Choline-modulated arsenic trioxide-induced prolongation of cardiac repolarization in Guinea pig.
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+)](i)) in guinea pig ventricular myocytes. Choline corrected As(2)O(3)-mediated alterations of action potential duration, I(Ca-L) and [Ca(2+)](i), 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+)](i) in ventricular myocytes during As(2)O(3) application.
Sun
Hong-Li
HL
Department of Pharmacology, Harbin Medical University, Biopharmaceutical Engineering Key Laboratory of Heilongjiang Province, Incubator of State Key Laboratory, Harbin 150086, P.R. China.
Chu
Wen-Feng
WF
Dong
De-Li
DL
Liu
Yan
Y
Bai
Yun-Long
YL
Wang
Xiao-Hui
XH
Zhou
Jin
J
Yang
Bao-Feng
BF
D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002794:Choline / Q000494:pharmacology*; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010087:Oxides / Q000494:pharmacology*; D018408:Patch-Clamp Techniques
D001152:Arsenicals; D010087:Oxides; D002794:Choline; D000077237:Arsenic Trioxide; D002118:Calcium