Choline-modulated arsenic trioxide-induced prolongation of cardiac repolarization in guinea pig

Arsenic trioxide (As2O3) has been found to be effective for relapsed or refractory acute promyelocytic leukaemia, but its clinical use is burdened by QT prolongation, Torsade de pointes tachycardias, and sudden cardiac death. The aim of the present study was to elucidate the ionic mechanisms of As2O3-induced abnormalities of cardiac electrophysiology and the therapeutic action of choline on As2O3-caused QT prolongation in guinea pig. Intravenous administration of As2O3 prolonged the QT interval in a dose- and time-dependent manner in guinea pig hearts, and the QT prolongation could be modulated by choline. By using whole-cell patch clamp technique and confocal laser scanning microscopy, we found that As2O3 significantly lengthened action potential duration measured at 50 and 90% of repolarization, enhanced L-type calcium currents (ICa-L), inhibited delayed rectifier potassium currents (I-K), and increased intracellular calcium concentration ([Ca2+](i)) in guinea pig ventricular myocytes. Choline corrected As2O3-mediated alterations of action potential duration, ICa-L and [Ca2+](i), but had no effect on the I-K inhibition. As2O3 markedly disturbed the normal equilibrium of transmembrane currents (increasing ICa-L and suppressing I-K) in guinea pig cardiomyocyte, and induced prolongation of action potential duration, further degenerated into QT prolongation. Choline normalized QT interval abnormality and corrected lengthened action potential duration by inhibiting the elevated ICa-L and [Ca2+](i) in ventricular myocytes during As2O3 application.