title: Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action.
abstract: 1. The class III antiarrhythmic azimilide has previously been shown to inhibit I(Ks) and I(Kr) in guinea-pig cardiac myocytes and I(Ks) (minK) channels expressed in Xenopus oocytes. Because HERG channels underly the conductance I(Kr), in human heart, the effects of azimilide on HERG channels expressed in Xenopus oocytes were the focus of the present study. 2. In contrast to other well characterized HERG channel blockers, azimilide blockade was reverse use-dependent, i.e., the relative block and apparent affinity of azimilide decreased with an increase in channel activation frequency. Azimilide blocked HERG channels at 0.1 and 1 Hz with IC50s of 1.4 microM and 5.2 microM respectively. 3. In an envelope of tail test, HERG channel blockade increased with increasing channel activation, indicating binding of azimilide to open channels. 4. Azimilide blockade of HERG channels expressed in Xenopus oocytes and I(Kr) in mouse AT-1 cells was decreased under conditions of high [K+]e, whereas block of slowly activating I(Ks) channels was not affected by changes in [K+]e. 5. In summary, azimilide is a blocker of cardiac delayed rectifier channels, I(Ks) and HERG. Because of the distinct effects of stimulation frequency and [K+]e on azimilide block of I(Kr) and I(Ks) channels, we conclude that the relative contribution of block of each of these cardiac delayed rectifier channels depends on heart frequency. [K+]e and regulatory status of the respective channels.
authors.affiliation: Institute of Physiology I, Eberhard-Karls University of Tübingen, Germany.
authors.forename: A E
authors.initials: AE
authors.lastname: Busch
authors.forename: B
authors.initials: B
authors.lastname: Eigenberger
authors.forename: N K
authors.initials: NK
authors.lastname: Jurkiewicz
authors.forename: J J
authors.initials: JJ
authors.lastname: Salata
authors.forename: A
authors.initials: A
authors.lastname: Pica
authors.forename: H
authors.initials: H
authors.lastname: Suessbrich
authors.forename: F
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008564:Membrane Potentials / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000096:biosynthesis; D015534:Trans-Activators; D014981:Xenopus
chemical_list: D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D015534:Trans-Activators; C086123:azimilide; D011188:Potassium