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.
Hou
V Y
VY
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Hirshman
C A
CA
Emala
C W
CW
D000818:Animals; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane; D006224:Cricetinae; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D010197:Pancuronium / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011994:Recombinant Proteins
D003473:Neuromuscular Nondepolarizing Agents; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; D010197:Pancuronium