Interaction of Nondepolarizing Muscle Relaxants with M2and M3Muscarinic Receptors in Guinea Pig Lung and Heart

Abstract

Background Neuromuscular blocking agents such as gallamine and pancuronium bind to muscarinic cholinergic receptors and alter parasympathetically mediated airway caliber and heart rate. In the lungs, acetylcholine induces bronchoconstriction via M3 muscarinic receptors on airway smooth muscle, whereas in the heart M2 muscarinic receptors mediate bradycardia. Moreover, release of acetylcholine from parasympathetic nerves in the lung is decreased by inhibitory M2 receptors on the nerves, which represent a negative feedback system. Blockade of these receptors potentiates vagally induced bronchoconstriction, which may be clinically important if the M3 receptors on airway muscle are not blocked. These experiments were designed to examine the effects of the newer, nondepolarizing muscle relaxants pipecuronium, doxacurium, and mivacurium on pulmonary and cardiac muscarinic receptors. Methods Guinea pigs were anesthetized with urethane, paralyzed with succinylcholine, and their lungs mechanically ventilated. Pulmonary inflation pressure and heart rate were measured before and after electrical stimulation of both vagus nerves to evaluate prejunctional M2 muscarinic receptor function and after intravenous acetylcholine to evaluate postjunctional M3 and M2 receptor function in the presence of increasing concentrations of pancuronium, mivacurium, pipecuronium, and doxacurium. Results Pancuronium was an antagonist for M2 and M3 muscarinic receptors. Mivacurium was a more potent antagonist of M3 than M2 receptors. Pipecuronium was an antagonist of M2 but not M3 receptors. Doxacurium was not an antagonist of either M2 or M3 muscarinic receptors. Only pancuronium and pipecuronium potentiated vagally induced bronchoconstriction. With pipecuronium, the potentiation occurred at concentrations greater than those used clinically. Conclusions Although pipecuronium is an M2 receptor antagonist with no M3 receptor antagonist properties, potentiation of reflex-induced bronchoconstriction is unlikely, because this effect occurred only at doses greater than those used clinically.