Interactions of antazoline with human ether-à-go-go-related gene channels

BACKGROUND Antazoline is a first generation antihistaminic drug with a proven high efficiency in termination of atrial fibrillation (AF) (72% vs 10% - placebo). However, the mechanisms of antiarrhythmic action of antazoline and its impact on the ion channels in myocardium are still unknown. Unlike quinidine it has fewer side effects i.e. does not produce severe hypotension when given intravenously. Furthermore, it may be free of the problem of 'sudden death' occasionally attributed to quinidine. As inhibition of human ether-a-go-go-related gene (hERG) channel is one of the leading causes of acquired long QT syndrome such knowledge would be required. PURPOSE The aim of this preliminary study was to investigate the effects of antazoline on hERG channel as an element of its safety profile. METHODS To address this issue electrophysiological recordings with an automated patch clamp apparatus (CytoPatch 2, Rostock, Germany) were performed. A range of antazoline concentrations (from 0.1 μM to 10 μM) were tested for its potential to hERG potassium channel inhibition. hERG currents were recorded from HEK293 cells using the whole-cell patch-clamp technique at physiological temperature (35-370). Only cells with a stable wholecell membrane resistance of more than 500 MOhm and a hERG tail current amplitude of at least 300 pA were used for analysis. hERG tail currents were averaged over 50 s at the end of the control phase and at the end of each application phase. Fractional block was calculated by dividing the mean tail current in the presence of the drug by the mean tail current of the control phase. For a comparison, the data for quinidine, which can be considered a standard IKr inhibiting substance, were obtained with the same protocol and was therefore used as a positive control. Dose-response relationships for each drug were determined by fitting the Hill equation to the concentration (C) - inhibition of peak tail current amplitudes I(C) curve: I(C) = 100/1+ (IC50/C)n, where IC50 is the median inhibitory concentration (concentration of a drug that causes 50% current inhibition) and n is the slope parameter (Hill coefficient). RESULTS In physiological temperature antazoline showed three times lower hERG inhibitory potential as compared to quinidine (IC50∼3 μM and ∼1 μM, respectively). CONCLUSIONS Antazoline inhibits hERG current, but this effect is less pronounced as compared to quinidine. While the hERG IC50 of 1 uM is widely accepted as a threshold of concerns for proarrhythmic propensity, the results of this study show that antazoline might carry lower cardiac risk as compared with quinidine, therefore its use for termination of AF can be considered for clinical use.