State-Dependent Blocking Actions of Azimilide Dihydrochlo-ride (NE-10064) on Human Cardiac Na+ Channels

• 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
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.68.703

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)