The Role of Cholinesterase at the Myoneural Junction

Barnes, J. M.; Duff, Janet I.

doi:10.1111/j.1476-5381.1953.tb00803.x

Cited by 27 publications

(16 citation statements)

References 7 publications

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“…The percentage inhibition of acetylcholinesterase sites in tissues can be determined by measurement of the acetylcholinesterase activity of tissue homogenates (so-called total acetylcholinesterase assay). Studies of the relationship between enzyme inhibition, determined in this way, and tetanic fade (Berry & Evans, 1951;Barnes & Duff, 1953) have shown that only a very small percentage of the acetylcholinesterase sites at the neuromuscular junction is required for a normal muscle response to nerve stimulation at 0007-1188/79/060323-07 S01.00 higher frequencies. Subsequently, Koelle & Steiner (1956) and Mclsaac & Koelle (1959) provided evidence that only a fraction of all the acetylcholinesterase sites at a cholinergic junction is involved in the hydrolysis of acetylcholine released from the nerve terminals.…”

Section: Introductionmentioning

confidence: 99%

“…3.1.1.7) prolongs the postsynaptic action of acetylcholine and this renders striated muscle unable to maintain a contraction in response to nerve stimulation at higher frequencies (tetanic fade, Wedensky inhibition). It also reduces the concentration of exogenous acetylcholine which produces neuromuscular block by postsynaptic depolarization (Burgen & Hobbiger, 1951;Barnes & Duff, 1953). The percentage inhibition of acetylcholinesterase sites in tissues can be determined by measurement of the acetylcholinesterase activity of tissue homogenates (so-called total acetylcholinesterase assay).…”

Section: Introductionmentioning

confidence: 99%

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Relationship Between Inhibition of Acetylcholinesterase and Response of the Rat Phrenic Nerve‐diaphragm Preparation to Indirect Stimulation at Higher Frequencies

Heffron

Hobbiger

1979

British J Pharmacology

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I Rat isolated diaphragm preparations were stimulated indirectly either intermittently at 20, 50 or 100 Hz or continuously at 0.2 Hz. 2 Addition of 1.8 gM paraoxon (which inhibits acetylcholinesterase by forming a phosphorylated enzyme which undergoes slow spontaneous reactivation) for 5 min to the organ bath produced a failure of the muscle to maintain tetanic tension (tetanic fade, Wedensky inhibition) and potentiated the neuromuscular blocking activity of exogenous acetylcholine. The rates of recovery from both these effects were recorded. 3 In a series of experiments with dyflos (which inhibits acetylcholinesterase by forming a phosphorylated enzyme which does not undergo spontaneous reactivation) the relationship between functional acetylcholinesterase activity and neuromuscular blocking activity of exogenous acetylcholine was also determined. 4 From the data obtained, the relationship between functional acetylcholinesterase activity and tetanic fade was calculated. These calculations show that (i) a considerable reduction in functional acetylcholinesterase activity is required before the diaphragm loses its ability to respond with a sustained tetanus to indirect stimulation at higher frequencies, (ii) the minimum (critical) level of functional acetylcholinesterase activity required for a normal tetanic response is directly related to the frequency of stimulation and (iii) once functional acetylcholinesterase activity has been reduced to the critical level, a very small further reduction leads to a complete tetanic fade. 5 The meaning of functional acetylcholinesterase assays and of conclusions which can be drawn . from them, is discussed,

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationship Between Inhibition of Acetylcholinesterase and Response of the Rat Phrenic Nerve‐diaphragm Preparation to Indirect Stimulation at Higher Frequencies

Heffron

Hobbiger

1979

British J Pharmacology

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“…However, these paralysing compounds are themselves anticholinesterases. Barnes and Duff (1953) have recently shown that inhibition of cholinesterase per se does not block neuromuscular transmission. Our evidence, too, suggests, that the paralysing action of these cholinesterase inhibitors is independent of the inhibition of the enzyme-whereas, in a series of compounds with a polymethylene chain uniting two isoquinoline groups, curariform activity paralleled inhibition of the true enzyme (Smith, Pelikan, Maramba, and Unna, 1953).…”

Section: Resultsmentioning

confidence: 99%

Some Selective Inhibitors of True Cholinesterase*

Fulton

Mogey

1954

British Journal of Pharmacology and Chemotherapy

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While studying certain diphenyl pentanones as possible neuromuscular blocking agents, it was found that 1: 5-bis(4-trimethyl-ammoniumphenyl)-n-pentan-3-one diiodide (62C47, Wellcome) had a marked selective inhibitory action on " true cholinesterase." The distribution of this type of activity was therefore investigated in further members of this and analogous series. The general formula of the compounds iswherein R, and R2 are usually substituted quaternary nitrogens of varying degrees of complexity, and A is usually either CO or CHOH (Table I). Copp (1953) has described their chemical properties. The present paper deals with some of their pharmacological actions. METHODSCholinesterase Inhibition.-Anticholinesterase activity was determined manometrically at 37' C. in the Warburg apparatus (Ammon, 1933) with 0.025 MNaHCO3 as medium equilibrated with 5% CO2 and 95% N2. Rat brain, homogenized in 15 parts by weight of 0.025M-NaHCO3, was the source of the true enzyme and horse serum that of pseudo-cholinesterase. The enzyme preparation-i ml. rat brain homogenate or 0.3 ml. horse serum-was introduced into the main compartment of the bottle together with a fresh solution of the inhibitor dissolved in 0.025 MNaHCO3. The substrate, also dissolved in 0.025 MNaHCO3, was placed in the side arm. The total fluid volume, adjusted by the addition of 0.025 M-NaHCO3, was always 3.0 ml. The final substrate concentrations were 0.003 M or 0.012 M-acetylcholine (bromide) when testing true cholinesterase activity and 0.008 Mbenzoylcholine (iodide) when testing pseudo-cholinesterase inhibition. Enzyme and inhibitor were in contact for 25 min. while gaseous and thermal equilibria were being established, before the substrate was added. All the results were corrected for non-enzymic * The gist of this paper formed a communication (by Gertrude E. Glock and G. A. M.) to the British Pharmacological Society in Edinburgh, July, 1948: a few members of the series were included in a demonstration (by J. W. Trevan and G. A. M.) to the Society at Beckenham, January, 1948. t Present address: Department of Pharmacology, University of Leeds.hydrolysis of the substrate, and the inhibitor values were calculated from the results obtained after equilibrium had been established between enzyme, substrate and inhibitor.Action on Nerve-Muscle Preparations.-The rat diaphragm-phrenic nerve preparation (Btilbring, 1946) was used to investigate (a) the ability to increase the response to indirect stimulation by square pulses of 0.34 msec. duration, (b) antagonism to the paralysing action of (+)-tubocurarine chloride by the method of Mogey and Young (1949), and (c) paralysing activity. This last was compared directly against, and expressed as a percentage of, the activity of (+)-tubocurarine in the way described by Mogey, Trevan, and Young (1949) except that, instead of allowing drugs to act for a standard period, time was given for equilibrium to be reached. The compounds were added at intervals until activity was shown or a concentration of 10-'5 had been ...

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“…In spite of this, substantial reversal of the twitch potentiation occured within 1 h of removal of paraoxon from the organ bath, which, if a marked decline of twitch potentiation had occurred, involved a transient phase of further potentiation. Thus, as is the case with the tetanic fade produced by the organophosphate anticholinesterases (Berry & Lovatt-Evans, 1951;Barnes & Duff, 1953;Fleisher, Hansa, Kilos & Harrison, 1960;Van der Meer & Wolthuis, 1965;Heffron & Hobbiger, 1979), small changes in the level of enzyme inhibition can produce marked changes in the muscle response to nerve stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…the rate of onset of twitch potentiation was delayed and the subsequent decline was reduced or abolished. Spontaneous muscle fasciculations accompany twitch potentiation produced by paraoxon (Barnes & Duff, 1953) and DFP (Van der Meer & Meeter, 1956) in rat diavhraam t,reoarations. These fasciculations are thought to be due to antidromic action potentials (ADF) being initiated at one nerve terminal and transmitted to other terminals of the same neurone, thus giving rise to repetitive action potentials in the muscle fibres contained within the same motor unit (Feng & Li, 1941;Webb & Bowman, 1974).…”

Section: Discussionmentioning

confidence: 99%

Twitch potentiation by organophosphate anticholinesterases in rat phrenic nerve diaphragm preparations

Clark

Hobbiger

1983

British J Pharmacology

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1Twitch potentiation produced by anticholinesterases has been variously attributed to the prolonged postjunctional action of acetylcholine (ACh), a prejunctional action of ACh involving the initiation of antidromic firing (ADF) in the nerve or a direct action of the anticholinesterases on nerve terminals initiating ADF.2 The organophosphate anticholinesterases, paraoxon (diethyl-4-nitrophenylphosphate) and DFP (diisopropyl fluorophosphate), when applied to rat isolated diaphragm preparations for 30 min, produced twitch potentiation which subsequently declined. 3 The rates of onset and decline of twitch potentiation were directly related to the concentration of the organophosphates and the reversibility of their effects was in line with the reactivation of the phosphorylated enzymes formed by them, whether reactivation was spontaneous or induced by the oxime, N,N'-trimethylene-1, 3-bis (pyridinium-4-aldoxime). 4 Reducing the output of ACh from nerve terminals (by reducing the ratio of calcium: magnesium ions in the bathing solution) or reducing the affinity of ACh for the nicotinic cholinoceptor (using the disulphide bond reducing agent, dithiothreitol) produced the same effects as did lowering the concentration of the organophosphates. 5 It is concluded that the twitch potentiation produced by paraoxon and DFP, and its failure to be maintained when the higher concentrations of the organophosphates were used, were the direct result of the excess of ACh in the synaptic cleft, following inhibition of acetylcholinesterase.

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The Role of Cholinesterase at the Myoneural Junction

Cited by 27 publications

References 7 publications

Relationship Between Inhibition of Acetylcholinesterase and Response of the Rat Phrenic Nerve‐diaphragm Preparation to Indirect Stimulation at Higher Frequencies

Relationship Between Inhibition of Acetylcholinesterase and Response of the Rat Phrenic Nerve‐diaphragm Preparation to Indirect Stimulation at Higher Frequencies

Some Selective Inhibitors of True Cholinesterase*

Twitch potentiation by organophosphate anticholinesterases in rat phrenic nerve diaphragm preparations

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