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

Abstract

1 Amitriptyline has been known to induce QT prolongation and torsades de pointes which causes sudden death. We studied the e ects of amitriptyline on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on the rapidly activating delayed recti®er 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. IC 50 for amitriptyline block of HERG current was progressively decreased according to depolarization: IC 50 values at 730, 710, +10 and +30 mV were 23.0, 8.71, 5.96 and 4.66 mM, 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: IC 50 was 3.26 mM in 2 mM [K + ] o . It was increased to 4.78 mM in 4 mM [K + ] o , suggesting that the a nity of amitriptyline on HERG was decreased by external K + . 5 In rat atrial myocytes bathed in 358C, 5 mM amitriptyline blocked I Kr by 55%. However, transient outward K + current (I to ) was not signi®cantly a ected. 6 In summary, the data suggest that the block of HERG currents may contribute to arrhythmogenic side e ects of amitriptyline.

Inhibition of ATP‐sensitive potassium channels by haloperidol

“…The mechanism of this effect was not explored but theoretically could involve a reduction in haloperidol binding (either by direct competition or via an allosteric effect), interference with the transduction mechanism by which haloperidol binding results in closure of the channel, or, if the drug interacts preferentially with a particular gating state, an effect of external potassium ions on gating. It has been shown that the binding of open channel blockers, including haloperidol, to voltage-gated potassium channels are reduced at higher [K þ ] o (Kuo, 1998;Jo et al, 6770.25, 3.0670.65, 8.9770.95, 14.8472.75, and 23.8872 Shuba et al, 2001). The detailed mechanism is still not clear, but it has been proposed that external potassium ions compete with the open channel blocker imipramine for binding to the external pore region of the A-type potassium channel in rat hippocampal neurons (Kuo, 1998 Kobayashi et al, 2000), which may possibly lead to underestimation of the safety margin of these compounds as is the case for haloperidol (Redfern et al, 2003).…”

Tricyclic antidepressant amitriptyline alters sarcoplasmic reticulum calcium handling in ventricular myocytes

“…Electrocardiogram abnormalities are frequent, and a wide variety of cardiac arrhythmias can occur, the most common being sinus tachycardia and intraventricular conduction delay (QRS prolongation) (36). Previous studies have shown that tricyclic antidepressants modulate sarolemmal ion channels involved in cardiac excitation-contraction coupling (6,13,19). The aim of the present study was to investigate effects of AMT on SR Ca handling in ventricular myocytes.…”

The Effects of the Adenosine Receptor Antagonists on the Reverse of Cardiovascular Toxic Effects Induced by Citalopram In-Vivo Rat Model of Poisoning

“…In cellular electrophysiological studies, it has been shown that citalopram has a high degree of potential to inhibit the K + current which is responsible for the action potential repolarization phase in the heart; the prolongation of the QTc interval induced by a toxic dose of citalopram is associated with this condition. Also, it has been shown that citalopram causes a prolongation in action potential time, a prolongation of the QTc interval, as well as an increase in torsade de pointes risk and sudden death by inhibiting G-protein activated inward rectifier potassium channels (GIRK) and hERG potassium channels (17)(18)(19)(20)(21)(22).…”