Rapacuronium, a new rapidly acting nondepolarizing neuromuscular blocking drug, was released for use in 1999. It was developed specifically to facilitate tracheal intubation during the induction of general anesthesia, but has been associated with life threatening bronchospasm. At least five patients have died and the drug was recently withdrawn from clinical use. The mechanism underlying this airway constriction is not currently known. Possible mechanisms include histamine release, cholinesterase inhibition, M3 muscarinic receptor agonism and M2 muscarinic receptor antagonism. It is extremely important that we understand the mechanism by which this drug induces airway constriction to prevent this from ever occurring again with newly introduced neuromuscular blocking agents. A safe and effective ultra-short acting nondepolarizing neuromuscular blocker is urgently needed for routine clinical use, and until one is found the search will continue. We hypothesize that neuromuscular blocking agents that have selective M2 antagonistic properties potentiate parasympathetic release of acetylcholine mediating bronchoconstriction. During intubation of the trachea, parasympathetic nerves release acetylcholine that act on M3 muscarinic receptors on airway smooth muscle to promote bronchoconstriction. Preliminary data generated from this proposal strongly suggest that the mechanism by which rapacuronium induced fatal bronchospasm is by selective inhibition of M2 muscarinic receptors. We will use in vivo and in vitro approaches to define the mechanism of neuromuscular blocking agent-induced potentiation of bronchoconstriction. Neuromuscular affinities for M2 and M3 muscarinic receptors will be defined by radioligand binding and functional assays (adenylyl cyclase and inositol phosphate assays). Neuromuscular blocking agents effects on acetyl cholinesterase activity will also be measured. The ability of neuromuscular blocking agents to enhance acetylcholine release from parasympathetic nerves will be measured using guinea pig trachea in organ baths. The ability of neuromuscular blocking agents to potentiate vagal nerve mediated bronchoconstriction or to increase airway pressure via histamine release will be measured in vivo using a well-characterized guinea pig model. This mechanism needs to be clearly characterized so that it can serve as a gold standard screen for new agents developed for clinical practice. It is imperative that the mechanism of neuromuscular blocking agents potential to induce bronchospasm be understood so that the millions of patients who undergo general anesthesia on a yearly basis are not subjected to unnecessary life threatening bronchospasm.
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