Bosch R F, Gaspo R, Busch A E, Lang H J, Li G R, Nattel S
Department of Medicine and Research Center, Montreal Heart Institute, Quebec, Canada.
Cardiovasc Res. 1998 May;38(2):441-50. doi: 10.1016/s0008-6363(98)00021-2.
The slow component of the delayed rectifier K+ current (IKs) 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 HERG 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.
Whole-cell patch clamp techniques were applied to assess the effects of 293B on isolated myocytes at 36 degrees C.
Delayed rectifier current (IK) 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 microM), but IK during pulses to -10 mV was unaffected (3.9 +/- 8.4% inhibition at 50 microM). Half-activation voltages, current-voltage relations, and current densities of drug-resistant and drug-sensitive IK correspond to those of IKr and IKs 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 microM, less than one twentieth the potency for IKs 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.
293B is a selective IKs blocker, and the frequency dependence of APD prolongation caused by this IKs blocker is different from that caused by IKr blockade: 293B may be an interesting tool to study the physiologic role of IKs and the antiarrhythmic potential of IKs blockade.
延迟整流钾电流（IKs）的缓慢成分被认为在心脏复极化过程中起重要作用，可能是抗心律失常药物的潜在靶点，但其研究因缺乏特异性阻滞剂而受到限制。色满醇衍生物293B可阻断非洲爪蟾卵母细胞中由minK而非HERG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。我们旨在确定293B对人和豚鼠心肌细胞中钾离子、钠离子和钙离子电流以及动作电位的影响。
采用全细胞膜片钳技术，在36℃下评估293B对分离的心肌细胞的影响。
在豚鼠心肌细胞中，从 -50 mV的钳制电位向 +60 mV 脉冲引发的延迟整流电流（IK）受到293B的强烈抑制（最大抑制率96.9±0.8%；50%抑制浓度，EC50，1.02 μM），但向 -10 mV 脉冲期间的IK不受影响（50 μM时抑制率为3.9±8.4%）。耐药性和药物敏感性IK的半激活电压、电流 - 电压关系和电流密度分别与IKr和IKs的对应关系一致。内向整流钾电流、钠离子电流和L型钙离子电流不受293B影响。293B抑制人心室肌细胞中的瞬时外向电流，EC50为24 μM，效力不到豚鼠心肌细胞中IKs抑制效力的二十分之一。虽然多非利特以强烈的反向使用依赖性延长动作电位时程（APD），但293B在所有频率下将豚鼠和人心室APD延长至相似的分数程度。
293B是一种选择性IKs阻滞剂，这种IKs阻滞剂引起的APD延长的频率依赖性与IKr阻断引起的不同：293B可能是研究IKs生理作用和IKs阻断抗心律失常潜力的有趣工具。
