Affiliation:
1. From the Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Abstract
Background—
Cases of QT prolongation, torsades de pointes, and sudden death have been reported with arsenic trioxide (As
2
O
3
), a highly effective agent for acute promyelocytic leukemia. In this study, we evaluated the effects of As
2
O
3
on repolarizing cardiac ion currents.
Methods and Results—
In HERG- or KCNQ1+KCNE1-transfected CHO cells (n=32; total), As
2
O
3
caused concentration-dependent block of both
I
Kr
and
I
Ks
, with an IC
50
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, As
2
O
3
also activated a time-independent current that additional experiments identified as
I
K-ATP
.
Conclusions—
As
2
O
3
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
92 articles.
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