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(Circulation. 2004;109:26-29.)
© 2004 American Heart Association, Inc.

Brief Rapid Communications

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

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

Correspondence to Dan M. Roden, MD, Professor of Medicine and Pharmacology, Director, Division of Clinical Pharmacology, 532 Robinson Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232. E-mail dan.roden{at}vanderbilt.edu

Received October 8, 2003; revision received November 4, 2003; accepted November 14, 2003.

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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