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Vol. 287, Issue 3, 877-883, December 1998
Department of Pharmacology, Georgetown University Medical Center,
Washington, DC
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 µmol/l tamoxifen with no recovery after 15 min of washout. At +50 mV,
tamoxifen 1 and 3.3 µmol/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 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 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.
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