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Tamoxifen inhibits Na⁺ and K⁺ currents in rat ventricular myocytes

¹Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6; and ²Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Submitted 2 August 2002 ; accepted in final form 11 April 2003

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 µmol/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 µmol/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.

electrophysiology; arrhythmia; cardiac; torsades de pointes; QT prolongation

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