Acidification alters Antiarrhythmic Drug Blockade of the ether‐a‐go‐go‐related Gene (HERG) Channels

Abstract

Acidosis is one of the important deleterious factors during myocardial ischaemia and reperfusion. The ether-ago-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 π 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 mM) 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 (nΩ7, PϽ0.05). The IC 50 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 (PϽ0.01). Acidification weakened the inhibitory effects of quinidine and azimilide on HERG channels. At 0 mV, the percent block of quinidine (10 mM) under pH 6.5 was 24∫2.8% versus 62.5∫9.0% under pH 7.5 (nΩ4, PϽ0.01), The percent block of azimilide (10 mM) under pH 6.5 was similar to that under pH 7.5 (nΩ6). Acidification markedly potentiated dofetilide blockade of the HERG channels but weakened the inhibitory effects of quinidine and azimilide.

Mechanism of hERG Channel Block by the Psychoactive Indole Alkaloid Ibogaine

“…Accordingly, extracellular acidification was shown to reduce current inhibition for clinically relevant hERG channel blockers, such as quinidine, azimilide, flecainide, and verapamil. Similar to ibogaine, all of these agents have alkaline pK a values, and their loss of effect resulting from lowered pH o is taken as evidence for membrane permeation before channel block (Zhang et al, 1999;Dong et al, 2004). Further evidence for membrane permeation was provided by the enhanced action of ibogaine under intracellular acidification.…”

Pharmacological Inhibition of the hERG Potassium Channel Is Modulated by Extracellular But Not Intracellular Acidosis

“…There is some evidence from experiments in which hERG has been expressed in Xenopus oocytes that both class I (quinidine) and methanesulphonanilide (dofetilide, ibutilide) blocks of hERG are reduced when extracellular pH is lowered, 11–14 which feasibly could lead to heterogeneity in extent of the I Kr block between areas of the heart with normal and acid pH levels. However, the potency of hERG‐blocking drugs is generally underestimated when using Xenopus oocytes 15 and it is not possible with this expression system to perform experiments at mammalian body temperature 2,15 .…”

“…However, the potency of hERG‐blocking drugs is generally underestimated when using Xenopus oocytes 15 and it is not possible with this expression system to perform experiments at mammalian body temperature 2,15 . Moreover, conflicting results regarding the effect of acidosis on dofetilide inhibition of hERG (both reduced and increased potency) have been reported from experiments using Xenopus oocytes 12,14 and, given that hERG blockers are considered generally to access the channel's inner cavity after crossing the cell membrane, 1,2 a question arises whether the effects of extracellular acidosis on the drug block result from the reduction in extracellular pH per se , or may arise from secondary changes to intracellular pH that affect drug action. This study was undertaken to determine the effects of acidified extracellular solution on the potency of I hERG inhibition by selected antiarrhythmic drugs (flecainide, dofetilide, and amiodarone) at 37 °C, using mammalian hERG‐expressing cells, compared with the effects of acidifying intracellular solution on the I hERG drug block and kinetics.…”

L-type Calcium Current (I_Ca,L) and Inward Rectifier Potassium Current (I_K1) are Involved in QT Prolongation Induced by Arsenic Trioxide in Rat

“…In addition, the K + currents (I K ) [18][19][20] are also substaintial in controlling the speed of membrane repolarization. Function and density alterations of the cardiac K + channel might be responsible for some pathophysiological results in various cardiac diseases, such as heart failure, myocardial ischemia, and also malignant arrhythmias [21,22].…”