Published Online
on December 22, 2003

A more recent version of this article appeared on January 6, 2004

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Submitted on October 8, 2003
Revised on November 4, 2003
Accepted on November 14, 2003

Unusual Effects of a QT-Prolonging Drug, Arsenic Trioxide, on Cardiac Potassium Currents

Benoit Drolet PhD, Chantale Simard PhD, and Dan M. Roden MD^*

From the Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.

^* To whom correspondence should be addressed. E-mail: dan.roden{at}vanderbilt.edu.

Background--Cases of QT prolongation, torsades de pointes, and sudden death have been reported with arsenic trioxide (As₂O₃), a highly effective agent for acute promyelocytic leukemia. In this study, we evaluated the effects of As₂O₃ on repolarizing cardiac ion currents.

Methods and Results--In HERG- or KCNQ1+KCNE1-transfected CHO cells (n=32; total), As₂O₃ caused concentration-dependent block of both I_Kr and I_Ks, with an IC₅₀ for tail current block of 0.14±0.01 µmol/L for I_Kr and 1.13±0.06 µmol/L for I_Ks. In contrast to other QT-prolonging drugs, As₂O₃ also activated a time-independent current that additional experiments identified as I_K-ATP.

Conclusions--As₂O₃ blocks both I_Kr and I_Ks at clinically relevant concentrations. On the other hand, it also activates I_K-ATP, which maintains normal repolarization. We infer that variability in the extent of QT interval prolongation and onset of ventricular arrhythmias during arsenic therapy represents competing effects to block and activate multiple repolarizing potassium currents.

Key words: torsades de pointes • drugs • ion channels

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