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

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  • Miake Junichiro
    Department of Cardiovascular Medicine, Tottori University Hospital
  • Kurata Yasutaka
    Department of Physiology, Kanazawa Medical University
  • Iizuka Kazuhiko
    Department of Cardiovascular Medicine, Tottori University Hospital
  • Furuichi Hitomi
    Division of Regenerative Medicine and Therapeutics, Department of Gene Therapy and Regenerative Medicine, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science
  • Manabe Kasumi
    Division of Regenerative Medicine and Therapeutics, Department of Gene Therapy and Regenerative Medicine, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science
  • Sasaki Norihito
    Division of Regenerative Medicine and Therapeutics, Department of Gene Therapy and Regenerative Medicine, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science
  • Yamamoto Yasutaka
    Division of Regenerative Medicine and Therapeutics, Department of Gene Therapy and Regenerative Medicine, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science
  • Hoshikawa Yoshiko
    Division of Regenerative Medicine and Therapeutics, Department of Gene Therapy and Regenerative Medicine, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science
  • Taniguchi Shin-ichi
    Department of Cardiovascular Medicine, Tottori University Hospital
  • Yoshida Akio
    Department of Cardiovascular Medicine, Tottori University Hospital
  • Igawa Osamu
    Department of Cardiovascular Medicine, Tottori University Hospital
  • Makita Naomasa
    Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine
  • Shiota Goshi
    Division of Gene Therapy, Department of Gene Therapy and Regenerative Medicine, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science
  • Nanba Eiji
    Gene Research Center, Tottori University
  • Ohgi Shigetsugu
    Department of Cardiovascular Surgery, Tottori University Hospital
  • Narahashi Toshio
    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School
  • Hisatome Ichiro
    Division of Regenerative Medicine and Therapeutics, Department of Gene Therapy and Regenerative Medicine, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science

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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)<br>

収録刊行物

  • Circulation Journal

    Circulation Journal 68 (7), 703-711, 2004

    一般社団法人 日本循環器学会

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