抄録
[Background] Arsenic trioxide (As2O3), a newly introduced agent for acute promyelocytic leukemia, has been shown to induce QT prolongation of the electrocardiogram (ECG), thereby potentially causing life-threatening ventricular arrhythmias. The purpose of the present study was to elucidate the electrophysiological mechanisms that underlie the arrhythmogenic effects of As2O3. [Methods and Results] We obtained ECG signals by a radio transmitter from control and the As2O3-treated rats. The QT intervals were significantly increased in the As2O3-treated rats (control 45.3 ± 0.2 ms versus As2O3 58.5 ± 0.4 ms, p<0.01). Action potentials (AP) of rat papillary muscle were recorded by using intracellular microelectrode technique. As2O3 significantly prolonged AP durations (APD) measured at 90% of repolarization (APD90; control 54.4 ± 9.6 ms versus As2O3 91.3 ± 36.3 ms, p<0.01). Furthermore, whole-cell patch clamp studies show that As2O3 significantly depressed inward rectifier K+ currents (IK1) (control -15.3 ± 1.1 pA/pF versus As2O3 -11.1 ± 1.0 pA/pF at -120 mV, p<0.01) and increased Ca2+ currents (ICaL) (control -6.8 ± 0.7 pA/pF versus As2O3 -9.9 ± 0.3 pA/pF at 0 mV, p<0.01). [Conclusion] The results of this study indicate that inhibition of IK1 and an increase in ICaL by As2O3 may underlie AP prolongation in cardiac myocyte and thereby contribute to prolonged QT intervals observed in patients. [Jpn J Physiol 55 Suppl:S136 (2005)]
