Key result
Chlorpromazine blocked cloned HERG potassium channels with an IC50 value of 21.6 micro M, displaying reverse frequency dependence and blocking in the closed and activated states.
Effect estimate: IC50 21.6 micro M
Chlorpromazine blocks HERG potassium channels with an IC50 of 21.6 micro M, providing a biophysical mechanism for its association with acquired long QT syndrome.
Chlorpromazine warrants QTc monitoring in at-risk patients; leaves open the incidence of torsades in clinical cohorts.
(1) Acquired long QT syndrome (aLQTS) is caused by prolongation of the cardiac action potential because of blockade of cardiac ion channels and delayed repolarization of the heart. Patients with aLQTS carry an increased risk for torsade de pointes arrhythmias and sudden cardiac death. Several antipsychotic drugs may cause aLQTS. Recently, cases of QTc prolongation and torsade de pointes associated with chlorpromazine treatment have been reported. Blockade of human ether-a-go-go-related gene (HERG) potassium channels, which plays a central role in arrhythmogenesis, has previously been reported to occur with chlorpromazine, but information on the mechanism of block is currently not available. We investigated the effects of chlorpromazine on cloned HERG potassium channels to determine the biophysical mechanism of block. (2) HERG channels were heterologously expressed in Xenopus laevis oocytes, and ion currents were measured using the two-microelectrode voltage-clamp technique. (3) Chlorpromazine blocked HERG potassium channels with an IC(50) value of 21.6 micro M and a Hill coefficient of 1.11. (4) Analysis of the voltage dependence of block revealed a reduction of inhibition at positive membrane potentials. (5) Inhibition of HERG channels by chlorpromazine displayed reverse frequency dependence, that is, the amount of block was lower at higher stimulation rates. No marked changes in electrophysiological parameters such as voltage dependence of activation or inactivation, or changes of the inactivation time constant were observed. (6) In conclusion, HERG channels were blocked in the closed and activated states, and unblocking occurred very slowly.
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Thomas et al. (2003) studied Acquired long QT syndrome (aLQTS). Chlorpromazine was evaluated on HERG potassium channel blockade (IC50) (IC50 21.6 micro M). Chlorpromazine blocked cloned HERG potassium channels with an IC50 value of 21.6 micro M, displaying reverse frequency dependence and blocking in the closed and activated states.
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