The antiestrogen tamoxifen blocks the delayed rectifier potassium current, IKr, in rabbit ventricular myocytes.

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.