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.


RESULTS
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.


CONCLUSIONS
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.
Drolet
Benoit
B
Division of Clinical Pharmacology, 532 Robinson Research Building, Vanderbilt University School of Medicine, Nashville, Tenn 37232, USA.
Simard
Chantale
C
Roden
Dan M
DM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D008133:Long QT Syndrome / Q000139:chemically induced; D009206:Myocardium / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D020110:Pinacidil; D000077237:Arsenic Trioxide; D005905:Glyburide