Role of presynaptic acetylcholine autoreceptors at motor nerve endings on tetanic and train-of-four fade seen during a nondepolarizing neuromuscular block.

To the Editor:—We read with interest article by Jonsson et al. suggesting that nondepolarizing neuromuscular blocking agents concentration-dependently inhibit human neuronal acetylcholine autoreceptors (nAChRs). The authors argue that the inhibition of the presynaptic 3 2 nAChR subtype plays an important role in tetanic and train-of-four fade seen during nondepolarizing neuromuscular blockade. However, there is evidence from previous studies that are not consistent with this explanation. For example, -conotoxin MII, a highly selective antagonist for 3 2-containing nAChRs, does not result in tetanic fade, although acetylcholine release was decreased. This may be related to the high safety margin of neuromuscular transmission. If the fluid bathing the synapse is changed to one with a high concentration of magnesium, which reduces the release of acetylcholine, -conotoxin MII significantly decreases the tetanic ratio. These results suggested that, only under conditions of decreased safety margin, blockade of presynaptic 3 2 nAChRs could induce tetanic and train-of-four fade. Nondepolarizing neuromuscular blocking agents might influence synaptic safety margins in two ways. First, most nondepolarizing neuromuscular blocking agents used currently are nonselective antagonists for both presynaptic and postsynaptic nAChRs, and postsynaptic nAChRs are clearly one of the most important factors involved in transmission safety. Second, recent studies have found that release of acetylcholine was mediated by some metabotrophic receptors, which coexisted with nicotinic receptors at nerve endings. For example, purinergic P2Y, adenosine A1, 4 and muscarinic M1 receptors 5 were related to inhibition of acetylcholine release at rat neuromuscular junction. At least up to now, we cannot exclude the possibility that nondepolarizing neuromuscular blocking agents would impact acetylcholine release through these receptors. In summary, we think that during nondepolarizing neuromuscular blockade, tetanic and train-of-four fade cannot be explained simply by blockade of presynaptic 3 2 nAChRs; other unknown factors may be involved.