Mechanism of HERG potassium channel inhibition by tetra-n-octylammonium bromide and benzethonium chloride

• Published in: Toxicology and applied pharmacology Vol. 267; no. 2; pp. 155 - 166
• Main Authors: Long, Yan, Lin, Zuoxian, Xia, Menghang, Zheng, Wei, Li, Zhiyuan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-03-2013; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Benzethonium - pharmacology; Benzethonium chloride; Biological and medical sciences; CHLORIDES; CHO CELLS; CONCENTRATION RATIO; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; GENES; HAMSTERS; HERG channel blocker; HERG potassium channel; IN VIVO; Medical sciences; OVARIES; Patch clamp; POTASSIUM; Potassium Channel Blockers - pharmacology; Quaternary ammonium; QUATERNARY AMMONIUM COMPOUNDS; Quaternary Ammonium Compounds - pharmacology; Tetra-n-octylammonium bromide; Toxicology; Tetra-n-octylammonium bromide; Quaternary ammonium; HERG channel blocker; HERG; Benzethonium chloride; QACs; HERG potassium channel; IC50; Patch clamp; V1/2; κ; CHO; Ammonium; Electrophysiology; Patch clamp method; Ionic channel; Inorganic element; Bromides chlorides; Quaternary ammonium compound; Antiseptic; Bromides; Inhibitor; Antagonist; Inhibition; Disinfecting agent; Mechanism of action; Potassium
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.12.021

Tetra-n-octylammonium bromide and benzethonium chloride are synthetic quaternary ammonium salts that are widely used in hospitals and industries for the disinfection and surface treatment and as the preservative agent. Recently, the activities of HERG channel inhibition by these compounds have been found to have potential risks to induce the long QT syndrome and cardiac arrhythmia, although the mechanism of action is still elusive. This study was conducted to investigate the mechanism of HERG channel inhibition by these compounds by using whole-cell patch clamp experiments in a CHO cell line stably expressing HERG channels. Tetra-n-octylammonium bromide and benzethonium chloride exhibited concentration-dependent inhibitions of HERG channel currents with IC50 values of 4nM and 17nM, respectively, which were also voltage-dependent and use-dependent. Both compounds shifted the channel activation I–V curves in a hyperpolarized direction for 10–15mV and accelerated channel activation and inactivation processes by 2-fold. In addition, tetra-n-octylammonium bromide shifted the inactivation I–V curve in a hyperpolarized direction for 24.4mV and slowed the rate of channel deactivation by 2-fold, whereas benzethonium chloride did not. The results indicate that tetra-n-octylammonium bromide and benzethonium chloride are open-channel blockers that inhibit HERG channels in the voltage-dependent, use-dependent and state-dependent manners.
► Tetra-n-octylammonium and benzethonium are potent HERG channel inhibitors. ► Channel activation and inactivation processes are accelerated by the two compounds. ► Both compounds are the open-channel blockers to HERG channels. ► HERG channel inhibition by both compounds is use-, voltage- and state dependent. ► The in vivo risk of QT prolongation needs to be studied for the two compounds.