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 microM) reduced peak Na+ current (INa) obtained at a holding potential of -80 mV with an IC50 value of 9.5 (3.5-21.9) microM and a Hill coefficient of 1.1. These effects were rapid and reversible. Lubeluzole (10 microM) 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 microM) 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 microM; tau1=4.4 +/- 6.2, tau2=22.7 +/- 1.5 milliseconds for control and tau1=311 +/- 144, tau2 = 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.
Centre de Recherche Pierre Fabre, Divison of Cardiovascular Diseases, Castres, France.
Bruno
B
Le Grand
Jean-Michel
JM
Talmant
Jean-Pierre
JP
Rieu
Jean-François
JF
Patoiseau
Gareth W
GW
John
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology
D010880:Piperidines; D015222:Sodium Channels; D013844:Thiazoles; C097722:lubeluzole