title: State-dependent blocking actions of azimilide dihydrochlo-ride (NE-10064) on human cardiac Na(+) channels.
abstract: BACKGROUND
  Azimilide reportedly blocks Na(+) channels, although its mechanism remains unclear.
  
  
  RESULTS
  The kinetic properties of the azimilide block of the wild-type human Na(+) channels (WT: hH1) and mutant DeltaKPQ Na(+) channels (DeltaKPQ) expressed in COS7 cells were investigated using the whole-cell patch clamp technique and a Markovian state model. Azimilide induced tonic block of WT currents by shifting the h infinity curve in the hyperpolarizing direction and caused phasic block of WT currents with intermediate recovery time constant. The peak and steady-state DeltaKPQ currents were blocked by azimilide, although with only a slight shift in the h infinity curve. The phasic block of peak and steady-state DeltaKPQ currents by azimilide was significantly larger than the blocking of the peak WT current. The affinity of azimilide predicted by a Markovian state model was higher for both the activated state (Kd(A) =1.4 micromol/L), and the inactivated state (Kd(I) =1.4 micromol/L), of WT Na(+) channels than that for the resting state (Kd(R) =102.6 micromol/L).
  
  
  CONCLUSIONS
  These experimental and simulation studies suggest that azimilide blocks the human cardiac Na(+) channel in both the activated and inactivated states.
authors.affiliation: Department of Cardiovascular Medicine, Tottori University Hospital, Tottori, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Miake
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Kurata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Iizuka
authors.forename: Hitomi
authors.initials: H
authors.lastname: Furuichi
authors.forename: Kasumi
authors.initials: K
authors.lastname: Manabe
authors.forename: Norihito
authors.initials: N
authors.lastname: Sasaki
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Hoshikawa
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Akio
authors.initials: A
authors.lastname: Yoshida
authors.forename: Osamu
authors.initials: O
authors.lastname: Igawa
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Goshi
authors.initials: G
authors.lastname: Shiota
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Ohgi
authors.forename: Toshio
authors.initials: T
authors.lastname: Narahashi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
mesh_terms: D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006827:Hydantoins; D048289:Imidazolidines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008955:Models, Cardiovascular; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*
chemical_list: D006827:Hydantoins; D048289:Imidazolidines; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C086123:azimilide