Acidification alters antiarrhythmic drug blockade of the ether-a-go-go-related Gene (HERG) Channels

Basic & Clinical Pharmacology & Toxicology
Deli DongBaofeng Yang

Abstract

Acidosis is one of the important deleterious factors during myocardial ischaemia and reperfusion. The ether-a-go-go-related gene, HERG, is a primary target for blockade by many drugs including dofetilide, quinidine and azimilide. While most drugs lose their efficacy against arrhythmias associated with myocardial ischaemia and reperfusion, dofetilide remains effective. The unique ability of dofetilide to terminate ischaemia-induced arrhythmias is not yet fully explained. The aim of the present study is to elucidate the acidification modulation of antiarrhythmic drugs blockade of HERG channels. The human gene HERG encoding K+ channels were expressed in Xenopus oocytes, and Whole-cell macroscopic currents of Xenopus oocytes were recorded with conventional two-electrode techniques. The inhibitory effects of dofetilide (0.25 microM) were significantly enhanced with decreasing pH (from 7.5 to 6.5). The percent block of dofetilide under pH 6.5 at 0 mV was 69+/-6.1% versus 54+/-3.0% under pH 7.5 (n=7, P<0.05). The IC50 values, determined by the Hill equation with the currents recorded at 0 mV, were decreased by approximately half from 192+/-23 nM with pH 7.5 to 93+/-15 nM with pH 6.5 (P<0.01). Acidification weakened the inhibitory effe...Continue Reading

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Citations

Jul 12, 2011·The Journal of Membrane Biology·Guanghua TangRui Wang
Dec 24, 2013·European Biophysics Journal : EBJ·Yu Patrick ShiTom W Claydon
Apr 21, 2006·Basic & Clinical Pharmacology & Toxicology·Hong-Li SunBao-Feng Yang
Jan 13, 2006·Biochemical and Biophysical Research Communications·Yan ZhangBaofeng Yang
Aug 15, 2012·International Journal of Cardiology·Hongli ShanZhimin Du
Oct 13, 2016·Scientific Reports·Yibo WangSergei Yu Noskov
Apr 12, 2005·Journal of Cardiovascular Pharmacology and Therapeutics·Congrong LinJohn Somberg
Jun 20, 2018·Phytotherapy Research : PTR·Mehrnoosh SedighiBahram Rasoulian
Jan 12, 2011·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Xichuang ChenZhimin Du
Jul 28, 2019·Biochemical and Biophysical Research Communications·Zhongrui LiHongli Shan

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