title: A kinetic study on the stereospecific inhibition of KCNQ1 and I(Ks) by the chromanol 293B.
abstract: 1. Recently we and others have demonstrated a stereoselective inhibition of slowly activating human I(Ks) (KCNQ1/MinK) and homomeric KCNQ1 potassium channels by the enantiomers of the chromanol 293B. Here, we further characterized the mechanism of the 293B block and studied the influence of the 293B enantiomers on the gating kinetics of both channels after their heterologous expression in Xenopus oocytes. 2. Kinetic analysis of currents partially blocked with 10 microM of each 293B enantiomer revealed that only 3R,4S-293B but not 3S,4R-293B exhibited a time-dependent block of I(Ks) and KCNQ1 currents, indicating preferential open channel block activity. 3. Inhibition of both KCNQ1 and I(Ks) channels by 3R,4S-293B but not by 3S,4R-293B increased during a 2 Hz train of stimuli. 4. At high extracellular potassium concentrations the inhibition of KCNQ1 by 3R,4S-293B and 3S,4R-293B was unaffected. Drug inhibition of KCNQ1 and I(Ks) by both enantiomers also did not display a significant voltage-dependence, indicating that 293B does not strongly interact with permeant ions in the pore. 5. The inhibitory properties of 3R,4S-293B on I(Ks)-channels but not those of 3S,4R-293B fulfill the theoretical requirements for a novel class III antiarrhythmic drug, i.e. positive use-dependency. This enantiomer therefore represents a valuable pharmacological tool to evaluate the therapeutic efficiency of I(Ks)blockade.
authors.affiliation: Aventis Pharma Deutschland GmbH, DG Cardiovascular diseases, D-65926 Frankfurt am Main, Germany. Guiscard.Seebolm@gmx.de
authors.forename: G
authors.initials: G
authors.lastname: Seebohm
authors.forename: C
authors.initials: C
authors.lastname: Lerche
authors.forename: M
authors.initials: M
authors.lastname: Pusch
authors.forename: K
authors.initials: K
authors.lastname: Steinmeyer
authors.forename: A
authors.initials: A
authors.lastname: Brüggemann
authors.forename: A E
authors.initials: AE
authors.lastname: Busch
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001665:Binding Sites; D002839:Chromans / Q000378:metabolism / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D013237:Stereoisomerism; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics; D014981:Xenopus
chemical_list: D000889:Anti-Arrhythmia Agents; D002839:Chromans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane