State-dependent blocking actions of azimilide dihydrochlo-ride (NE-10064) on human cardiac Na(+) channels.
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.
Miake
Junichiro
J
Department of Cardiovascular Medicine, Tottori University Hospital, Tottori, Japan.
Kurata
Yasutaka
Y
Iizuka
Kazuhiko
K
Furuichi
Hitomi
H
Manabe
Kasumi
K
Sasaki
Norihito
N
Yamamoto
Yasutaka
Y
Hoshikawa
Yoshiko
Y
Taniguchi
Shin-Ichi
S
Yoshida
Akio
A
Igawa
Osamu
O
Makita
Naomasa
N
Shiota
Goshi
G
Nanba
Eiji
E
Ohgi
Shigetsugu
S
Narahashi
Toshio
T
Hisatome
Ichiro
I
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*
D006827:Hydantoins; D048289:Imidazolidines; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C086123:azimilide