Sun Hong-Li, Chu Wen-Feng, Dong De-Li, Liu Yan, Bai Yun-Long, Wang Xiao-Hui, Zhou Jin, Yang Bao-Feng
Department of Pharmacology, Harbin Medical University, Biopharmaceutical Engineering Key Laboratory of Heilongjiang Province, Incubator of State Key Laboratory, Harbin 150086, P.R. China.
Basic Clin Pharmacol Toxicol. 2006 Apr;98(4):381-8. doi: 10.1111/j.1742-7843.2006.pto_319.x.
Arsenic trioxide (As(2)O(3)) 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 As(2)O(3)-induced abnormalities of cardiac electrophysiology and the therapeutic action of choline on As(2)O(3)-caused QT prolongation in guinea pig. Intravenous administration of As(2)O(3) 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 As(2)O(3) significantly lengthened action potential duration measured at 50 and 90% of repolarization, enhanced L-type calcium currents (I(Ca-L)), inhibited delayed rectifier potassium currents (I(K)), and increased intracellular calcium concentration (Ca(2+)) in guinea pig ventricular myocytes. Choline corrected As(2)O(3)-mediated alterations of action potential duration, I(Ca-L) and Ca(2+), but had no effect on the I(K) inhibition. As(2)O(3) markedly disturbed the normal equilibrium of transmembrane currents (increasing I(Ca-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 I(Ca-L) and Ca(2+) in ventricular myocytes during As(2)O(3) application.
三氧化二砷（As₂O₃）已被发现对复发或难治性急性早幼粒细胞白血病有效，但其临床应用因QT间期延长、尖端扭转型室性心动过速和心源性猝死而受到限制。本研究的目的是阐明As₂O₃诱导心脏电生理异常的离子机制以及胆碱对As₂O₃所致豚鼠QT间期延长的治疗作用。静脉注射As₂O₃可使豚鼠心脏的QT间期呈剂量和时间依赖性延长，且QT间期延长可被胆碱调节。通过使用全细胞膜片钳技术和共聚焦激光扫描显微镜，我们发现As₂O₃显著延长了复极化50%和90%时测量的动作电位时程，增强了L型钙电流（I(Ca-L)），抑制了延迟整流钾电流（I(K)），并增加了豚鼠心室肌细胞内的钙浓度（[Ca²⁺]i）。胆碱纠正了As₂O₃介导的动作电位时程、I(Ca-L)和[Ca²⁺]i的改变，但对I(K)的抑制没有影响。As₂O₃明显扰乱了豚鼠心肌细胞跨膜电流的正常平衡（增加I(Ca-L)并抑制I(K)），并诱导动作电位时程延长，进而发展为QT间期延长。胆碱通过抑制As₂O₃应用期间心室肌细胞中升高的I(Ca-L)和[Ca²⁺]i，使QT间期异常恢复正常并纠正延长的动作电位时程。
