Neuromuscular Blocking Agents' Differential Bronchoconstrictive

Anesthesiology 2007; 106:763–72 Copyright © 2007, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Neuromuscular Blocking Agents’ Differential Bronchoconstrictive Potential in Guinea Pig Airways Edmund Jooste, M.B., ChB.,* Yi Zhang, M.D.,† Charles W. Emala, M.D.‡ Background: Neuromuscular blocking agents are designed to or bronchoconstriction due to vagal nerve preganglionic antagonize nicotinic cholinergic receptors on skeletal muscle M2 muscarinic receptor antagonism, positive allosterism but also antagonize muscarinic receptors. Several muscle relaxants have the potential to promote bronchoconstriction due to with acetylcholine at the postjunctional smooth muscle unintended effects exemplified by histamine release of atra- M3 muscarinic receptors, or histamine release. curium or mivacurium and detrimental interactions with mus- Five subtypes of muscarinic receptors are known, with carinic receptors by rapacuronium. Although interactions of three subtypes expressed on airway structures. Acetyl- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/106/4/763/364238/0000542-200704000-00018.pdf by guest on 27 September 2021 muscle relaxants with muscarinic receptors have been exten- choline activation of M3 muscarinic receptors expressed sively characterized in vitro, limited information is available on their potential interactions with airway tone in vivo. on airway smooth muscle initiates airway smooth muscle Methods: Changes in pulmonary inflation pressures and contraction. M2 muscarinic receptors are expressed on heart rates induced by vagal nerve stimulation and intravenous at least two airway structures. They classically function acetylcholine were measured in the absence and presence of as negative feedback autoreceptors on the presynaptic increasing doses of gallamine, pancuronium, mivacurium, vecuronium, cisatracurium, rocuronium, or rapacuronium in side of postganglionic parasympathetic nerves, where guinea pigs. Mivacurium’s and rapacuronium’s potential of in- they inhibit further release of acetylcholine. In addition, ducing bronchoconstriction by histamine release was also eval- M2 muscarinic receptors are expressed on airway uated. smooth muscle, where their activation is thought to Results: Rapacuronium potentiated both vagal nerve–stimu- inhibit airway smooth muscle relaxation. M1 muscarinic lated and intravenous acetylcholine–induced increases in airway pressures, which were totally blocked by atropine but not receptors have been identified in parasympathetic gan- 3,4 pyrilamine. Vecuronium, rocuronium, mivacurium, and cisatra- glia, where they facilitate neurotransmission. Concep- curium were devoid of significant airway effects. Mivacurium, at tually, activation of these M1 receptors would potentiate high doses, increased pulmonary inflation pressures, which vagally induced bronchoconstriction, whereas antago- were attenuated by pyrilamine. nizing them would decrease acetylcholine release. Conclusion: Rapacuronium was unique among muscle relaxants evaluated in that it potentiated both vagal nerve– and The upper airways are heavily innervated by parasym- intravenous acetylcholine–induced bronchoconstriction with pathetic nerves and are a key component in an irritant no evidence of histamine release. The dual detrimental interac- reflex arc that controls airway caliber. Irritation of the tions of rapacuronium with muscarinic receptors previously upper airway by a foreign body (e.g., endotracheal tube) demonstrated in vitro correlate with in vivo muscarinic receptor mechanisms of bronchoconstriction and may account for results in the liberation of acetylcholine from parasym- the profound bronchoconstriction seen with its clinical use. pathetic nerves causing bronchoconstriction. Typically, These findings may establish pharmacologic characteristics to ongoing acetylcholine release is attenuated by the acti- avoid with new muscle relaxants intended for clinical use. vation of presynaptic M2 muscarinic receptors, thus limiting vagally induced bronchoconstriction. However, se- NEUROMUSCULAR blocking agents are designed to an- lective antagonism of these presynaptic M2 muscarinic tagonize nicotinic cholinergic receptors on skeletal mus- receptors by any agent (e.g., a muscle relaxant with M2 cle to facilitate intubation of the trachea, certain surgical antagonistic affinity) during a period of heightened para- procedures, and mechanical ventilation. Acetylcholine is sympathetic activity (e.g., intubation) would block this the endogenous ligand for the nicotinic ligand-gated ion protective negative feedback effect, leading to enhanced channel as well as for the G protein–coupled muscarinic vagally induced bronchoconstriction. Likewise, M2 mus- receptors. Therefore, it is not surprising that agents carinic receptor antagonism in the heart results in tachy- designed to be antagonists at nicotinic receptors may cardia due to this functional vagolytic effect. Current and have affinities for muscarinic receptors.1,2 Many neuro- previously used neuromuscular blocking agents such as muscular blocking agents have significant clinical side pancuronium and gallamine have well-characterized M2 effects on the cardiac and respiratory systems, including muscarinic receptor antagonism5 and are known to tachycardia due to M2 muscarinic receptor antagonism, cause tachycardia and enhance vagally induced bronchoconstriction.6 Pancuronium’s failure to elicit clinically * Assistant Professor, † Research Associate, ‡ Associate Professor. significant bronchoconstriction is likely due to its coin- 6,7 Received from the Department of Anesthesiology, Columbia University, New cident potent M3 muscarinic receptor antagonism on York, New York. Submitted for publication September 12, 2006. Accepted for airway smooth muscle limiting the bronchoconstrictive publication January 4, 2007. Supported by grant No. GM065281 from the Na- tional Institutes of Health, Bethesda, Maryland. effect of any liberated acetylcholine. Address correspondence to Dr. Emala: Department of Anesthesiology, Colum- We recently showed a novel mechanism by which a bia University, 630 West 168th Street, PH 505, New York, New York 10032. clinically relevant concentration of the neuromuscular [email protected]. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. blocking agent rapacuronium could allosterically en- Anesthesiology, V 106, No 4, Apr 2007 763 764 JOOSTE ET AL. hance acetylcholine’s effect at M3 muscarinic recep- nary inflation pressure (Ppi) was measured just proximal tors.8 Although neuromuscular blocking agents are pro- to the cannula through a side port via rigid plastic totypical allosteric agents at some muscarinic receptor extension tubing connected independently to two pres- subtypes,9,10 never before had clinically relevant con- sure modules with differing ranges of sensitivity centrations of a neuromuscular blocking agent been (TSD160B 0–12.5 cm H2O and TSD160C 0–25 cm H2O; linked to such potent bronchoconstriction. Despite our Biopac Systems, Inc., Goleta, CA). Peak Ppi has been extensive characterization of currently used neuromus- used in this model for many years as a reflection of cular blocking agents with muscarinic receptors in changes in airway tone.5,6,11–16 Paralysis standardizes vitro, most currently used neuromuscular blocking chest wall compliance and a constant volume ventilator agents, including vecuronium, rocuronium, and cisatra- standardizes inspiratory volume such that changes in curium, have not been characterized for their interaction airway tone are reflected in changes in peak Ppi. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/106/4/763/364238/0000542-200704000-00018.pdf by guest on 27 September 2021 with airway muscarinic receptors in vivo. Moreover, it is Both jugular veins were cannulated with PE-50 tubing not known whether the demonstrated in vitro detrimen- for the administration of drugs, at which time the ani- tal effects of rapacuronium at airway muscarinic recep- mals were paralyzed with succinylcholine (170 ␮g ⅐ kgϪ1 tors translate into enhanced bronchoconstriction in ⅐ minϪ1), which has been shown previously to have no vivo. Therefore, the current study was undertaken to effect on baseline Ppi, heart rate, or blood pressure and demonstrate that the previously described in vitro inter- to have no effect on vagally induced increases in airway actions of muscle relaxants with muscarinic receptors pressures.6,11 The carotid artery was cannulated with correlated with in vivo detrimental effects on airway PE-50 tubing and connected to a pressure transducer in tone. Such a correlation would establish the importance line with a Biopac TSD104A module for monitoring heart of evaluating newly designed muscle relaxants’ func- rate and blood pressure. Throughout the experiments, tional interaction with muscarinic receptors as one mea- sympathetically mediated changes in hemodynamics (hy- sure of their clinical safety. pertension, tachycardia) were monitored as an indicator of the depth of anesthesia after muscle paralysis. A 20% increase in heart rate or systolic blood pressure was Materials and Methods treated with incremental urethane (0.2 g/kg intraperito- neal). Both vagus nerves were tightly tied but not cut, Male Hartley guinea pigs weighing 400 Ϯ 10.1 g were and the distal ends were placed on shielded electrodes used. Guinea pigs were handled in accordance with the immersed in a pool of liquid mineral oil.5,6,11–16

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