ClC-1 Inhibition as a Mechanism for Accelerating Skeletal Muscle Recovery After Neuromuscular Block in Rats

Marianne Skals; Martin Broch-Lips; Martin Brandhøj Skov; Anders Riisager; Judith Ceelen; Ole Bækgaard Nielsen; Sorin J. Brull; Hans D. de Boer; Thomas Holm Pedersen

doi:10.1038/s41467-024-53237-x

ClC-1 Inhibition as a Mechanism for Accelerating Skeletal Muscle Recovery After Neuromuscular Block in Rats

Marianne Skals, Martin Broch-Lips, Martin Brandhøj Skov, Anders Riisager, Judith Ceelen, Ole Bækgaard Nielsen, Sorin J. Brull, Hans D. de Boer, Thomas Holm Pedersen^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

1 Citationer (Scopus)

Abstract

Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents. Here, we show that inhibition of the skeletal muscle-specific chloride ion (Cl^-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and, important physiologically, sustained (tetanic) contractions in a rat model mimicking neuromuscular blocking agent-induced muscle block used during surgery. This suggests ClC-1 inhibition as a mechanism for fast and efficacious recovery of neuromuscular function induced by any neuromuscular blocking agents.

Originalsprog	Engelsk
Artikelnummer	9289
Tidsskrift	Nature Communications
Vol/bind	15
Nummer	1
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-024-53237-x
Status	Udgivet - dec. 2024

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10.1038/s41467-024-53237-xLicens: CC BY-NC-ND

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title = "ClC-1 Inhibition as a Mechanism for Accelerating Skeletal Muscle Recovery After Neuromuscular Block in Rats",

abstract = "Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents. Here, we show that inhibition of the skeletal muscle-specific chloride ion (Cl-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and, important physiologically, sustained (tetanic) contractions in a rat model mimicking neuromuscular blocking agent-induced muscle block used during surgery. This suggests ClC-1 inhibition as a mechanism for fast and efficacious recovery of neuromuscular function induced by any neuromuscular blocking agents.",

author = "Marianne Skals and Martin Broch-Lips and Skov, {Martin Brandh{\o}j} and Anders Riisager and Judith Ceelen and Nielsen, {Ole B{\ae}kgaard} and Brull, {Sorin J.} and {de Boer}, {Hans D.} and Pedersen, {Thomas Holm}",

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AU - Skals, Marianne

AU - Broch-Lips, Martin

AU - Skov, Martin Brandhøj

AU - Riisager, Anders

AU - Ceelen, Judith

AU - Nielsen, Ole Bækgaard

AU - Brull, Sorin J.

AU - de Boer, Hans D.

AU - Pedersen, Thomas Holm

PY - 2024/12

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N2 - Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents. Here, we show that inhibition of the skeletal muscle-specific chloride ion (Cl-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and, important physiologically, sustained (tetanic) contractions in a rat model mimicking neuromuscular blocking agent-induced muscle block used during surgery. This suggests ClC-1 inhibition as a mechanism for fast and efficacious recovery of neuromuscular function induced by any neuromuscular blocking agents.

AB - Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents. Here, we show that inhibition of the skeletal muscle-specific chloride ion (Cl-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and, important physiologically, sustained (tetanic) contractions in a rat model mimicking neuromuscular blocking agent-induced muscle block used during surgery. This suggests ClC-1 inhibition as a mechanism for fast and efficacious recovery of neuromuscular function induced by any neuromuscular blocking agents.

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ClC-1 Inhibition as a Mechanism for Accelerating Skeletal Muscle Recovery After Neuromuscular Block in Rats

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