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The action of non-depolarising muscle relaxants at nicotinic acetylcholine receptors

The action of non-depolarising muscle relaxants at nicotinic acetylcholine receptors
The action of non-depolarising muscle relaxants at nicotinic acetylcholine receptors

The mechanism of action of short-acting, non-depolarising neuromuscular blocking agents at nicotinic acetylcholine receptors (nAChRs) was investigated. The effect of three such antagonists, d-tubocurarine (d-TC), pancuronium and its structural analogue vecuronium on nAChRs were investigated at nAChRs expressed in Xenopus laevis oocytes following injection of in vitro transcribed mRNA, and also in the in vivo preparation of the mouse phrenic nerve diaphragm. The foetal and adult forms of the mouse muscle nAChR were expressed in oocytes. Two-electrode voltage-clamp techniques were used to study the receptors. Acethylcholine concentration-response curves were obtained (EC50 11.6±4.3μM, n=21 foetal; 17.4±1.0μM, n=31 adult). The doses of acetylcholine used to construct the concentration-response curve were repeated in the presence of 10nM pancuronium, 10nM d-TC and 10nM vecuronium. The block produced by 10nM vecuronium was greater than 70% for all the concentrations of acethylcholine used. Dose ratios were calculated for d-TC and pancuronium, which were used to estimate the apparent dissociation constants (KD'), 6.54nM and 0.71nM respectively for foetal, and 1.88nM (d-TC) and 0.61nM (pancuronium). The antagonism for all three compounds was reversible. In both receptor subtypes, the antagonists blocked the response to 1μM ACh in a voltage-independent manner (-40mV to - 100mV). The IC50 values for the 3 antagonists against 1μM ACh at the foetal muscle nAChR (clamped at -80mV), were: d-TC 7400±800pM (n=4), pancuronium 5.0±1.9pM (n=4), vecuronium 5.9±2.1pM (n=4). Two neuronal type nAChRs, α4β2 and the homomeric α7 were also expressed in oocytes. Pancuronium was shown to be more potent than d-TC at the α4β2 nAChR, whilst both compounds were equipotent at the α7 nAChR. A chimaeric receptor comprising of muscle α, ε and δ subunits with the neuronal β2 was expressed in oocytes.

University of Southampton
Garland, Catherine Mary
Garland, Catherine Mary

Garland, Catherine Mary (1997) The action of non-depolarising muscle relaxants at nicotinic acetylcholine receptors. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

The mechanism of action of short-acting, non-depolarising neuromuscular blocking agents at nicotinic acetylcholine receptors (nAChRs) was investigated. The effect of three such antagonists, d-tubocurarine (d-TC), pancuronium and its structural analogue vecuronium on nAChRs were investigated at nAChRs expressed in Xenopus laevis oocytes following injection of in vitro transcribed mRNA, and also in the in vivo preparation of the mouse phrenic nerve diaphragm. The foetal and adult forms of the mouse muscle nAChR were expressed in oocytes. Two-electrode voltage-clamp techniques were used to study the receptors. Acethylcholine concentration-response curves were obtained (EC50 11.6±4.3μM, n=21 foetal; 17.4±1.0μM, n=31 adult). The doses of acetylcholine used to construct the concentration-response curve were repeated in the presence of 10nM pancuronium, 10nM d-TC and 10nM vecuronium. The block produced by 10nM vecuronium was greater than 70% for all the concentrations of acethylcholine used. Dose ratios were calculated for d-TC and pancuronium, which were used to estimate the apparent dissociation constants (KD'), 6.54nM and 0.71nM respectively for foetal, and 1.88nM (d-TC) and 0.61nM (pancuronium). The antagonism for all three compounds was reversible. In both receptor subtypes, the antagonists blocked the response to 1μM ACh in a voltage-independent manner (-40mV to - 100mV). The IC50 values for the 3 antagonists against 1μM ACh at the foetal muscle nAChR (clamped at -80mV), were: d-TC 7400±800pM (n=4), pancuronium 5.0±1.9pM (n=4), vecuronium 5.9±2.1pM (n=4). Two neuronal type nAChRs, α4β2 and the homomeric α7 were also expressed in oocytes. Pancuronium was shown to be more potent than d-TC at the α4β2 nAChR, whilst both compounds were equipotent at the α7 nAChR. A chimaeric receptor comprising of muscle α, ε and δ subunits with the neuronal β2 was expressed in oocytes.

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Published date: 1997

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Local EPrints ID: 460266
URI: http://eprints.soton.ac.uk/id/eprint/460266
PURE UUID: aaabbed9-77aa-4447-a113-c59b64eedff5

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Date deposited: 04 Jul 2022 18:17
Last modified: 04 Jul 2022 18:17

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Author: Catherine Mary Garland

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