Pharmacological modulation of human cardiac Na+ channels

• Published in: European journal of pharmacology Vol. 266; no. 3; p. 245
• Main Authors: Krafte, D S, Davison, K, Dugrenier, N, Estep, K, Josef, K, Barchi, R L, Kallen, R G, Silver, P J, Ezrin, A M
• Format: Journal Article
• Language: English
• Published: Netherlands 15-02-1994
• Subjects: Animals; Azetidines - pharmacology; Cardiotonic Agents - pharmacology; Electrophysiology; Female; Flecainide - pharmacology; Humans; Lidocaine - pharmacology; Mercaptopurine - analogs & derivatives; Mercaptopurine - pharmacology; Myocardium - metabolism; Oocytes - metabolism; Piperazines - pharmacology; Quinidine - pharmacology; RNA, Complementary - genetics; Sodium Channels - drug effects; Sodium Channels - metabolism; Tetrodotoxin - pharmacology; Transcription, Genetic; Xenopus laevis
• ISSN: 0014-2999
• DOI: 10.1016/0922-4106(94)90133-3

Pharmacological modulation of human sodium current was examined in Xenopus oocytes expressing human heart Na+ channels. Na+ currents activated near -50 mV with maximum current amplitudes observed at -20 mV. Steady-state inactivation was characterized by a V1/2 value of -57 +/- 0.5 mV and a slope factor (k) of 7.3 +/- 0.3 mV. Sodium currents were blocked by tetrodotoxin with an IC50 value of 1.8 microM. These properties are consistent with those of Na+ channels expressed in mammalian myocardial cells. We have investigated the effects of several pharmacological agents which, with the exception of lidocaine, have not been characterized against cRNA-derived Na+ channels expressed in Xenopus oocytes. Lidocaine, quinidine and flecainide blocked resting Na+ channels with IC50 values of 521 microM, 198 microM, and 41 microM, respectively. Use-dependent block was also observed for all three agents, but concentrations necessary to induce block were higher than expected for quinidine and flecainide. This may reflect differences arising due to expression in the Xenopus oocyte system or could be a true difference in the interaction between human cardiac Na+ channels and these drugs compared to other mammalian Na+ channels. Importantly, however, this result would not have been predicted based upon previous studies of mammalian cardiac Na+ channels. The effects of DPI 201-106, RWJ 24517, and BDF 9148 were also tested and all three agents slowed and/or removed Na+ current inactivation, reduced peak current amplitudes, and induced use-dependent block. These data suggest that the alpha-subunit is the site of interaction between cardiac Na+ channels and Class I antiarrhythmic drugs as well as inactivation modifiers such as DPI 201-106.