Mesoridazine: an open-channel blocker of human ether-a-go-go-related gene K + channel

Abstract

Mesoridazine, a phenothiazine antipsychotic agent, prolongs the QT interval of the cardiac electrocardiogram and is associated with Torsade de pointes-type arrhythmias. In this study, we examined the effects of mesoridazine on human ether-a-go-go-related gene (HERG) K + currents. HERG channels were stably expressed in human embryonic kidney 293 cells and studied using standard whole-cell patch-clamp technique (37 °C). Mesoridazine blocked HERG currents in a concentration-dependent manner (IC 50 550 nM at 0 mV); block increased significantly over the voltage range where HERG activates and saturated at voltages eliciting maximal HERG channel activation. Tonic block of HERG current by mesoridazine (1.8 μM) was minimal (<2–4%). The rate of the onset of HERG channel block was rapid and dose dependent ( τ = 54 ± 7 ms at 0 mV and 1.8 μM mesoridazine), but not significantly affected by test potentials ranging from –30 to +30 mV. The V 1/2 for steady-state activation was shifted from –31.2 ± 1.0 to –39.2 ± 0.5 mV ( P < 0.01). The apparent rate of HERG channel deactivation was significantly reduced (fast τ = 153 ± 8 vs. 102 ± 6 ms at –50 mV, P < 0.01; slow τ = 1113 ± 63 vs. 508 ± 27 ms, P < 0.01). The inactivation kinetics and voltage dependence of steady-state inactivation of the HERG channel were not significantly altered by mesoridazine. These findings demonstrate that mesoridazine is a potent and rapid open-channel blocker of HERG channels. This block would explain the QT prolongation seen clinically at therapeutic concentrations (0.3–3.6 μM).