Pharmacological Characteristics of the Inhibition of Nondepolarizing Neuromuscular Blocking Agents at Human Adult Muscle Nicotinic Acetylcholine Receptor

Background: Nondepolarizing neuromuscular blocking agents (NMBAs) are classic competitive-inhibitors at the muscle nicotinic acetylcholine receptor (nAChR). Although the fetal subtype muscle nAChR has been extensively studied at a molecular level, less is known about the interaction between nondepolarizing NMBAs and die human adult muscle nAChR. The aim of this study was to investigate die effect of clinically used nondepolarizing NMBAs at human adult muscle nAChRs and die mechanisms behind die inhibition. Methods: Human subunits for the adult alpha(1)beta(1)delta epsilon muscle nAChR were cloned and expressed into Xenopus oocytes and thereafter studied with two-electrode voltage clamp. The effect of the clinically used nondepolarizing NMBAs, including atracurium, cis-atracurium, mivacurium, pancuronium, rocuronium, vecuronium, and d-tubocurarine, on acetylcholine-induced and dimethylphenylpiperazinium-induced currents were investigated. Results: All nondepolarizing NMBAs tested inhibited acetylcholine- and dimethylphenylpiperazinium-induced currents in human adult alpha(1)beta(1)delta epsilon muscle nAChRs, and no receptor activation was seen. Interestingly, acetylcholine desensitized die human adult alpha(1)beta(1)delta epsilon muscle type receptor and attenuated the inhibition caused by nondepolarizing NMBAs, as evident by lack of increase in IC50 values for die nondepolarizing NMBAs with increased concentrations of acetylcholine. In contrast, dimethylphenylpiperazinium-induced currents were competitively inhibited by the nondepolarizing NMBAs. Conclusions: This study demonstrates that nondepolarizing NMBAs inhibit human adult muscle nAChRs expressed in Xenopus oocytes by mixed mechanisms. When using die nondesensitizing agonist dimethylphenylpiperazinium, inhibition by the NMBA is competitive, whereas activation with high concentrations of acetylcholine in combination with NMBA induces a noncompetitive inhibition, which die authors speculate can involve receptor desensitization similar to that observed in the neuromuscular junction.