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 nicotinic 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 d etermined with the use of voltage-clamp studies of their ability to el icit currents or to block currents elicited by acetylcholine. Each age nt 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 ad ult-type receptors by ACh, consistent with the idea that occupation of either the high or low affinity site completely blocks activation whe n acetylcholine binds to the other site on the receptor. The concentra tion dependence of the inhibition of acetylcholine-elicited current wa s predictable from the affinities estimated from independent measureme nts of the inhibition of alpha-bungarotoxin binding. Gallamine and pan curonium also acted as competitive inhibitors of fetal-type receptors, and, again, the concentration dependence of the inhibition was predic table from binding data, However, metocurine and atracurium could pote ntiate the responses of fetal-type receptors to low concentrations of acetylcholine. The interaction of metocurine and atracurium with acety lcholine at fetal-type receptors could be accounted for by a weak part ial agonist activity, It has been suggested that some pairs of nondepo larizing neuromuscular blocking agents might be more efficacious becau se the high affinity site for one agent might be the low affinity site for another. This hypothesis was tested for the pair of agents metocu rine and gallamine by determining the ability of a mixture of agents t o inhibit the binding of alpha-bungarotoxin. The results are consisten t with the idea that both metocurine and gallamine have a high affinit y 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.