Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Hofer, D;.
Interaction of the muscle relaxant tolperisone with different sodium channel isoforms.
[ Dissertation ] Graz Medical University; 2007. pp.111.
- Autor*innen der Med Uni Graz:
- Hofer Doris
- Betreuer*innen:
- Quasthoff Stefan
- Schreibmayer Wolfgang
- Altmetrics:
- Abstract:
- Voltage dependent sodium channels (VDSC) are large proteins forming a central pore in the cell membrane of excitable tissues like muscle, heart and nerve. Voltage jumps from negative resting membrane Potentials to hyperpolarized positive potentials cause a sodium influx thorough the pore resulting in an electric impulse, the action potential. As VDSC may occupy distinct states concerning opening, closing and availability they show complex kinetics in respect of activation, inactivation and recovery of inactivation. There are several different sodium channel isoforms which occur tissue-specific. Each of them has a unique toxicological and pharmacological profile. VDSC have receptor sites for several neurotoxin and therapeutic drugs. Sodium channel blocking is of interest in pain therapy, as transmission of the pain signals may be reduced or even prevented. The drug tolperisone is applied as a muscle relaxant and in the treatment of chronic pain states. Tolperisone interaction with the sodium channel isoforms Nav1.3, Nav1.6 and Nav1.7 was investigated and compared to the action of the structurally related local anaesthetic lidocaine. The Xenopus laevis oocyte expression system is applied for sodium channel protein expression and the two electrode voltage clamp technique is used for electrophysiological recordings. Cumulative dose response relations revealed differences between the tow drugs on identical isoforms, as well as between isoforms concerning the drug dose required to achieve 50% block (IC50). A detailed kinetic analysis showed that tolperisone as well as lidocaine display a use-dependent block via state dependent association/dissociation. This typical effect of local anaesthetics resulted in a shift in steady-state inactivation to more negative potentials. In addition, both drugs were found to exert a use-independent (tonic) block on all isoform inactivation was influenced considerably by tolperisone and lidocaine. Interestingly, lidocaine prolonged the time constant of the fast recovery process of the isoforms Nav1.3 and Nav1.7, while tolperisone hardly showed any effect in this matter. Possibly these tow isoforms share a satructural property in the local anaesthetic receptor site on the channel protein. In addition to the systematic comparison of tolperiscone and lidocaine action on three sodium channel Xenopus laevis oocytes. For this purpose, the Nav1.9 gene (Scn11a) was cloned into a specific oocyte expression vector and coexpressed with the receptor tyrosine kinase B.