Abstract

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 (I_Kr), the inward rectifier (I_K1), the transient outward current (I_to), and the inward L-type calcium current (I_Ca) 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 I_Kr in a time-, concentration- and voltage-dependent fashion. I_Kr tail currents were completely blocked by 10 μmol/l tamoxifen with no recovery after 15 min of washout. At +50 mV, tamoxifen 1 and 3.3 μmol/l blocked I_Kr by 39.5 ± 1.7% (P < .01) and 84.8 ± 1.3% (P < .01) respectively, while no significant block of I_K1 or I_to was observed. Significant block of I_Ca by tamoxifen was also observed at concentrations greater than 1 μmol/l, with almost complete inhibition at 10 μmol/l. Tamoxifen showed no significant effect on APD at concentrations up to 3.3 μmol/l. We conclude that tamoxifen potently blocks both I_Kr and I_Ca at clinically relevant concentrations. The observed QT prolongation by tamoxifen in humans may be a result of its predominant effect on I_Kr. Inhibition of I_Kr, in conjunction with other QT-prolonging factors in patients could increase their risk of developing torsades de pointes-type cardiac arrhythmias.