Neuromuscular relaxants as antagonists for M₂ and M₃ muscarinic receptors

Background: Neuromuscular relaxants such as pancuronium bind to M₂ and M₃ muscarinic receptors as antagonists. Blockade of muscarinic receptors in atria of the M₂ subtype mediates tachycardia. In the lung, blockade of M₂ receptors on parasympathetic nerves potentiates vagally induced bronchospasm, whereas blockade of M₃ receptors on bronchial smooth muscle inhibits bronchospasm. The current study was designed to quantify the affinity of a series of neuromuscular relaxants for the M₂ and M₃ muscarinic receptors, which were individually stably transfected in Chinese hamster ovary cell lines. Methods: Competitive radioligand binding assays determined the relative binding affinities of the neuromuscular relaxants pancuronium, succinylcholine, mivacurium, doxacurium, atracurium, rocuronium, gallamine, and pipecuronium for the muscarinic receptor in the presence of a muscarinic receptor antagonist (³H-QNB) in membranes prepared from cells individually expressing either the M₂ or M₃ muscarinic receptor. Results: All muscle relaxants evaluated displaced ³H-QNB from muscarinic receptors. The relative order of potency for the M₂ muscarinic receptor (highest to lowest) was pancuronium, gallamine, rocuronium, atracurium, pipecuronium, doxacurium, mivacurium, and succinylcholine. The relative order of potency for the M₃ muscarinic receptor (highest to lowest) was pancuronium, atracurium, pipecuronium, rocuronium, mivacurium, gallamine, succinylcholine, and doxacurium. Conclusions: All neuromuscular relaxants studied had affinities for the M₂ and M₃ muscarinic receptor, but only pancuronium and gallamine had affinities within the range of concentrations achieved with clinical use. The high affinities of gallamine and pancuronium for the M₂ muscarinic receptor are consistent with a mechanism of M₂ receptor blockade in relaxant-induced tachycardia.