ClC-1 Inhibition as a Novel Mechanism for Accelerating Recovery of Skeletal Muscle Function After Neuromuscular Block in an Experimental Rat Model

Abstract

Abstract Neuromuscular blocking agents (NMBAs) are commonly used 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 NMBAs 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 NMBAs. 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 physiologically important sustained contractions (tetanic) in a novel rat model mimicking NMBA-induced muscle block used during surgery. ClC-1 inhibition was found to reverse any NMBA with superior properties to existing reversal agents. This suggests ClC-1 inhibition as a novel mechanism for fast and efficacious reversal from neuromuscular block.