Blockade of the HERG human cardiac K+ channel by the antidepressant drug amitriptyline

1 Amitriptyline has been known to induce QT prolongation and torsades de po intes which causes sudden death. We studied the effects of amitriptyline on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus o ocytes 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 de creased by amitriptyline dose-dependently. The decrease became more pronoun ced at more positive potential, suggesting that the block of HERG by amitri ptyline 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 faste r block at higher activation frequency. Subsequent decrease in frequency af ter 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 affinit y of amitriptyline on HERG was decreased by external K+. 5 In rat atrial myocytes bathed in 35 degrees C, 5 mu M amitriptyline block ed I-Kr by 55%. However, transient outward K+ current (I-to) was not signif icantly affected. 6 In summary, the data suggest that the block of HERG currents may contribu te to arrhythmogenic side effects of amitriptyline.