Acidification alters antiarrhythmic drug blockade of the ether-a-go-go-related Gene (HERG) Channels.
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 effects of quinidine and azimilide on HERG channels. At 0 mV, the percent block of quinidine (10 microM) under pH 6.5 was 24+/-2.8% versus 62.5+/-9.0% under pH 7.5 (n=4, P<0.01), The percent block of azimilide (10 microM) under pH 6.5 was similar to that under pH 7.5 (n=6). Acidification markedly potentiated dofetilide blockade of the HERG channels but weakened the inhibitory effects of quinidine and azimilide.
Dong
De-Li
DL
Department of Pharmacology, Harbin Medical University, Heilongjiang Key Laboratory of Bio-pharmaceutical-engineering, Harbin, 150086, P. R. China.
Li
Zhe
Z
Wang
Hui-Zhen
HZ
Du
Zhi-Min
ZM
Song
Wei-Hua
WH
Yang
Bao-Feng
BF
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006827:Hydantoins; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D017202:Myocardial Ischemia / Q000188:drug therapy; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000096:biosynthesis / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D011802:Quinidine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D014981:Xenopus
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C086123:azimilide; D011802:Quinidine; C063533:dofetilide