Effect of a neuroprotective drug, eliprodil on cardiac repolarisation:: importance of the decreased repolarisation reserve in the development of proarrhythmic risk
Effect of a neuroprotective drug, eliprodil on cardiac repolarisation:: importance of the decreased repolarisation reserve in the development of proarrhythmic risk
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DOI：
10.1038/sj.bjp.0705901
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发表时间：
2004-09-01
影响因子：
7.3
通讯作者：
Varró, A
中科院分区：
文献类型：
--
作者：
Lengyel, C;Dézsi, L;Varró, A
1 本研究的目的是分析埃利普地尔（一种具有神经保护特性的非心脏药物）在体外、正常条件下以及通过用 BaCl2 阻断内向整流钾电流 (I-K1) 电流衰减“复极储备”后对心脏复极的影响。2 通过应用传统微电极技术在犬右心室乳头肌中，正常情况下，埃利普地尔 (1 muM) 产生了动作电位持续时间的中度反向速率依赖性延长（周期长度为 300、1000 和 5000 ms 时分别为 7.4 +/- 1.5、8.9 +/- 2.1 和 9.9 +/- 1.8%；n = 9）。3 在 I-K1 先前被 BaCl2 (10 mM) 阻断的制剂中，这种效应得到增强。 BaCl2 单独以反向频率依赖性方式延长 APD（在周期长度为 300、1000 和 5000 ms 时分别为 7.0 +/- 1.3、14.2 +/- 1.6 和 28.1 +/- 2.1%；n = 8）。当将 eliprodil (1 mM) 施用到这些制剂中时，相对于施用 BaCl2 后测量的 APD 值，该药物诱导显着的进一步延长（在周期长度为 300、1000 和 5000 ms 时分别为 12.5 +/- 1.0、17.6 +/- 1.5 和 20.5 +/- 0.9%；n = 8）。4 Langendorff 灌注的兔心脏，eliprodil (1 muM) 在 1 Hz 刺激频率下产生显着的 QT(c) 延长（12.7 +/- 1.8%，n = 9）。 I-K1 阻滞剂 BaCl2 (10 muM) 减弱“复极储备”后，埃利普地尔引起的 QT(c) 延长大大增强（28.5 +/- 7.9%，n = 6）。在六分之二的 Langendorff 制剂中，这种 QTc 延长退化为尖端扭转型室性心动过速。5 Eliprodil 显着降低了延迟整流钾电流 (I-Kr) 的快速分量的幅度，但当应用膜片钳技术的全细胞配置在狗心室肌细胞中进行测量时，慢分量 (I-Ks)、瞬态外向电流 (I-to) 和 I-K1 并未受到药物的显着影响。 6 结果表明在正常条件下，eliprodil 通过抑制 I-Kr 适度延长心脏复极。然而，在正常“复极储备”减弱后，该药物可引起明显的 QT 间期延长，这可能导致致心律失常作用。
1 The aim of this study was to analyse the effects of eliprodil, a noncardiac drug with neuroprotective properties, on the cardiac repolarisation under in vitro circumstances, under normal conditions and after the attenuation of the 'repolarisation reserve' by blocking the inward rectifier potassium current (I-K1) current with BaCl2.2 In canine right ventricular papillary muscle by applying the conventional microelectrode technique, under normal conditions, eliprodil ( 1 muM) produced a moderate reverse rate-dependent prolongation of the action potential duration (7.4 +/- 1.5, 8.9 +/- 2.1 and 9.9 +/- 1.8% at cycle lengths of 300, 1000 and 5000 ms, respectively; n = 9).3 This effect was augmented in preparations where I-K1 was previously blocked by BaCl2 ( 10 mM). BaCl2 alone lengthened APD in a reverse frequency-dependent manner (7.0 +/- 1.3, 14.2 +/- 1.6 and 28.1 +/- 2.1% at cycle lengths of 300, 1000 and 5000 ms, respectively; n = 8). When eliprodil ( 1 mM) was administered to these preparations, the drug induced a marked further lengthening relative to the APD values measured after the administration of BaCl2 (12.5 +/- 1.0, 17.6 +/- 1.5 and 20.5 +/- 0.9% at cycle lengths of 300, 1000 and 5000 ms, respectively; n = 8).4 In the normal Langendorff-perfused rabbit heart, eliprodil ( 1 muM) produced a significant QT(c) prolongation at 1 Hz stimulation frequency (12.7 +/- 1.8%, n = 9). After the attenuation of the 'repolarisation reserve' by the I-K1 blocker BaCl2 ( 10 muM), the eliprodil-evoked QT(c) prolongation was greatly enhanced (28.5 +/- 7.9%, n = 6). In two out of six Langendorff preparations, this QTc lengthening degenerated into torsade de pointes ventricular tachycardia.5 Eliprodil significantly decreased the amplitude of rapid component of the delayed rectifier potassium current (I-Kr), but slow component (I-Ks), transient outward current (I-to) and I-K1 were not considerably affected by the drug when measured in dog ventricular myocytes by applying the whole-cell configuration of the patch-clamp technique.6 The results indicate that eliprodil, under normal conditions, moderately lengthens cardiac repolarisation by inhibition of I-Kr. However, after the attenuation of the normal 'repolarisation reserve', this drug can induce marked QT interval prolongation, which may result in proarrhythmic action.