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 degrees C). Mesoridazine blocked HERG currents in a concentration-dependent manner (IC50 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 microM) was minimal (< 2-4%). The rate of the onset of HERG channel block was rapid and dose dependent (tau = 54 +/- 7 ms at 0 mV and 1.8 microM mesoridazine), but not significantly affected by test potentials ranging from -30 to +30 mV. The V1/2 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 tau = 153 +/- 8 vs. 102 +/- 6 ms at -50 mV, P < 0.01; slow tau = 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 microM).

• Authors: Zhi Su, Ruth Martin, Bryan F Cox, Gary Gintant
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 36 Issue 1 Pg. 151-60 (Jan 2004) ISSN: 0022-2828 [Print] England
• PMID: 14734057 (Publication Type: Journal Article)

Chemical References

• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• Potassium Channel Blockers
• Potassium Channels
• Potassium Channels, Voltage-Gated
• Mesoridazine
• Potassium

Topics

• Cell Line
• Dose-Response Relationship, Drug
• ERG1 Potassium Channel
• Electric Conductivity
• Electrophysiologic Techniques, Cardiac
• Ether-A-Go-Go Potassium Channels
• Humans
• Kinetics
• Mesoridazine (pharmacology)
• Potassium (metabolism)
• Potassium Channel Blockers (pharmacology)
• Potassium Channels (metabolism)
• Potassium Channels, Voltage-Gated
• Time Factors