Study of the Interaction of Lubeluzole with Cardiac Sodium Channels

Bruno Le Grand, Jean Michel Talmant, Jean Pierre Rieu, Jean François Patoiseau, Gareth W. John

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The effects of lubeluzole on sodium currents were examined in guinea-pig isolated cardiac myocytes by use of the whole-cell patch clamp technique. Lubeluzole (0.01-100 μM) reduced peak Na+ current (I Na) obtained at a holding potential of -80 mV with an IC 50 value of 9.5 (3.5-21.9) μM and a Hill coefficient of 1.1. These effects were rapid and reversible. Lubeluzole (10 μM) produced a shift in the inactivation curve to hyperpolarized potentials (by -9.7 mV, P < 0.05), but produced no change in the voltage-dependence of activation. Lubeluzole (10 μM) produced significant tonic block of INa obtained at a holding potential of -120 mV (2.7 ± 1.4% and 27.5 ± 5.8% for control and lubeluzole, respectively; n = 6; P < 0.05). Use-dependent block of INa was also observed. Recovery from block was delayed by lubeluzole (10 μM; τ1=4.4 ± 6.2, τ2=22.7 ± 1.5 milliseconds for control and τ1=311 ± 144, τ2 = 672 ± 23 milliseconds for lubeluzole; n = 6; P < 0.001) confirming use-dependency of block. The results indicate that lubeluzole produces both tonic and use-dependent block of cardiac sodium channels at concentrations similar to those that block neuronal sodium channels, due mainly to interaction of the drug with channels in the inactivated state.

Original languageEnglish
Pages (from-to)581-587
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume42
Issue number5
DOIs
StatePublished - Nov 2003
Externally publishedYes

Keywords

  • Cardiomyocyte
  • Lubeluzole
  • Sodium channels
  • State-dependent block
  • Stroke

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