA
大多数III类抗心律失常药物减少延迟整流电流（I Kr）的快速激活成分，而不影响缓慢激活成分（I Ks）。最近据报道，新型抗心律失常药阿齐利特 (NE-10064) 在低（纳摩尔）浓度下可增强 IKs，在较高（微摩尔）浓度下可阻断 IKr 和 IKs。为了进一步了解阿齐利特的电生理效应，我们比较了它对犬心室肌细胞的 I Kr 和 I Ks（通过使用全细胞钳技术）和动作电位（微电极和穿孔贴片技术）的影响。较低的阿齐利特浓度 (50 nM) 不会增强 I Ks。相比之下，治疗性阿齐利特浓度（2 μM）在去极化测试脉冲期间减少 I Kr（300 毫秒等时线）和 I Ks（3 s 等时线）约 40% 以及减少复极化时的 I Kr（减少 38%）和 I Ks（减少 33%）尾电流方面是等效的。 I Ks 的阻滞与正测试电位下的电压无关。在动作电位研究中，50 nM 阿齐利特对动作电位持续时间 (APD) 没有影响，而 2 μM 阿齐利特延迟复极并对 APD 产生反向速率依赖性影响。尽管阿齐利特引起的 APD 延长程度与无药物 APD 无关，但阿齐利特优先夸大了在无药物条件下表现出最陡 APD 速率关系的肌细胞的 APD 速率关系。总之，引起犬心室 I Kr 和 I Ks 相当降低的阿齐利特治疗浓度会产生反向速率依赖性效应，这取决于 APD 速率关系的陡度。
Most class III antiarrhythmic drugs reduce the rapidly activating component of delayed-rectifier current (I Kr) without affecting the slowly activating component (I Ks). Recently the novel antiarrhythmic agent azimilide (NE-10064) was reported to enhance I Ks at low (nanomolar) concentrations and to block both I Kr and I Ks at higher (micromolar) concentrations. Further to understand the electrophysiologic effects of azimilide, we compared its effects on I Kr and I Ks (by using whole cell clamp techniques) and action potentials (microelectrode and perforated-patch techniques) on canine ventricular myocytes. A lower azimilide concentration (50 nM) did not enhance I Ks. In contrast, a therapeutic azimilide concentration (2 μM) was equieffective in reducing I Kr (300-ms isochrones) and I Ks (3-s isochrones) by∼ 40% during depolarizing test pulses, as well as reducing I Kr (38% decrease) and I Ks (33% decrease) tail currents on repolarization. Block of I Ks was independent of voltage at positive test potentials. In action-potential studies, 50 nM azimilide had no effect on the action-potential duration (APD), whereas 2 μM azimilide delayed repolarization and caused reverse rate-dependent effects on the APD. Whereas the extent of APD prolongation by azimilide was not correlated with the drug-free APD, azimilide preferentially exaggerated the APD-rate relationship of myocytes displaying the steepest APD-rate relationship under drug-free conditions. In conclusion, therapeutic concentrations of azimilide that cause comparable reduction of canine ventricular I Kr and I Ks exert reverse rate-dependent effects, which are dependent on the steepness of the APD-rate relationship.