Advertisement

Pflügers Archiv

, Volume 419, Issue 6, pp 603–609 | Cite as

Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre

  • Evelyne Benoit
  • Denis Escande
Excitable Tissues and Central Nervous Physiology

Abstract

The effects of 0.15–250 μM riluzole, a novel psychotropic agent with anticonvulsant properties, were studied on voltage-clamped nodes of Ranvier of isolated nerve fibres of the frog. When added to the external solution, the drug rapidly and reversibly inhibited both K and Na currents with an apparent dissociation constant of 0.09 mM. The riluzole-induced decrease of these currents was not “use-dependent”. At concentrations up to 100μM, the drug had no noticeable effect on the time course of Na current inactivation nor on the shape and the position along voltage axis of the Na conductance/voltage relationship. On the other hand, it induced substantial shifts towards negative voltages of the steady-state Na inactivation/voltage curve. From these results, according to the modulated-receptor model, an apparent dissociation constant of 0.29 μM could be calculated for riluzole-induced blockage of inactivated Na channels. The recovery from Na current inactivation was also affected by the drug. It is concluded that riluzole is a highly specific blocker of inactivated Na channels, which is more than 300 times more effective on these channels than on K or resting Na channels.

Key words

Node of Ranvier Voltage clamp Riluzole Ionic channels Inactivated sodium channels Modulated-receptor model 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Benoit E, Dubois JM (1985) Cooperativity of tetrodotoxin action in the frog node of Ranvier. Pflügers Arch 405:237–243Google Scholar
  2. 2.
    Benoit E, Corbier A, Dubois JM (1985) Evidence for two transient sodium currents in the frog node of Ranvier. J Physiol (Lond) 361:339–360Google Scholar
  3. 3.
    Benoit E, Carratù MR, Mitolo-Chieppa D (1988) Mechanism of action of a structural analog of alphaxalone on myelinated nerve fibre. Eur J Pharmacol 158:1–9Google Scholar
  4. 4.
    Chiu SY (1977) Inactivation of sodium channels: second-order kinetics in myelinated nerve. J Physiol (Lond) 273:573–596Google Scholar
  5. 5.
    Clarkson CW, Follmer CH, Ten Eick RE, Hondeghem LM, Yeh JZ (1988) Evidence for two components of sodium channel block by lidocaine in isolated cardiac myocytes. Circ Res 63:869–878Google Scholar
  6. 6.
    Dubois JM, Benoit E (1985) Perméabilité au sodium de la fibre nerveuse myélinisée: hypothèses et conclusions. Funkt Biol Med 4:37–41Google Scholar
  7. 7.
    Frankenhaeuser B (1960) Quantitative description of sodium currents in myelinated nerve fibres of Xenopus laevis. J Physiol (Lond) 151:491–501Google Scholar
  8. 8.
    Hille B (1977) Local anaesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69:497–515Google Scholar
  9. 9.
    Hondeghem LM, Katzung BG (1977) Time- and voltage-dependent actions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472:373–398Google Scholar
  10. 10.
    Meeder T, Ulbricht W (1987) Action of benzocaine on sodium channels of frog nodes of Ranvier treated with chloramine-T. Pflügers Arch 409:265–273Google Scholar
  11. 11.
    Mizoule J, Meldrum B, Mazadier M, Croucher M, Ollat C, Uzan A, Legrand JJ, Gueremy C, Le Fur G (1985) 2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission: I. Neuropharmacology 24:767–773Google Scholar
  12. 12.
    Nonner W (1969) A new voltage clamp method for Ranvier nodes. Pflügers Arch 309:176–192Google Scholar
  13. 13.
    Schmidtmayer J (1985) Behaviour of chemically modified sodium channels in frog nerve supports a three-state model of inactivation. Pflügers Arch 404:21–28Google Scholar
  14. 14.
    Schmidtmayer J (1989) Voltage and temperature dependence of normal and chemically modified inactivation of sodium channels. Quantitative description by a cyclic three-state model. Pflügers Arch 414:273–281Google Scholar
  15. 15.
    Schneider MF, Dubois JM (1986) Effects of benzocaine on the kinetics of normal and batrachotoxin-modified Na channels in frog node of Ranvier. Biophys J 50:523–530Google Scholar
  16. 16.
    Stämpfli R, Hille B (1976) Electrophysiology of the peripheral myelinated nerve. In: Llinas R, Precht W (eds) Handbook of frog neurobiology. Springer, Berlin Heidelberg New York, pp 3–32Google Scholar
  17. 17.
    Willow M, Gonoi T, Catterall WA (1985) Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol Pharmacol 27:549–558Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Evelyne Benoit
    • 1
  • Denis Escande
    • 2
  1. 1.Laboratoire de Physiologie comparée, URA CNRS 1121, bât. 443Université Paris SudOrsay CedexFrance
  2. 2.Rhône-Poulenc Rorer, Centre de Recherches de VitryVitry-sur-SeineFrance

Personalised recommendations