title: Pharmacological inhibition of the hERG potassium channel is modulated by extracellular but not intracellular acidosis.
abstract: BACKGROUND
  Human ether-à-go-go related gene (hERG) is responsible for channels that mediate the rapid delayed rectifier K(+) channel current (I(Kr) ), which participates in repolarization of the ventricles and is a target for some antiarrhythmic drugs. Acidosis occurs in the heart in some pathological situations and can modify the function and responses to drugs of ion channels. The aim of this study was to determine the effects of extracellular and intracellular acidosis on the potency of hERG channel current (I(hERG)) inhibition by the antiarrhythmic agents dofetilide, flecainide, and amiodarone at 37 °C.
  
  
  RESULTS
  Whole-cell patch-clamp recordings of I(hERG) were made at 37 °C from hERG-expressing Human Embryonic Kidney (HEK293) cells. Half-maximal inhibitory concentration (IC(50)) values for I(hERG) tail inhibition at -40 mV following depolarizing commands to +20 mV were significantly higher at external pH 6.3 than at pH 7.4 for both flecainide and dofetilide, but not for amiodarone. Lowering pipette pH from 7.2 to 6.3 altered neither I(hERG) kinetics nor the extent of observed I(hERG) blockade by any of these drugs.
  
  
  CONCLUSIONS
  Conditions leading to localized extracellular acidosis may facilitate heterogeneity of action of dofetilide and flecainide, but not amiodarone via modification of hERG channel blockade. Such effects depend on the external pH change rather than intracellular acidification.
authors.affiliation: School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, The University of Bristol, Bristol, UK.
authors.forename: C Y
authors.initials: CY
authors.lastname: DU
authors.forename: A
authors.initials: A
authors.lastname: El Harchi
authors.forename: Y H
authors.initials: YH
authors.lastname: Zhang
authors.forename: C H
authors.initials: CH
authors.lastname: Orchard
authors.forename: J C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000638:Amiodarone / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005424:Flecainide / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D005424:Flecainide; D000638:Amiodarone; C063533:dofetilide; D011188:Potassium