Effects of local anesthetics on Na+ channels containing the equine hyperkalemic periodic paralysis mutation.
Abstract: We examined the ability of local anesthetics to correct altered inactivation properties of rat skeletal muscle Na+ channels containing the equine hyperkalemic periodic paralysis (eqHPP) mutation when expressed in Xenopus oocytes. Increased time constants of current decay in eqHPP channels compared with wild-type channels were restored by 1 mM benzocaine but were not altered by lidocaine or mexiletine. Inactivation curves, which were determined by measuring the dependence of the relative peak current amplitude after depolarization to -10 mV on conditioning prepulse voltages, could be shifted in eqHPP channels back toward that observed for wild-type (WT) channels using selected concentrations of benzocaine, lidocaine, and mexiletine. Recovery from inactivation at -80 mV (50-ms conditioning pulse) in eqHPP channels followed a monoexponential time course and was markedly accelerated compared with wild-type channels (tauWT = 10.8 +/- 0.9 ms; taueqHPP = 2.9 +/- 0.4 ms). Benzocaine slowed the time course of recovery (taueqHPP,ben = 9.6 +/- 0.4 ms at 1 mM) in a concentration-dependent manner. In contrast, the recovery from inactivation with lidocaine and mexiletine had a fast component (taufast,lid = 3.2 +/- 0.2 ms; taufast,mex = 3.1 +/- 0.2 ms), which was identical to the recovery in eqHPP channels without drug, and a slow component (tauslow,lid = 1,688 +/- 180 ms; tauslow,mex = 2,323 +/- 328 ms). The time constant of the slow component of the recovery from inactivation was independent of the drug concentration, whereas the fraction of current recovering slowly depended on drug concentrations and conditioning pulse durations. Our results show that local anesthetics are generally incapable of fully restoring normal WT behavior in inactivation-deficient eqHPP channels.
Publication Date: 1998-08-04 PubMed ID: 9688593DOI: 10.1152/ajpcell.1998.275.2.C389Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The study explores the impact of local anesthetics on Na+ (sodium) channels in rat skeletal muscle which contain mutations related to equine hyperkalemic periodic paralysis (eqHPP) when expressed in Xenopus oocytes. Researchers identified that one anesthetic, benzocaine, restored functions of these mutant channels, although other anesthetics like lidocaine and mexiletine do not.
Experiment Methodology
- The research was carried out on rat skeletal muscle Na+ channels with eqHPP mutation, expressed in Xenopus oocytes (frog’s eggs).
- Time constants of current decay in mutated Na+ channels were compared to wild-type (normal) channels.
- The different constants observed between the eqHPP and WT channels were affected by benzocaine anesthetic, but not by lidocaine or mexiletine.
- This was followed by measuring the recovery from inactivation at -80 mV (which is a 50ms conditioning pulse) in eqHPP channels, which revealed a single exponential time course and observed to be much quicker compared to wild-type channels.
Findings of the Experiments
- Benzocaine slowed down the rapid time course of recovery in eqHPP channels in a concentration-dependent manner.
- On the contrary, recovery from inactivation with lidocaine and mexiletine posed both fast and slow components, which was identical to the recovery in eqHPP channels without any drug influence.
- The time constant of the slow recovery component was unaffected by the concentration of the drug, whereas the slow recovery fraction was dependent on the drug concentrations and the duration of the conditioning pulses.
Research Conclusions
- The study concludes that local anesthetics are generally unable to fully restore regular WT behavior in Na+ channels that are deficient in inactivation due to eqHPP mutation.
- However, Benzocaine showed some potential in restoring the behavior, hinting at possible specific combinations or concentrations of local anesthetics that can efficiently manage these channel abnormalities.
Cite This Article
APA
Sah RL, Tsushima RG, Backx PH.
(1998).
Effects of local anesthetics on Na+ channels containing the equine hyperkalemic periodic paralysis mutation.
Am J Physiol, 275(2), C389-C400.
https://doi.org/10.1152/ajpcell.1998.275.2.C389 Publication
Researcher Affiliations
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
MeSH Terms
- Anesthetics, Local / pharmacology
- Animals
- Benzocaine / pharmacology
- Electrophysiology / methods
- Female
- Horse Diseases / genetics
- Horses
- Hyperkalemia / genetics
- Hyperkalemia / veterinary
- In Vitro Techniques
- Lidocaine / pharmacology
- Membrane Potentials / drug effects
- Membrane Potentials / physiology
- Mexiletine / pharmacology
- Mutagenesis, Site-Directed
- Oocytes / physiology
- Paralyses, Familial Periodic / genetics
- Paralyses, Familial Periodic / veterinary
- Point Mutation
- Rats
- Sodium Channels / drug effects
- Sodium Channels / genetics
- Sodium Channels / physiology
- Xenopus laevis
Citations
This article has been cited 5 times.- Takahashi MP, Cannon SC. Mexiletine block of disease-associated mutations in S6 segments of the human skeletal muscle Na(+) channel. J Physiol 2001 Dec 15;537(Pt 3):701-14.
- Felix R. Channelopathies: ion channel defects linked to heritable clinical disorders. J Med Genet 2000 Oct;37(10):729-40.
- Haeseler G, Mamarvar M, Bufler J, Dengler R, Hecker H, Aronson JK, Piepenbrock S, Leuwer M. Voltage-dependent blockade of normal and mutant muscle sodium channels by benzylalcohol. Br J Pharmacol 2000 Jul;130(6):1321-30.
- Haeseler G, Leuwer M, Kavan J, Würz A, Dengler R, Piepenbrock S. Voltage-dependent block of normal and mutant muscle sodium channels by 4-Chloro-m-Cresol. Br J Pharmacol 1999 Nov;128(6):1259-67.
- Desaphy JF, Conte Camerino D, Franchini C, Lentini G, Tortorella V, De Luca A. Increased hindrance on the chiral carbon atom of mexiletine enhances the block of rat skeletal muscle Na+ channels in a model of myotonia induced by ATX. Br J Pharmacol 1999 Nov;128(6):1165-74.
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