Ability of nondepolarizing neuromuscular blocking drugs to act as partial agonists at fetal and adult mouse muscle nicotinic receptors.
We studied the ability of four nondepolarizing neuromuscular blocking agents (atracurium, gallamine, metocurine, and pancuronium) to act as competitive antagonists at mouse adult- and fetal-type muscle nictinic receptors. Receptor subunits for the fetal type (alpha, beta, gamma, and delta) and adult-type (alpha, beta, epsilon, and delta) receptors were stably expressed in quail fibroblasts. Binding for each drug was determined by the ability of the agents to reduce the initial rate of labeled alpha-bungarotoxin binding, and functional consequences were determined with the use of voltage-clamp studies of their ability to elicit currents or to block currents elicited by acetylcholine. Each agent has a different affinity for the two acetylcholine-binding sites on a single receptor; the rank order of affinities is the same for both fetal- and adult-type receptors. All agents inhibited activation of adult-type receptors by ACh, consistent with the idea that occupation of either the high or low affinity site completely blocks activation when acetylcholine binds to the other site on the receptor. The concentration dependence of the inhibition of acetylcholine-elicited current was predictable from the affinities estimated from independent measurements of the inhibition of alpha-bungarotoxin binding. Gallamine and pancuronium also acted as competitive inhibitors of fetal-type receptors, and, again, the concentration dependence of the inhibition was predictable from binding data. However, metocurine and atracurium could potentiate the responses of fetal-type receptors to low concentrations of acetylcholine. The interaction of metocurine and atracurium with acetylcholine at fetal-type receptors could be accounted for by a weak partial agonist activity. It has been suggested that some pairs of nondepolarizing neuromuscular blocking agents might be more efficacious because the high affinity site for one agent might be the low affinity site for another. This hypothesis was tested for the pair of agents metocurine and gallamine by determining the ability of a mixture of agents to inhibit the binding of alpha-bungarotoxin. The results are consistent with the idea that both metocurine and gallamine have a high affinity for the same site on the receptor. The ability of gallamine to block the partial agonist action of metocurine at fetal-type receptors was tested as well and also indicated that both agents share the same high affinity site.
Fletcher
G H
GH
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Steinbach
J H
JH
D000818:Animals; D002478:Cells, Cultured; D003370:Coturnix; D006168:Guinea Pigs; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects / Q000196:embryology; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D011994:Recombinant Proteins
D003473:Neuromuscular Nondepolarizing Agents; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins