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

• Published in: Circulation (New York, N.Y.) Vol. 109; no. 1; pp. 26 - 29
• Main Authors: DROLET, Benoit, SIMARD, Chantale, RODEN, Dan M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 06-01-2004; American Heart Association, Inc
• Subjects: Animals; Antineoplastic Agents - pharmacology; Arsenicals - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; CHO Cells; Cricetinae; Cricetulus; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Glyburide - pharmacology; Heart - drug effects; Long QT Syndrome - chemically induced; Medical sciences; Myocardium - metabolism; Oxides - pharmacology; Pinacidil - pharmacology; Potassium Channels - drug effects; Potassium Channels, Inwardly Rectifying - drug effects; Potassium Channels, Voltage-Gated - drug effects; Wave burst; Arrhythmia; Heart disease; Cardiovascular disease; Arsenic trioxide; Potassium; Excitability disorder
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.0000109484.00668.ce

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