Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes
Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes
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DOI：
10.1016/s0008-6363(98)00021-2
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发表时间：
1998-05-01
影响因子：
10.8
通讯作者：
Nattel, S
中科院分区：
文献类型：
--
作者：
Bosch, RF;Gaspo, R;Nattel, S
目的：延迟整流钾电流的慢成分被认为在心脏复极中起重要作用，并可能成为抗心律失常药物的潜在靶点，但由于缺乏特异性阻滞剂，其研究一直受到限制。色满酚衍生物293B阻断非洲爪哇卵母细胞上由水貂表达的电流，而不是KERG表达的电流，但对其对天然电流和动作电位的影响知之甚少。本实验旨在观察293B对人和豚鼠心肌细胞K+、Na+、Ca~(2+)电流和动作电位的影响。方法：采用全细胞膜片钳技术，在36℃条件下观察293B对豚鼠心肌细胞延迟整流电流(I-K)的影响。结果：293B对豚鼠心肌细胞延迟整流电流(I-K)有较强的抑制作用(最大抑制率为96.9+/-0.8%；50%抑制浓度，EC50，1.02微米)，而I-K在脉冲至-10 mV时不受影响(在50微米时抑制率为3.9+/-8.4%)，耐药和敏感I-K的半激活电压、电流-电压关系和电流密度分别与I-Kr和I-Ks相当。293B对内向整流钾电流、钠电流和L钙电流无影响。人心室肌细胞瞬时外向电流被293B抑制，EC50为24微米，不到豚鼠心肌细胞抑制I_1的二十分之一。尽管多非利特延长动作电位时程，并具有强烈的反向使用依赖性，但293B在所有频率下延长豚鼠和人的心室动作电位时程的程度相似。结论：293B是一种选择性的I_1受体阻滞剂，该受体阻滞剂引起的动作电位时程延长的频率依赖性与I_1受体阻滞剂不同：293B可能是研究I_1受体阻滞剂的生理作用和抗心律失常作用的一种有趣的工具。(C)1998 Elsevier Science B.V.保留所有权利。
Objectives: The slow component of the delayed rectifier K+ current (I,) is believed to be important in cardiac repolarization, and may be a potential target for antiarrhythmic drugs, but its study has been limited by a lack of specific blockers. The chromanol derivate 293B blocks currents expressed by minK and not KERG in Xenopus oocytes, but little is known about its effects on native currents and action potentials. We aimed to establish the effects of 293B on K+, Na+ and Ca2+ currents and action potentials in human and guinea pig cardiomyocytes. Methods: Whole-cell patch clamp techniques were applied to assess the effects of 293B on isolated myocytes at 36 degrees C. Results: Delayed rectifier current (I-K) elicited by pulses to + 60 mV from a holding potential of - 50 mV in guinea pig myocytes was strongly inhibited by 293B (maximum inhibition 96.9 +/- 0.8%; 50% inhibitory concentration, EC50, 1.02 mu M), but I-K during pulses to -10 mV was unaffected (3.9 +/- 8.4% inhibition at 50 mu M) Half-activation voltages, current-voltage relations, and current densities of drug-resistant and drug-sensitive I-K correspond to those of I-Kr and I-Ks respectively. Inward rectifier K+ current, Na+ current and L-type Ca2+ current were unaffected by 293B. Transient outward current in human ventricular myocytes was inhibited by 293B at an EC50 of 24 mu M, less than one twentieth the potency for I, inhibition in guinea pig myocytes. While dofetilide prolonged action potential duration (APD) with strong reverse use dependence, 293B prolonged guinea pig and human ventricular APD to a similar fractional extent at all frequencies. Conclusions: 293B is a selective I,, blocker, and the frequency dependence of APD prolongation caused by this I,, blocker is different from that caused by I,, blockade: 293B may be an interesting tool to study the physiologic role of I,, and the antiarrhythmic potential of I,, blockade. (C) 1998 Elsevier Science B.V. All rights reserved.