Rapacuronium preferentially antagonizes the function of M2 versus M3 muscarinic receptors in guinea pig airway smooth muscle

Background: Rapacuronium, a nondepolarizing muscle relaxant that was proposed as a replacement for succinylcholine for rapid intubation, was withdrawn from clinical use as a result of fatal bronchospasm, but the mechanism of this effect is not known. Preferential antagonism of presynaptic M2 muscarinic receptors versus postsynpatic M3 muscarinic receptors can facilitate bronchoconstriction. The authors questioned whether rapacuronium preferentially antagonized M2 versus M3 muscarinic receptors in intact airway. Methods: Guinea pig tracheal rings were suspended in organ baths and muscle relaxants' antagonism of prejunctional M2 muscarinic autoreceptors was evaluated by augmentation of muscle contraction elicited by electrical field stimulation. Muscle relaxants' antagonism of postjunctional M3 muscarinic receptors was assessed by attenuation of muscle contraction elicited by acetylcholine. Results: Rapacuronium displayed a 50-fold higher affinity for antagonism of the M2 versus M3 muscarinic receptor. Moreover, its affinity for the M2 but not the M3 receptor was within concentrations achieved clinically. in addition, rapacuronium caused an increase in baseline tone of airway smooth muscle that was antagonized by atropine but not by previous depletion of nonadrenergic noncholinergic neurotransmitters or by inhibitors of histamine receptors, tachykinin receptors, leukotriene receptors, or calcium channels. Conclusion: These findings are consistent with the hypothesis that rapacuronium may precipitate bronchoconstriction by selective antagonism of the M2 muscarinic receptor on parasympathetic nerves, enhancing acetylcholine release to act upon unopposed M3 muscarinic receptors on airway muscle. An additional mechanism of rapacuronium-induced bronchoconstriction is suggested by increases in baseline muscle tension.