期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 129, 期 7, 页码 1474-1480出版社
STOCKTON PRESS
DOI: 10.1038/sj.bjp.0703222
关键词
amitriptyline; rapidly activating delayed rectifier K+ current; HERG channel; LQT; torsades de pointes; use dependence; voltage dependence
1 Amitriptyline has been known to induce QT prolongation and torsades de pointes which causes sudden death. We studied the effects of amitriptyline on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on the rapidly activating delayed rectifier K+ current (I-Kr) in rat atrial myocytes. 2 The amplitudes of steady-state currents and tail currents of HERG were decreased by amitriptyline dose-dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by amitriptyline is voltage dependent. IC50 for amitriptyline block of HERG current was progressively decreased according to depolarization: IC50 values at -30, -10, +10 and +30 mV were 23.0, 8.71, 5.96 and 4.66 mu M, respectively. 3 Block of HERG by amitriptyline was use dependent: exhibiting a much faster block at higher activation frequency. Subsequent decrease in frequency after high activation frequency resulted in a partial relief of HERG blockade. 4 Steady-state block by amitriptyline was obtained while depolarization to +20 mV for 0.5 s was applied at 0.5 Hz: IC50 was 3.26 mu M in 2 mM [K+](o). It was increased to 4.78 mu M in 4 mM [K+](o), suggesting that the affinity of amitriptyline on HERG was decreased by external K+. 5 In rat atrial myocytes bathed in 35 degrees C, 5 mu M amitriptyline blocked I-Kr by 55%. However, transient outward K+ current (I-to) was not significantly affected. 6 In summary, the data suggest that the block of HERG currents may contribute to arrhythmogenic side effects of amitriptyline.
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