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

Acidosis and hERGK(+) Channel Pharmacology. Introduction: Human Ether-a-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 degrees C. Methods and Results: Whole-cell patch-clamp recordings of I-hERG were made at 37 degrees C from hERG-expressing Human Embryonic Kidney (HEK293) cells. Half-maximal inhibitory concentration (IC50) 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. Conclusion: 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. (J Cardiovasc Electrophysiol, Vol. 22, pp. 1163-1170, October 2011)