{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:59:03Z","timestamp":1788245943771,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>The skeletal muscle Cl<jats:sup>\u2212<\/jats:sup> channels, the ClC\u20101 channels, stabilize the resting membrane potential and dampen muscle fibre excitability. This study explored whether ClC\u20101 inhibition can recover nerve\u2010stimulated force in isolated muscle under conditions of compromised neuromuscular transmission akin to disorders of myasthenia gravis and Lambert\u2013Eaton syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Nerve\u2010muscle preparations were isolated from rats. Preparations were exposed to pre\u2010or post\u2010synaptic inhibitors (\u03c9\u2010agatoxin, elevated extracellular Mg<jats:sup>2+<\/jats:sup>, \u03b1\u2010bungarotoxin or tubocurarine). The potential of ClC\u20101 inhibition (9\u2010AC or reduced extracellular Cl<jats:sup>\u2212<\/jats:sup>) to recover nerve\u2010stimulated force under these conditions was assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ClC\u20101 inhibition recovered force in both slow\u2010twitch soleus and fast\u2010twitch EDL muscles exposed to 0.2\u00a0\u00b5mol\/L tubocurarine or 3.5\u00a0mmol\/L Mg<jats:sup>2+<\/jats:sup>. Similarly, ClC\u20101 inhibition recovered force in soleus muscles exposed to \u03b1\u2010bungarotoxin or \u03c9\u2010agatoxin. Moreover, the concentrations of tubocurarine and Mg<jats:sup>2+<\/jats:sup> required for reducing force to 50% rose from 0.14\u00a0\u00b1\u00a00.02\u00a0\u00b5mol\/L and 4.2\u00a0\u00b1\u00a00.2\u00a0mmol\/L in control muscles to 0.45\u00a0\u00b1\u00a00.03\u00a0\u00b5mol\/L and 4.7\u00a0\u00b1\u00a00.3\u00a0mmol\/L in muscles with 9\u2010AC respectively (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05, paired <jats:italic>T<\/jats:italic> test). Inhibition of acetylcholinesterase (neostigmine) and inhibition of voltage\u2010gated K<jats:sup>+<\/jats:sup> channels (4\u2010AP) relieve symptoms in myasthenia gravis and Lambert\u2013Eaton syndrome, respectively. Neostigmine and 9\u2010AC additively increased the tubocurarine concentration required to reduce nerve\u2010stimulated force to 50% (0.56\u00a0\u00b1\u00a00.05\u00a0\u00b5mol\/L with 9\u2010AC and neostigmine) and, similarly, 4\u2010AP and 9\u2010AC additively increased the Mg<jats:sup>2+<\/jats:sup> concentration required to reduce nerve\u2010stimulated force to 50% (6.5\u00a0\u00b1\u00a00.2\u00a0mmol\/L with 9\u2010AC and 4\u2010AP).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study shows that ClC\u20101 inhibition can improve neuromuscular function in pharmacological models of compromised neuromuscular transmission.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13690","type":"journal-article","created":{"date-parts":[[2021,5,22]],"date-time":"2021-05-22T11:16:13Z","timestamp":1621682173000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Chloride channel inhibition improves neuromuscular function under conditions mimicking neuromuscular disorders"],"prefix":"10.1111","volume":"233","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1060-4989","authenticated-orcid":false,"given":"Thomas Holm","family":"Pedersen","sequence":"first","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Alexander","family":"Macdonald","sequence":"additional","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Broch\u2010Lips","sequence":"additional","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osk","family":"Halldorsdottir","sequence":"additional","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole","family":"B\u00e6kgaard Nielsen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus 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