title: Effect of channel modulation and pH on IsK inhibition by the novel class III antiarrhythmic azimilide (NE-10064).
abstract: Inhibition of human IsK channels expressed in Xenopus oocytes by the novel class III antiarrhythmic azimilide was studied under distinct treatments known to increase IsK (hypotonic solution, A23187 and isoproterenol) Azimilide inhibited IsK under all conditions with similar potency. Reduction of ionic strength or pH changes from pH 6.5 to 8.5 did not alter IsK amplitude. However, inhibition of IsK by azimilide was decreased by reduced pH, but not by reduced ionic strength. Further, the apparent affinity of azimilide was increased more than tenfold by increasing pH from 6.5 to 8.5. The data suggest that the neutral form of azimilide, a weak base, inhibits IsK via a lipophilic protein-drug interaction. pH-dependence of azimilide may significantly alter its effects on IsK under distinct pathophysiological conditions (acidosis vs. alkalosis) and in distinct locations (heart vs. kidney).
authors.affiliation: Physiologisches Institut I, Eberhard-Karls-Universität Tübingen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Herzer
authors.forename: C A
authors.initials: CA
authors.lastname: Wagner
authors.forename: S
authors.initials: S
authors.lastname: Waldegger
authors.forename: F
authors.initials: F
authors.lastname: Lang
authors.forename: A E
authors.initials: AE
authors.lastname: Busch
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects; D006801:Humans; D006827:Hydantoins; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007545:Isoproterenol / Q000494:pharmacology; D009865:Oocytes; D010879:Piperazines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D014981:Xenopus
chemical_list: D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; D015221:Potassium Channels; C086123:azimilide; D007545:Isoproterenol