Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells

• Published in: General pharmacology 1999-05, Vol.32 (5), p.541-550
• Main Authors: Tanaka, Yasunori, Hisatome, Ichiro, Sasaki, Norihito, Ahmmed, Gias U, Yatsuhashi, Toru, Yamanouchi, Yumi, Uchida, Kazuhiko, Hamada, Toshihiro, Taniguchi, Shin-ichi, Ogino, Kazuhide, Igawa, Osamu, Yoshida, Akio, Shigemasa, Chiaki, Sato, Ryoichi
• Format: Article
• Language: English
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Electrophysiology; Fast inactivation process; Guinea Pigs; Heart - drug effects; Heart - physiology; Heart Ventricles - cytology; Hydrophobic pathway; In Vitro Techniques; Modulated receptor hypothesis; Na channels; Sodium Channel Blockers; Sodium Channels - physiology; Tocainide; Tocainide - pharmacology; Ventricular myocytes
• ISSN: 0306-3623; 1879-0011
• DOI: 10.1016/S0306-3623(98)00228-6

Tocainide blocked the Na current ( I Na) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state ( Kd i = 18 μM) than for the rested state ( Kd rest = 606 μM). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holding potential (HP). The recovery-time constant from the phasic block of I Na induced by tocainide was independent of either the HP or the removal of fast inactivation. After removal of fast inactivation, tocainide showed the pulse-duration dependency of phasic block but not the voltage dependency. These results suggest that tocainide could bind to the inactivated-state receptor through the hydrophilic pathway and leave the receptor through the hydrophobic pathway, producing the tonic and phasic block of I Na.