Chloride channel inhibition improves neuromuscular function under conditions mimicking neuromuscular disorders

Abstract

Abstract 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 Mg 2+ , 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 Mg 2+ . Similarly, ClC‐1 inhibition recovered force in soleus muscles exposed to α‐bungarotoxin or ω‐agatoxin. Moreover, the concentrations of tubocurarine and Mg 2+ 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 < .05, paired T test). Inhibition of acetylcholinesterase (neostigmine) and inhibition of voltage‐gated K + channels (4‐AP) relieve symptoms in myasthenia gravis and Lambert–Eaton syndrome, respectively. Neostigmine and 9‐AC additively increased the tubocurarine concentration required to reduce nerve‐stimulated force to 50% (0.56 ± 0.05 µmol/L with 9‐AC and neostigmine) and, similarly, 4‐AP and 9‐AC additively increased the Mg 2+ concentration required to reduce nerve‐stimulated force to 50% (6.5 ± 0.2 mmol/L with 9‐AC and 4‐AP). Conclusion This study shows that ClC‐1 inhibition can improve neuromuscular function in pharmacological models of compromised neuromuscular transmission.

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