Chloride channel inhibition improves neuromuscular function under conditions mimicking neuromuscular disorders
| Autor: | Ole Bækgaard Nielsen, Osk Halldorsdottir, Martin Broch-Lips, William Alexander Macdonald, Thomas Holm Pedersen |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Physiology neuromuscular transmission disorders Neuromuscular transmission Neuromuscular Junction 030204 cardiovascular system & hematology Synaptic Transmission Membrane Potentials 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Chloride Channels ClC-1 Cl channels Internal medicine muscle contractions medicine Extracellular Animals Membrane potential Chemistry Skeletal muscle medicine.disease Acetylcholinesterase Myasthenia gravis Neostigmine Rats 030104 developmental biology Endocrinology medicine.anatomical_structure Chloride channel medicine.drug |
| Zdroj: | Pedersen, T H, Macdonald, W A, Broch-Lips, M, Halldorsdottir, O & Bækgaard Nielsen, O 2021, ' Chloride channel inhibition improves neuromuscular function under conditions mimicking neuromuscular disorders ', Acta Physiologica, vol. 233, no. 2, e13690 . https://doi.org/10.1111/apha.13690 |
| Popis: | 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 + 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 Mg2+ 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. |
| Databáze: | OpenAIRE |
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