Chloride channel inhibition improves neuromuscular function under conditions mimicking neuromuscular disorders

• Published in: Acta Physiologica 2021-10, Vol.233 (2), p.e13690-n/a
• Main Authors: Pedersen, Thomas Holm, Macdonald, William Alexander, Broch‐Lips, Martin, Halldorsdottir, Osk, Bækgaard Nielsen, Ole
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Bungarotoxin; ClC‐1 Cl− channels; Excitability; Magnesium; Membrane potential; Mimicry; Muscle contraction; muscle contractions; Myasthenia; Myasthenia gravis; Neostigmine; Neuromuscular diseases; Neuromuscular junctions; neuromuscular transmission disorders; Potassium channels (voltage-gated); Skeletal muscle; Tubocurarine
• ISSN: 1748-1708; 1748-1716
• DOI: 10.1111/apha.13690

Aim The skeletal muscle Cl− channels, the ClC‐1 channels, stabilize the resting membrane potential and dampen muscle fibre excitability. This study explored whether ClC‐1 inhibition can recover nerve‐stimulated force in isolated muscle under conditions of compromised neuromuscular transmission akin to disorders of myasthenia gravis and Lambert–Eaton syndrome. Methods Nerve‐muscle preparations were isolated from rats. Preparations were exposed to pre‐or post‐synaptic inhibitors (ω‐agatoxin, elevated extracellular Mg2+, α‐bungarotoxin or tubocurarine). The potential of ClC‐1 inhibition (9‐AC or reduced extracellular Cl−) to recover nerve‐stimulated force under these conditions was assessed. Results ClC‐1 inhibition recovered force in both slow‐twitch soleus and fast‐twitch EDL muscles exposed to 0.2 µmol/L tubocurarine or 3.5 mmol/L Mg2+. Similarly, ClC‐1 inhibition recovered force in soleus muscles exposed to α‐bungarotoxin or ω‐agatoxin. Moreover, the concentrations of tubocurarine and Mg2+ required for reducing force to 50% rose from 0.14 ± 0.02 µmol/L and 4.2 ± 0.2 mmol/L in control muscles to 0.45 ± 0.03 µmol/L and 4.7 ± 0.3 mmol/L in muscles with 9‐AC respectively (P