322 The different effects of neuromuscular blocking agents on adult- and fetal-types of nicotinic acetylcholine receptors

1996 ◽  
Vol 25 ◽  
pp. S55
Author(s):  
Yasue Yamada ◽  
Hideaki Sada ◽  
Takashi Ban
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Agents ◽  
Nicotinic Acetylcholine ◽  
Blocking Agents

Distinct Pharmacologic Properties of Neuromuscular Blocking Agents on Human Neuronal Nicotinic Acetylcholine Receptors

2006 ◽  
Vol 105 (3) ◽  
pp. 521-533 ◽  
Author(s):  
Malin Jonsson ◽  
David Gurley ◽  
Michael Dabrowski ◽  
Olof Larsson ◽  
Edwin C. Johnson ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Messenger Rna ◽  
Motor Nerve ◽  
Neuromuscular Block ◽  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Agents ◽  
Xenopus Laevis Oocytes ◽  
Motor Nerve Ending ◽  
Nicotinic Acetylcholine ◽  
Blocking Agents

Background Nondepolarizing neuromuscular blocking agents (NMBAs) are extensively used in the practice of anesthesia and intensive care medicine. Their primary site of action is at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction, but their action on neuronal nAChRs have not been fully evaluated. Furthermore, observed adverse effects of nondepolarizing NMBAs might originate from an interaction with neuronal nAChRs. The aim of this study was to examine the effect of clinically used nondepolarizing NMBAs on muscle and neuronal nAChR subtypes. Methods Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human alpha1beta1epsilondelta, alpha3beta2, alpha3beta4, alpha4beta2, and alpha7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge. Results All nondepolarizing NMBAs inhibited both muscle and neuronal nAChRs. The neuronal nAChRs were reversibly and concentration-dependently inhibited in the low micromolar range. The mechanism (i.e., competitive vs. noncompetitive) of the block at the neuronal nAChRs was dependent both on subtype and the NMBA tested. The authors did not observe activation of the nAChR subtypes by any of the NMBAs tested. Conclusions The authors conclude that nondepolarizing NMBAs concentration-dependently inhibit human neuronal nAChRs. The inhibition of the presynaptic alpha3beta2 nAChR subtype expressed at the motor nerve ending provides a possible molecular explanation for the tetanic and train-of-four fade seen during a nondepolarizing neuromuscular block.

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

2009 ◽  
Vol 110 (6) ◽  
pp. 1244-1252 ◽  
Author(s):  
Malin Jonsson Fagerlund ◽  
Michael Dabrowski ◽  
Lars I. Eriksson
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Xenopus Oocytes ◽  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Agents ◽  
Nicotinic Acetylcholine ◽  
Adult Muscle ◽  
Blocking Agents ◽  
Human Adult ◽  
Induced Currents

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 the human adult muscle nAChR. The aim of this study was to investigate the effect of clinically used nondepolarizing NMBAs at human adult muscle nAChRs and the mechanisms behind the 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 the 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 IC(50) values for the 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 the 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 the authors speculate can involve receptor desensitization similar to that observed in the neuromuscular junction.

scholarly journals Resistance to d-Tubocurarine of the Rat Diaphragm as Compared to a Limb Muscle

2009 ◽  
Vol 110 (5) ◽  
pp. 1011-1015 ◽  
Author(s):  
Tu Nguyen-Huu ◽  
Jordi Molgó ◽  
Denis Servent ◽  
Philippe Duvaldestin
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Binding Sites ◽  
Acetylcholine Receptors ◽  
Neuromuscular Blocking ◽  
Quantal Content ◽  
Nicotinic Acetylcholine ◽  
The Mean ◽  
Edl Muscle ◽  
Alpha Bungarotoxin ◽  
Endplate Potentials

Background The diaphragm is resistant to competitive neuromuscular blocking agents, as compared to peripheral muscles. The basis of this difference may be a higher concentration of acetylcholine released or higher number of postsynaptic nicotinic acetylcholine receptors in diaphragmatic neuromuscular junctions. Methods Nerve-evoked twitch-tension was measured in rat hemidiaphragm as was Extensor digitorum longus (EDL) nerve-muscle preparation to determine the effective D-tubocurarine concentration that decreased twitch responses by 50%. The mean quantal content of endplate potentials was determined in single junctions in a low-Ca(2+), high-Mg(2+) Krebs-Ringer medium. Strips of hemidiaphragm and EDL muscle, containing the endplate regions, were used to determine the number of nAChR nicotinic acetylcholine receptor binding sites with the aid of radiolabeled [(125)I]alpha-bungarotoxin. Results The effective D-tubocurarine concentration that decreased twitch responses by 50% (median [interquartile range]) was seven-fold higher in the hemidiaphragm than in the EDL (1.82 microm [1.43-2.20] vs. 0.26 microm [0.23-0.29], P < 0.01). The median of the mean quantal content was higher in the hemidiaphragm than in the EDL (0.57 [0.44-0.84] vs. (0.14 [0.11-0.19], P < 0.01). The number of specific [(125)I]alpha-bungarotoxin binding sites to junctional nicotinic acetylcholine receptors was higher in the diaphragm than in the EDL (1.15 fmol/mg [0.48-1.70] vs. 0.55 fmol/mg [0.23-0.70 ], P < 0.05). Conclusion The current study indicates that the resistance of the diaphragm to neuromuscular blocking agents can be explained by both a higher mean quantal content of endplate potentials and a higher number of nicotinic acetylcholine receptor binding sites than in the peripheral EDL muscle.

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