Effects of pentobarbitone on acetylcholine‐activated channels in mammalian muscle

Gage, Peter W.; McKinnon, David

doi:10.1111/j.1476-5381.1985.tb08851.x

Cited by 28 publications

(14 citation statements)

References 16 publications

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“…It is known that pentobarbitone decreases the binding of acetylcholine to the acetylcholine receptor of the Torpedo electroplax (Sauter et al, 1980) and this may also be true ofits action on the nicotinic receptor ofthe chromaffin cell. However, it may act directly on the Na+ channel associated with the nicotinic receptor as Adams (1976) has shown that, at the neuromuscular junction, barbiturates preferentially block ion channels in the open conformation possibly by rendering the open state less stable (Gage & McKinnon, 1985). The resolution of this issue in our preparation will depend on a detailed analysis of channel properties and receptor binding.…”

Section: Discussionmentioning

confidence: 99%

The action of pentobarbitone on stimulus‐secretion coupling in adrenal chromaffin cells

Pocock

Richards

1987

British J Pharmacology

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1 The action ofpentobarbitone on stimulus-secretion coupling was studied in bovine isolated adrenal medullary cells. 2 Pentobarbitone inhibited catecholamine release evoked by 5001M carbachol with half maximal inhibition (IC50) around 50 pM. It also inhibited catecholamine release induced by depolarization with 77 mM potassium (IC50 100 gM). These effects of pentobarbitone were observed with concentrations that lie within the range encountered during general anaesthesia. 3 Evoked secretion required the presence of calcium in the extracellular medium and was associated with an influx of Ca2" through voltage-sensitive channels. Pentobarbitone inhibited 45Ca influx in response to both carbachol (IC50 50 gM) and K+-depolarization (IC50 150 pM).4 The action of pentobarbitone on the relationship between intracellular free Ca and exocytosis was examined using electropermeabilised cells which were suspended in solutions containing a range of concentrations ofionised calcium between 10-8 and 10-4 M. Catecholamine secretion was measured in the presence of 0, 50, 200 or 500 pM pentobarbitone. The anaesthetic had no effect on the activation of exocytosis by intracellular free calcium. 5 When catecholamine secretion in response to potassium or carbachol was modulated by varying extracellular calcium or by adding pentobarbitone to the incubation medium, the amount of catecholamine secretion for a given Ca2' entry was the same.6 Pentobarbitone inhibited the secretion and 45Ca uptake induced by carbachol in a non-competitive manner.7 The secretion evoked by nicotinic agonists was associated with an increase in 22Na influx.Pentobarbitone inhibited this influx with an ICm of IOO1M. 8 We concluded that: (a) Pentobarbitone inhibits the catecholamine secretion from bovine adrenal chromaffin cells induced by nicotinic agonists by non-competitive inhibition of the nicotinic receptor. (b) The decrease in Ca influx caused by pentobarbitone accounts fully for the decrease in secretion in response to depolarization with potassium.

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Section: Discussionmentioning

confidence: 99%

The action of pentobarbitone on stimulus‐secretion coupling in adrenal chromaffin cells

Pocock

Richards

1987

British J Pharmacology

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“…While the actions of a number of channel blockers can be described by a sequential scheme, e.g. tubocurarine (Manalis, 1977;Ascher, Marty & Neild, 1978;Katz & Miledi, 1978;Colquhoun, Dreyer & Sheridan, 1979;Ascher, Large & Rang, 1979;Rang, 1982), gallamine (Katz & Miledi, 1978;Colquhoun & Sheridan, 1981) and some barbiturate local anaesthetics (Adams, 1976), other drugs such as procaine (Katz & Miledi, 1975;Adams, 1977), substance P (Clapham & Neher, 1984a;Role, 1984), trifluoperazine (Clapham & Neher, 1984b), benzocaine (Ogden et al 1981), pentobarbitone (Gage & McKinnon, 1985) and even the classical ganglion blocker hexamethonium (Gurney & Rang, 1984) appear to have more complex blocking actions.…”

Section: Clonidine Action On the Nicotinic Receptor Channelmentioning

confidence: 99%

Acetylcholine receptor channels and their block by clonidine in cultured bovine chromaffin cells.

Cull-Candy

Mathie

Powis

1988

The Journal of Physiology

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SUMMARY1. Acetylcholine (10-50 /M) applied to bovine chromaffin cells under whole-cell voltage clamp produced an inward current and an increase in the noise level of the current trace. At concentrations > 20 fM the ACh current desensitized with time. Spectral analysis of the ACh-induced increase in current noise showed that it could be fitted by a single Lorentzian component with a time constant, Tnoise = 11 + 0-9 ms (Vm =-80 mV).2. Clonidine (2-30 /SM) markedly reduced the size of the ACh-induced whole-cell current, and altered the shape of the noise spectrum. In the presence of clonidine, ACh noise spectra were fitted by two Lorentzian components with time constants which varied with clonidine concentration. The single-channel conductance from noise (y = 24 pS) was unaltered by clonidine.3. The reduction in the size of the whole-cell ACh current, produced by clonidine, was not mimicked by adrenaline (at concentrations up to 60 uM). GABA-induced whole-cell currents and spectra of GABA noise were also unchanged suggesting that the effect of clonidine was specific for the ACh receptor channel.4. When applied intracellularly (from the patch pipette) clonidine had no apparent influence on the whole-cell ACh current. Furthermore, when clonidine was perfused over the cell surface at a concentration sufficient to block the whole-cell ACh response, single ACh channels could still be recorded under the patch-pipette tip (i.e. in cell-attached patches, not exposed to clonidine).5. Clonidine block showed little voltage dependence; the peak ACh current remained linearly dependent on clamp potential. In addition, the fast and slow time constants derived from ACh noise spectra in the presence of clonidine did not show the sort of dependence on antagonist concentration expected for simple channel block; this suggests that clonidine has a complex blocking action.6. Single ACh channels recorded in outside-out patches had a conductance of y = 39 + 0 7 pS, although a subpopulation of smaller and larger events also occurred in some patches. The mean single-channel conductance in outside-out patches was unaltered by clonidine.

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“…These data therefore support the earlier work in suggesting that another interaction mechanism must operate. A likely alternative, as suggested by Gage & McKinnon (1985), is that pentobarbitone binding to nicotinic receptors affects gating behaviour allosterically rather than physically. Biphasic effects of drugs on ion channels have been previously reported in a variety of systems.…”

Section: Resultsmentioning

confidence: 99%

“…In one corded at 1 kHz bandwidth and analysed usi intra-burst critical closed time of 20 ms, the were best fitted by two (Eusebi et al, 1987) where a single open distribution time )nly of the foetal constant of 9.5 ms was reported for less than 500 events reorm was studied corded at 2 kHz bandwidth, and others where two exponential experiment redistributions best described the data. The latter include time ing the standard constant estimates of 0.7 and 17.9 ms in denervated rat muscle burst durations cells (Gage & McKinnon, 1985), 3 and 15 ms (filter bandwidth )ntrol time con-250 Hz) for neuronal-like nicotinic receptors in bovine adrenal L26 events) and chromaffin cells (Jacobson et al, 1991), and 0.41 and 12.2 ms s from the same for bursts in receptors from rat sympathetic neurones (Mathie obarbitone gave et al, 1991). its) and 11.1 ms There were two main perspectives in this study, the first on ,independent of understanding pharmacological modulation of ion channel behaviour and the second, possible implications regarding general anaesthetic mechanisms and interaction of CNS depressants with ion channels.…”

Section: Resultsmentioning

confidence: 99%

“…Traditionally, central nervous system (CNS) depressant drugs have been thought to act by perturbing the lipid bilayer of nerve membranes, but it is now apparent that many of their pharmacological effects may be caused by direct interaction with receptors and ion channels. The nicotinic receptor has served as a model for these interactions , and inhibitory effects due to a concentration-dependent decrease in single channel open time have generally been found (Gage & McKinnon, 1985;Jacobson et al, 1991;Charlesworth & Richards, 1995). Less commonly in various in vitro studies there have been reports of biphasic CNS depressant effects (Roth et al, 1986;Reynolds & Prasad, 1991), and the aim of the present study was to seek further evidence of such multiple drug effects, with a view ultimately of improving understanding of the underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Biphasic effect of pentobarbitone on chick myotube nicotinic receptor channel kinetics

Liu

Madsen

1996

British J Pharmacology

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Effects of pentobarbitone on acetylcholine‐activated channels in mammalian muscle

Cited by 28 publications

References 16 publications

The action of pentobarbitone on stimulus‐secretion coupling in adrenal chromaffin cells

The action of pentobarbitone on stimulus‐secretion coupling in adrenal chromaffin cells

Acetylcholine receptor channels and their block by clonidine in cultured bovine chromaffin cells.

Biphasic effect of pentobarbitone on chick myotube nicotinic receptor channel kinetics

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