Liu X K, Katchman A, Ebert S N, Woosley R L
Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA.
J Pharmacol Exp Ther. 1998 Dec;287(3):877-83.
Tamoxifen is an antiestrogen drug commonly used to treat breast cancer and has been shown to cause prolongation of the electrocardiographic QT interval in humans. Because QT prolongation could influence cardiac arrhythmias, we sought to determine the electrophysiologic mechanism(s) underlying the tamoxifen action. The whole-cell patch-clamp technique was used to study the effect of tamoxifen on the delayed rectifier (IKr), the inward rectifier (IK1), the transient outward current (Ito), and the inward L-type calcium current (ICa) in rabbit ventricular myocytes. By switching to the current-clamp mode, the effect of tamoxifen on action potential duration (APD) was also studied. Tamoxifen blocked IKr in a time-, concentration- and voltage-dependent fashion. IKr tail currents were completely blocked by 10 micromol/l tamoxifen with no recovery after 15 min of washout. At +50 mV, tamoxifen 1 and 3.3 micromol/l blocked IKr by 39.5 +/- 1.7% (P <.01) and 84.8 +/- 1.3% (P <.01) respectively, while no significant block of IK1 or Ito was observed. Significant block of ICa by tamoxifen was also observed at concentrations greater than 1 micromol/l, with almost complete inhibition at 10 micromol/l. Tamoxifen showed no significant effect on APD at concentrations up to 3.3 micromol/l. We conclude that tamoxifen potently blocks both IKr and ICa at clinically relevant concentrations. The observed QT prolongation by tamoxifen in humans may be a result of its predominant effect on IKr. Inhibition of IKr, in conjunction with other QT-prolonging factors in patients could increase their risk of developing torsades de pointes-type cardiac arrhythmias.
他莫昔芬是一种常用于治疗乳腺癌的抗雌激素药物，已被证明可导致人体心电图QT间期延长。由于QT间期延长可能影响心律失常，我们试图确定他莫昔芬作用的电生理机制。采用全细胞膜片钳技术研究他莫昔芬对兔心室肌细胞延迟整流钾电流（IKr）、内向整流钾电流（IK1）、瞬时外向电流（Ito）和内向L型钙电流（ICa）的影响。通过切换到电流钳模式，还研究了他莫昔芬对动作电位时程（APD）的影响。他莫昔芬以时间、浓度和电压依赖性方式阻断IKr。10 μmol/L的他莫昔芬可完全阻断IKr尾电流，洗脱15分钟后无恢复。在+50 mV时，1 μmol/L和3.3 μmol/L的他莫昔芬分别使IKr阻断39.5±1.7%（P<.01）和84.8±1.3%（P<.01），而未观察到IK1或Ito的明显阻断。在浓度大于1 μmol/L时，也观察到他莫昔芬对ICa有明显阻断作用，在10 μmol/L时几乎完全抑制。在浓度高达3.3 μmol/L时，他莫昔芬对APD无明显影响。我们得出结论，他莫昔芬在临床相关浓度下可有效阻断IKr和ICa。他莫昔芬在人体中观察到的QT间期延长可能是其对IKr的主要作用所致。IKr的抑制，与患者体内其他QT间期延长因素共同作用，可能会增加他们发生尖端扭转型心律失常的风险。
