title: Characterisation of recombinant HERG K+ channel blockade by the Class Ia antiarrhythmic drug procainamide.
abstract: Class Ia antiarrhythmic drugs, including procainamide (PROC), are associated with cardiac sodium channel blockade, delayed ventricular repolarisation and with a risk of ventricular pro-arrhythmia. The HERG K(+) channel is frequently linked to drug-induced pro-arrhythmia. Therefore, in this study, interactions between PROC and HERG K(+) channels were investigated, with particular reference to potency and mechanism of drug action. Whole-cell patch-clamp recordings of HERG current (I(HERG)) were made at 37 degrees C from human embryonic kidney (HEK 293) cells stably expressing the HERG channel. Following activating pulses to +20 mV, I(HERG) tails were inhibited by PROC with an IC(50) value of approximately 139 microM. I(HERG) blockade was found to be both time- and voltage-dependent, demonstrating contingency upon HERG channel gating. However, I(HERG) inhibition by PROC was relieved by depolarisation to a highly positive membrane potential (+80 mV) that favoured HERG channel inactivation. These data suggest that PROC inhibits the HERG K(+) channel by a primarily 'open' or 'activated' channel state blocking mechanism and that avidity of drug-binding is decreased by extensive I(HERG) inactivation. The potency of I(HERG) blockade by PROC is much lower than for other Class Ia agents that have been studied previously under analogous conditions (quinidine and disopyramide), although the blocking mechanism appears similar. Thus, differences between the chemical structure of PROC and other Class Ia antiarrhythmic drugs may help provide insight into chemical determinants of blocking potency for agents that bind to open/activated HERG channels.
authors.affiliation: Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, BS8 1TD, Bristol, UK
authors.forename: John M
authors.initials: JM
authors.lastname: Ridley
authors.forename: James T
authors.initials: JT
authors.lastname: Milnes
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Benest
authors.forename: Joe D
authors.initials: JD
authors.lastname: Masters
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Witchel
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D027682:Cation Transport Proteins; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins; D004206:Disopyramide / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D020128:Inhibitory Concentration 50; D008133:Long QT Syndrome / Q000378:metabolism; D008564:Membrane Potentials; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011342:Procainamide / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D004206:Disopyramide; D011802:Quinidine; D011342:Procainamide