On the Principles of Postsynaptic Action of Neuromuscular Blocking Agents

Colquhoun, David

doi:10.1007/978-3-642-70682-0_3

Cited by 18 publications

(24 citation statements)

References 143 publications

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“…The mechanism of neuromuscular blockade by agonist-type depolarizing agents has been disputed for a long time (for comprehensive literatures, see Zaimis, 1976;Zaimis & Head, 1976;Colquhoun, 1986). It is generally attributed, at least for the initial phase of action, to the inactivation of voltagedependent sodium channels at the endplate zone resulting from a sustained depolarization (Burns & Paton, 1951;Zaimis, 1976;Zaimis & Head 1976;Colquhoun, 1986).…”

Section: Introductionmentioning

confidence: 99%

“…It is generally attributed, at least for the initial phase of action, to the inactivation of voltagedependent sodium channels at the endplate zone resulting from a sustained depolarization (Burns & Paton, 1951;Zaimis, 1976;Zaimis & Head 1976;Colquhoun, 1986). On the other hand, Thesleff (1955a,b) suggested that the neuromuscular block by succinylcholine (SCh) and decamethonium was largely a result of desensitization of the acetylcholine (ACh) receptor, but not of depolarization per se, in frog, guinea-pig, rabbit, rat and cat muscles.…”

Section: Introductionmentioning

confidence: 99%

“…Agonisttype muscle relaxants are also believed to block neuromuscular transmission by a dual mechanism, i.e., initially by depolarization and then, after a prolonged action, changing to a non-depolarizing block, presumably by desensitization of the receptor or by competitive inhibition (Zaimis, 1976). Since desensitization is an inactive closed state of the AChreceptor channel occurring in the presence of an agonist, the outcome of desensitization is difficult to discriminate from competitive blockade (Colquhoun, 1986). In addition to the postsynaptic effect, a presynaptic action has been reported for SCh (Edwards & Ikeda, 1962;Hubbard et al, 1965;Standaert & Adams, 1965) but this mechanism is unlikely to be essential for the block of neuromuscular transmission (Colquhoun, 1986).…”

Section: Introductionmentioning

confidence: 99%

“…Since desensitization is an inactive closed state of the AChreceptor channel occurring in the presence of an agonist, the outcome of desensitization is difficult to discriminate from competitive blockade (Colquhoun, 1986). In addition to the postsynaptic effect, a presynaptic action has been reported for SCh (Edwards & Ikeda, 1962;Hubbard et al, 1965;Standaert & Adams, 1965) but this mechanism is unlikely to be essential for the block of neuromuscular transmission (Colquhoun, 1986). Acetylcholine receptors on the motor endplate, in addition to those subsynaptic junctional ones, have been shown to extend to the perijunctional area by as far as 25-50 ym with decreasing densities (Salpeter et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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Selective antagonism to succinylcholine‐induced depolarization by α‐bungarotoxin with respect to the mode of action of depolarizing agents

Chang

Chiou

Hwang

1989

British J Pharmacology

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1 The interactions of a-bungarotoxin or tubocurarine with the neuromuscular block and endplate depolarization induced by succinylcholine (SCh) in the phrenic nerve-diaphragm preparation of mice were studied in order to elucidate the role of depolarization by SCh in the neuromuscular blockade. 2 The SCh concentrations required to depress the indirect twitch response by 20% and the evoked endplate potential in cut muscle preparations by 80% were 10M and 6pm, respectively, while only 2 pm SCh was needed to induce maximal endplate depolarization from -80 mV to about -60 mV. 3 SCh blocked the neuromuscular transmission synergistically with either a-bungarotoxin or tubocurarine. There was an initial partial reversal of the neuromuscular inhibition caused by tubocurarine, but not that by a-bungarotoxin. 4 a-Bungarotoxin (0.025 pM) antagonized SCh (10 pM)-induced depolarization more effectively than it depressed miniature endplate potentials and the antagonism was insurmountable by increasing SCh concentration. By contrast, tubocurarine preferentially depressed miniature endplate potentials and antagonized SCh-depolarization competitively. 5 The above difference was attributed to the irreversible nature of o-bungarotoxin binding to acetylcholine receptors, to the slow diffusion of the toxin molecule into the synaptic cleft and thus to the more rapid binding with perijunctional receptors compared with junctional ones. 6 It is concluded that the sustained depolarization of the endplate by SCh results largely from an action on the perijunctional receptor in mice and, unlike cats, the neuromuscular block by SCh is not due to the depolarization per se but rather to a direct attenuation of endplate potential.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Selective antagonism to succinylcholine‐induced depolarization by α‐bungarotoxin with respect to the mode of action of depolarizing agents

Chang

Chiou

Hwang

1989

British J Pharmacology

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“…Single AChR channel currents show characteristic kinetic alterations in the presence of local anaesthetics, and the voltage-dependence of cationic drug binding indicates that the binding site is within the membrane electric field (see review Colquhoun, 1986). The binding site of the muscle AChR channel for the open-channel blocker QX-222, a quaternary ammonium derivative of lignocaine, was recently probed using site-directed mutagenesis.…”

Section: Introductionmentioning

confidence: 99%

Local anaesthetic blockade of neuronal nicotinic ACh receptor‐channels in rat parasympathetic ganglion cells

Cuevas

Adams

1994

British J Pharmacology

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1 The effects of the local anaesthetics QX-222 and procaine on nicotinic acetylcholine (ACh)-evoked currents in cultured parasympathetic cardiac neurones of the rat were investigated by use of the whole-cell, perforated-patch, and outside-out recording configurations of the patch clamp method. 2 QX-222 and procaine, applied to the extracellular surface, reversibly inhibited the peak amplitude of the whole-cell nicotinic ACh-evoked current in a concentration-dependent manner, with half-maximal inhibitory concentrations (IC50) of 28 pM and 2.8 pLM, respectively, at -80 mV. In these neurones, the sustained inward current mediated by Ml muscarinic receptor activation was unaltered by QX-222, and neither local anaesthetic affected the adenosine 5'-triphosphate (ATP)-evoked current. 3 QX-222 and procaine block of nicotinic ACh-evoked inward current was voltage-dependent and enhanced by hyperpolarization. An e-fold change in their dissociation equilibrium constants (Kd) resulted from a 62 mV and a 122 mV change in membrane potential, respectively. 4 Both local anaesthetics produce a concentration-dependent increase in the half-time of decay of the nicotinic ACh-evoked inward current. 5 Measurements of unitary currents in outside-out patches showed that QX-222 reversibly increased the mean burst duration and closed time and reduced the mean channel open time and open-state probability of the nicotinic ACh receptor-channel (AChR) in a concentration-dependent manner. 6 The Kd and voltage sensitivity of local anaesthetic block of the nicotinic AChR in rat intracardiac neurones suggests that the pore-forming region of this channel differs from that of the AChR in frog and rat skeletal muscle and from the neuronal a42 ACh receptor-channel.

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Analysis of anticholinesterase‐induced neuromuscular transmission failure

Maselli

Leung

1993

Muscle and Nerve

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To define the underlying mechanism of neuromuscular transmission failure induced by anticholinesterases, we simultaneously performed surface recordings of compound muscle action potentials (CMAPs) and intracellular recordings of miniature end-plate potentials (MEPPs), miniature end-plate current (MEPCs), and end-plate potential (EPPs) in rat diaphragms exposed in vitro to 1 x 10(-4) to 2 x 10(-2) mmol/L neostigmine methylsulfate. At low concentrations of neostigmine, repetitive stimulation of the phrenic nerve resulted in decrement followed by complete recuperation of CMAP amplitudes. This bimodal pattern was associated with maximal end-plate depolarization at the beginning of the stimulation period, increased MEPP amplitudes, and prolonged time constants of MEPC decays. Higher concentrations of neostigmine resulted in a unimodal decline of amplitudes of CMAPs and EPPS, reduced MEPP amplitudes, and a double exponential time course of MEPC decays. These results indicate that low concentrations of anticholinesterases impaired neuromuscular transmission by producing transient depolarization of the end-plate region. Higher concentrations induced desensitization and direct blockade of the end-plate receptor channel, probably in its open conformation.

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On the Principles of Postsynaptic Action of Neuromuscular Blocking Agents

Cited by 18 publications

References 143 publications

Selective antagonism to succinylcholine‐induced depolarization by α‐bungarotoxin with respect to the mode of action of depolarizing agents

Selective antagonism to succinylcholine‐induced depolarization by α‐bungarotoxin with respect to the mode of action of depolarizing agents

Local anaesthetic blockade of neuronal nicotinic ACh receptor‐channels in rat parasympathetic ganglion cells

Analysis of anticholinesterase‐induced neuromuscular transmission failure

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