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a nondepolarizing muscle relaxant that was proposed as a replacement for succinylcholine for rapid intubation, was withdrawn from clinical use as a result of fatal bronchospasm, but the mechanism of this effect is not known.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.


CONCLUSIONS
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.
Jooste
Edmund
E
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Zhang
Yi
Y
Emala
Charles W
CW
D000818:Animals; D003959:Diamines / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D018727:Muscarinic Antagonists; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D017711:Nonlinear Dynamics; D010276:Parasympatholytics / Q000494:pharmacology; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000187:drug effects*; D043587:Receptor, Muscarinic M3 / Q000187:drug effects*; D012132:Respiratory Muscles / Q000187:drug effects*; D014673:Vecuronium Bromide / Q000031:analogs & derivatives* / Q000494:pharmacology*
D003959:Diamines; D007202:Indicators and Reagents; D018727:Muscarinic Antagonists; D003473:Neuromuscular Nondepolarizing Agents; D010276:Parasympatholytics; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D014673:Vecuronium Bromide; C082938:rapacuronium; C054938:methoctramine