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Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation

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peer-reviewed

Erstveröffentlichung
2020-11-23
Authors
Hoppe, Kerstin
Sartorius, Tina
Chaiklieng, Sunisa
Wietzorrek, Georg
Ruth, Peter
et al.
Wissenschaftlicher Artikel


Published in
Frontiers in Physiology ; 11 (2020). - Art.-Nr. 533946. - eISSN 1664-042X
Link to original publication
https://dx.doi.org/10.3389/fphys.2020.533946
Institutions
UKU. Klinik für Anästhesiologie
Zentrum für Seltene Erkrankungen (ZSE)
External cooperations
Universitätsklinikum Frankfurt
Universität Würzburg
Eberhard Karls Universität Tübingen
Khon Kaen University
Medizinische Universität Innsbruck
et al.
Document version
published version (publisher's PDF)
Abstract
Reduced Cl− conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca2+- and voltage-activated K+ channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK−/−) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T90/10) were monitored. Compared to wild type, fast-twitch muscle specimen of BK−/− mice resulted in a significantly decreased T90/10 in presence of 9-AC. Paxilline significantly shortened T90/10 of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T90/10. The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC).
Publication funding
Open-Access-Förderung durch die Medizinische Fakultät der Universität Ulm
Subject headings
[GND]: Muskelkrankheit
[MeSH]: Myotonia congenita | Large-conductance calcium-activated potassium channels
[Free subject headings]: Paxilline | NS1608 | Repetitive firing | Muscle disease | BK channel
[DDC subject group]: DDC 610 / Medicine & health
License
CC BY 4.0 International
https://creativecommons.org/licenses/by/4.0/

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DOI & citation

Please use this identifier to cite or link to this item: http://dx.doi.org/10.18725/OPARU-39185

Hoppe, Kerstin et al. (2021): Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation. Open Access Repositorium der Universität Ulm und Technischen Hochschule Ulm. http://dx.doi.org/10.18725/OPARU-39185
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