Tamoxifen inhibits Na+ and K+ currents in rat ventricular myocytes
Tamoxifen inhibits Na+ and K+ currents in rat ventricular myocytes
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DOI：
10.1152/ajpheart.00686.2002
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发表时间：
2003-08-01
影响因子：
4.8
通讯作者：
Ward, CA
中科院分区：
文献类型：
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作者：
He, JY;Kargacin, ME;Ward, CA
他莫昔芬是一种雌激素受体拮抗剂，用于治疗乳腺癌。然而，他莫昔芬已被证明可诱导心电图QT间期延长，从而可能导致危及生命的多形性室性心律失常。本研究的目的是阐明三苯氧胺致心律失常作用的电生理机制。我们使用标准的破裂全细胞和穿孔膜片钳技术对大鼠心室肌细胞的心脏动作电位（AP）波形和基础的K+电流的影响，调查他莫昔芬。三苯氧胺（3 μ mol/L）显著延长AP持续时间，降低最大去极化率，并降低静息膜电位。在此浓度下，他莫昔芬显著抑制了心肌细胞中钙非依赖性瞬时外向钾电流（I-to）、持续外向延迟整流钾电流（I-sus）、内向整流钾电流（I-K1）和钠电流（I-Na）。较低浓度的他莫昔芬（1 mumol/l）也降低了静息膜电位，并将I-K1显著降低至预处理值的79 +/- 5%（n = 5;-120 mV）。这项研究的结果表明，抑制I-to，I-sus，和I-K1的他莫昔芬可能是在心肌细胞AP延长，从而有助于延长QT间期观察到的患者。
Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. However, tamoxifen has been shown to induce QT prolongation of the electrocardiogram, thereby potentially causing life-threatening polymorphic ventricular arrhythmias. The purpose of the present study was to elucidate the electrophysiological mechanism(s) that underlie the arrhythmogenic effects of tamoxifen. We used standard ruptured whole cell and perforated patch-clamping techniques on rat ventricular myocytes to investigate the effects of tamoxifen on cardiac action potential (AP) waveforms and the underlying K+ currents. Tamoxifen (3 mumol/l) markedly prolonged AP duration, decreased maximal rate of depolarization, and decreased resting membrane potential. At this concentration, tamoxifen significantly depressed the Ca2+-independent transient outward K+ current (I-to), sustained outward delayed rectifier K+ current (I-sus), inward rectifier K+ current (I-K1), and Na+ current (I-Na) in the myocytes. Lower concentrations of tamoxifen (1 mumol/l) also decreased the resting membrane potential and significantly depressed I-K1 to 79 +/- 5% (n = 5; at -120 mV) of pretreatment values. The results of this study indicate that inhibition of I-to, I-sus, and I-K1 by tamoxifen may underlie AP prolongation in cardiac myocytes and thereby contribute to prolonged QT interval observed in patients.