Unusual effects of a QT-prolonging drug, arsenic trioxide, on cardiac potassium currents

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 mumol/L for I-Kr and 1.13 +/- 0.06 mumol/L for I-Ks. In contrast to other QT-prolonging drugs, As2O3 also activated a time-independent current that additional experiments identified as IK-ATP. Conclusions - As2O3 blocks both I-Kr and I-Ks at clinically relevant concentrations. On the other hand, it also activates IK-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.