Pharmacological modulation of human cardiac Na+ channels

Douglas S. Krafte, Kathleen Davison, Nancy Dugrenier, Kimberly Estep, Kurt Josef, Robert L. Barchi, Roland G. Kallen, Paul J. Silver, Alan M. Ezrin

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 V 1 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 μM. 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 μM, 198 μM, and 41 μM, 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 α-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.

Original languageEnglish (US)
Pages (from-to)245-254
Number of pages10
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Volume266
Issue number3
DOIs
StatePublished - Feb 15 1994
Externally publishedYes

Fingerprint

Xenopus
Flecainide
Oocytes
Quinidine
BDF 9148
Pharmacology
Lidocaine
Inhibitory Concentration 50
Sodium
Complementary RNA
Anti-Arrhythmia Agents
Tetrodotoxin
Pharmaceutical Preparations
DPI 201-106

All Science Journal Classification (ASJC) codes

  • Pharmacology

Keywords

  • DPI 201-106
  • Na channel (human)
  • Oocyte, Class I antiarrhythmic

Cite this

Krafte, Douglas S. ; Davison, Kathleen ; Dugrenier, Nancy ; Estep, Kimberly ; Josef, Kurt ; Barchi, Robert L. ; Kallen, Roland G. ; Silver, Paul J. ; Ezrin, Alan M. / Pharmacological modulation of human cardiac Na+ channels. In: European Journal of Pharmacology: Molecular Pharmacology. 1994 ; Vol. 266, No. 3. pp. 245-254.
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Krafte, DS, Davison, K, Dugrenier, N, Estep, K, Josef, K, Barchi, RL, Kallen, RG, Silver, PJ & Ezrin, AM 1994, 'Pharmacological modulation of human cardiac Na+ channels', European Journal of Pharmacology: Molecular Pharmacology, vol. 266, no. 3, pp. 245-254. https://doi.org/10.1016/0922-4106(94)90133-3

Pharmacological modulation of human cardiac Na+ channels. / Krafte, Douglas S.; Davison, Kathleen; Dugrenier, Nancy; Estep, Kimberly; Josef, Kurt; Barchi, Robert L.; Kallen, Roland G.; Silver, Paul J.; Ezrin, Alan M.

In: European Journal of Pharmacology: Molecular Pharmacology, Vol. 266, No. 3, 15.02.1994, p. 245-254.

Research output: Contribution to journalArticle

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AU - Krafte, Douglas S.

AU - Davison, Kathleen

AU - Dugrenier, Nancy

AU - Estep, Kimberly

AU - Josef, Kurt

AU - Barchi, Robert L.

AU - Kallen, Roland G.

AU - Silver, Paul J.

AU - Ezrin, Alan M.

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N2 - 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 V 1 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 μM. 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 μM, 198 μM, and 41 μM, 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 α-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.

AB - 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 V 1 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 μM. 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 μM, 198 μM, and 41 μM, 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 α-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.

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