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. Methods and Results The kinetic properties of the azimilide block of the wild-type human Na+ channels (WT: hH1) and mutant ΔKPQ Na+ channels (ΔKPQ) expressed in COS7 cells were investigated using the whole-c...

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Bibliographic Details
Published in:Circulation Journal 2004, Vol.68(7), pp.703-711
Main Authors: Miake, Junichiro, Kurata, Yasutaka, Iizuka, Kazuhiko, Furuichi, Hitomi, Manabe, Kasumi, Sasaki, Norihito, Yamamoto, Yasutaka, Hoshikawa, Yoshiko, Taniguchi, Shin-ichi, Yoshida, Akio, Igawa, Osamu, Makita, Naomasa, Shiota, Goshi, Nanba, Eiji, Ohgi, Shigetsugu, Narahashi, Toshio, Hisatome, Ichiro
Format: Article
Language:English
Subjects:
Activated state
Azimilide
Dose-Response Relationship, Drug
Electrophysiology - methods
Heart - drug effects
Heart - physiology
hH1
Humans
Hydantoins
Imidazolidines - pharmacology
Inactivated state
Membrane Potentials - drug effects
Models, Cardiovascular
Patch-Clamp Techniques
Piperazines - pharmacology
Sodium Channel Blockers - pharmacology
Sodium Channels - drug effects
Sodium Channels - physiology
ΔKPQ mutant
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Summary:Background Azimilide reportedly blocks Na+ channels, although its mechanism remains unclear. Methods and Results The kinetic properties of the azimilide block of the wild-type human Na+ channels (WT: hH1) and mutant ΔKPQ Na+ channels (ΔKPQ) 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∞ curve in the hyperpolarizing direction and caused phasic block of WT currents with intermediate recovery time constant. The peak and steady-state ΔKPQ currents were blocked by azimilide, although with only a slight shift in the h∞ curve. The phasic block of peak and steady-state ΔKPQ 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 (KdA =1.4 μmol/L), and the inactivated state (KdI =1.4 μmol/L), of WT Na+ channels than that for the resting state (KdR =102.6 μmol/L). Conclusions These experimental and simulation studies suggest that azimilide blocks the human cardiac Na+ channel in both the activated and inactivated states. (Circ J 2004; 68: 703 - 711)
ISSN:1346-9843
1347-4820
DOI:10.1253/circj.68.703