Study of the Interaction of Lubeluzole with Cardiac Sodium Channels

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 I_Na 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 I_Na 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.