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Am J Physiol Heart Circ Physiol (April 17, 2003). doi:10.1152/ajpheart.00686.2002
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Submitted on August 2, 2002
Accepted on April 11, 2003

Tamoxifen inhibits sodium and potassium currents in rat ventricular myocytes

Jianying He1, Margaret E. Kargacin2, Gary J. Kargacin2, and Christopher A. Ward1*

1 Department of Physiology, Queen's University, Kingston, Ontario, Canada
2 Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada

* To whom correspondence should be addressed. E-mail: wardc{at}post.queensu.ca.

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 potentially causing life-threatening polymorphic ventricular arrhythmias. The purpose of the present study was to elucidate the electrophysiological mechanism(s) underlying 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 waveforms and the underlying potassium currents. Tamoxifen (3 µmol/L) markedly prolonged action potential duration, decreased maximal rate of depolarization and decreased resting membrane potential. At this concentration, tamoxifen significantly depressed the Ca2+-independent transient outward K+ current (Ito), the delayed rectifier K+ current (Isus) and inward rectifier K+ current (IK1) and sodium currents (INa in the myocytes. Lower concentrations of tamoxifen (1 µmol/L) also decreased the resting membrane potential and significantly depressed IK1 to 79±5% (n=5; at -120 mV) of pre-treatment values. The results of this study indicate that inhibition of Ito, Isus and IK1 by tamoxifen may underlie action potential prolongation in cardiac myocytes and thereby contribute to prolonged QT interval observed in patients.




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