Multiple effects of α‐toxins on the nicotinic acetylcholine receptor

Bradley, Ronald J.; Pagala, Murali; Edge, Mark T.

doi:10.1016/0014-5793(87)80469-6

Cited by 15 publications

(7 citation statements)

References 26 publications

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“…Some authors claim that the intensification of the tetanic run-down of end-plate potentials, a presynaptic effect, is the major cause for the fade of the tetanic contraction in the presence of neuromuscular blockers (Bowman 1980;Chang & Hong 1987;Hong & Chang 1991), while others say that mainly postsynaptic mechanisms induce the fade of the tetanic contraction (Bradley et al 1987(Bradley et al & 1990.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying the Vecuronium‐Induced Tetanic Fade in the Isolated Rat Muscle

Oliveira

1999

Pharmacology & Toxicology

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Abstract:The cellular mechanisms underlying the effects of vecuronium on the tetanic contraction were studied in vitro with a combination of myographic and electrophysiologic techniques. We used the isolated sciatic nerve extensor digitorum longus muscle preparation of the rat. Indirect twitches were evoked at 0.1 Hz pulses and tetani at 50 Hz pulses. Trains of end-plate potentials were generated at 50 Hz. The electrophysiological variables used in the analysis of the end-plate potentials were: amplitude, tetanic run-down, quantal size and quantal content. The myographic study demonstrated that vecuronium at 0.4 pM caused tetanic fade, but left the twitch unaffected. Regarding electrophysiology, vecuronium (0.4 pM ) decreased the amplitude of end-plate potentials and increased their tetanic run-down. These changes were due to significant reductions in both the quantal content of the end-plate potentials and the quantal size. It is concluded that vecuronium has both pre-and postsynaptic effects at the neuromuscular junction, and that it induces fade of the tetanic contraction via a summation of these effects.The mechanisms underlying the fade of the tetanic contraction induced by two different blockers of neuromuscular transmission, hexamethonium (Gallacci & Oliveira 1990) and pancuronium (Gallacci & Oliveira 1994) have been previously studied in our laboratory. They both affected the tetanic contraction via a conjunction of preand postsynaptic effects. However, these compounds differed in the relative potency of presynaptic effect compared to postsynaptic effect. Thus, in the case of hexamethonium the postsynaptic effect was relatively more prominent than the presynaptic effect while the reverse held true in the case of pancuronium (Gallacci & Oliveira 1990.However, the presynaptic changes caused by hexamethonium and those caused by pancuronium are probably not molecularly identical, because they seem to involve different types of presynaptic receptors. Thus, in the case of hexamethonium, its presynaptic effect is probably the algebraic summation of two opposing mechanisms: one, facilitatory, is exerted via a presynaptic receptor resembling the ganglionic-type nicotinic receptor, and another, inhibitory, is exerted via a presynaptic receptor resembling the muscle-type nicotinic receptor (see Tian et al. 1994, for arguments in favour of the presence of both of these types of receptors in the motor nerve terminal). Although pancuronium is not effective on the ganglionic type of nicotinic receptor (Kharkevich & Shorr 1986), it can, how-

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Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying the Vecuronium‐Induced Tetanic Fade in the Isolated Rat Muscle

Oliveira

1999

Pharmacology & Toxicology

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“…Thus, this interpretation allows the prediction that the functional inactivation assay may have usefulness in dissecting sites and modes of nicotinic ligand action, including the long-noted idiosyncrasies (Rang and Ritter, 1970) in the actions of "metaphilic" ligands at nAChRs, and that pancuronium and alcuronium may not have open channel blocking activities found for d-TC and decamethonium. A third alternative is that selected antagonists and agonists share the ability to interact at novel regulatory sites (Takeyasu et al, 1983(Takeyasu et al, , 1986, some of which may interact differentially with neurotoxins (Hanley et al, 1978;Conti-Tronconi and Raftery, 1986;Bradley et al, 1987) or smaller ligands (Conti-Tronconi et al, 1982;Dunn and Raftery, 1982).…”

Section: Possible Mechanisms Of Antagonist Effectsmentioning

confidence: 99%

Effects of Chronic Nicotinic Ligand Exposure on Functional Activity of Nicotinic Acetylcholine Receptors Expressed by Cells of the PC12 Rat Pheochromocytoma or the TE671/RD Human Clonal Line

Lukas

1991

Journal of Neurochemistry

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Studies were conducted to ascertain the temporal and dose-dependent effects of nicotinic ligand exposure on functional activity of different nicotinic acetylcholine receptor (nAChR) subtypes, as expressed by cells of the PC12 rat pheochromocytoma (ganglia-type nAChR) or the TE671/RD human (muscle-type nAChR) clonal line. Chronic (3-72-h) agonist (nicotine or carbamylcholine) treatment of cells led to a complete (TE671) or nearly complete (PC12) loss of functional nAChR responses, which is referred to as "functional inactivation." Some inactivation of nAChR function was also observed for the nicotinic ligands d-tubocurarine (d-TC), mecamylamine, and decamethonium. Half-maximal inactivation of nAChR function was observed within 3 min for TE671 cells and within 10 min for PC12 cells treated with inactivating ligands. Functional inactivation occurred with dose dependencies that could not always be reconciled with those obtained for acute agonist activation of nAChR function or for acute inhibition of those responses by d-TC, decamethonium, or mecamylamine. Treatment of TE671 or PC12 cells with the nicotinic antagonist pancuronium or alcuronium alone had no effect on levels of expression of functional nAChRs. However, evidence was obtained that either of these antagonists protected TE671 cell muscle-type nAChRs or PC12 cell ganglia-type nAChRs from functional inactivation on long-term treatment with agonists. Recovery of TE671 cell nAChR function following treatment with carbamylcholine, nicotine, or d-TC occurred with half-times of 1-3 days whether cells were maintained in situ or harvested and replated after removal of ligand. By contrast, 50% recovery of functional nAChRs on PC12 cells occurred within 2-6 h after drug removal. In either case the time course for recovery from nAChR functional inactivation is much slower than recovery from nAChR "functional desensitization," which is a reversible process that occurs on shorter-term (0-5-min) agonist exposure of cells. These results indicate that ganglia-type and muscle-type nAChRs are similar in their sensitivities to functional inactivation by nicotinic ligands but differ in their rates of recovery from and onset of those effects. The ability of drugs such as the agonists d-TC, decamethonium, and mecamylamine to induce functional inactivation may relate to their activities as partial/full agonists, channel blockers, and/or allosteric regulators. Effects of drugs such as pancuronium and alcuronium are likely to reflect simple competitive inhibition of primary ligand binding at functional activation sites.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…These snake α-neurotoxins cause the blockade of postjunctional nicotinic receptors without inducing fade or marked rundown (Gibb and Marshall 1984;Bowman et al 1986) but upon washout fade becomes prominent and persists after the complete recovery from the postjunctional inhibitory effect (Bradley et al 1987(Bradley et al , 1990Chang and Hong 1987;Cheah and Gwee 1988). This indicates that tetanic fade or EPP run-down, can be dissociated from the blockade of postjunctional nicotinic receptors suggesting that snake α-neurotoxins bind at a prejunctional receptor with slow association/dissociation kinetics (Bradley et al 1987(Bradley et al , 1990Chang and Hong 1987;Cheah and Gwee 1988;Hong and Chang 1991). Interestingly however 3 H-acetylcholine release is unaffected by these agents arguing that snake α-neurotoxins do not block prejunctional nicotinic autoreceptors (Apel et al 1995).…”

Section: Introductionmentioning

confidence: 99%

Presynaptic snake β-neurotoxins produce tetanic fade and endplate potential run-down during neuromuscular blockade in mouse diaphragm

Wilson

Nicholson

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The present study investigated the ability of a number of presynaptic snake neurotoxins (snake beta-neurotoxins) to produce nerve-evoked train-of-four fade, tetanic fade and endplate potential run-down during the development of neuromuscular blockade in the isolated mouse phrenic-hemidiaphragm nerve-muscle preparation. All the snake beta-neurotoxins tested, with the exception of notexin, produced train-of-four and tetanic fade of nerve-evoked isometric muscle contractions. Train-of-four fade was not present during the initial depressant or facilitatory phases of muscle tension produced by the snake beta-neurotoxins but developed progressively during the final depressant phase that precedes complete neuromuscular blockade. The 'non-neurotoxic' bovine pancreatic phospholipase A2 and the 'low-toxicity' phospholipase A2 from Naja naja atra venom failed to elicit train-of-four fade, indicating that the phospholipase activity of the snake beta-neurotoxins is not responsible for the development of fade. Intracellular recording of endplate potentials (EPPs) elicited by nerve-evoked trains of stimuli showed a progressive run-down in EPP amplitude during the train following incubation with all snake beta-neurotoxins except notexin. Again this run-down in EPP amplitude was confined to the final depressant phase of snake beta-neurotoxin action. However when EPP amplitude fell to near uniquantal levels (< 3 mV) the extent of toxin induced-fade was reduced. Unlike postjunctional snake alpha-neurotoxins, prejunctional snake beta-neurotoxins interfere with acetylcholine release at the neuromuscular junction during the development of neuromuscular blockade. This study provides further support for the hypothesis that fade in twitch and tetanic muscle tension is due to an underlying rundown in EPP amplitude resulting from a prejunctional alteration of transmitter release rather than a use-dependent block of postjunctional nicotinic receptors.

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Multiple effects of α‐toxins on the nicotinic acetylcholine receptor

Cited by 15 publications

References 26 publications

Mechanisms Underlying the Vecuronium‐Induced Tetanic Fade in the Isolated Rat Muscle

Mechanisms Underlying the Vecuronium‐Induced Tetanic Fade in the Isolated Rat Muscle

Effects of Chronic Nicotinic Ligand Exposure on Functional Activity of Nicotinic Acetylcholine Receptors Expressed by Cells of the PC12 Rat Pheochromocytoma or the TE671/RD Human Clonal Line

Presynaptic snake β-neurotoxins produce tetanic fade and endplate potential run-down during neuromuscular blockade in mouse diaphragm

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