Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Objective evaluation of muscle relaxation during surgery is possible only by indirect stimulation of a skeletal muscle by means of a peripheral nerve stimulator. Most frequently the ulnar nerve is electrically stimulated and the resulting contraction of the hand muscles, i.e., twitching of the fingers is observed. This direct observation of the finger twitches induced by a nerve stimulator provides valuable information a) on the actual magnitude of neuromuscular blockade, b) on the development of a dual block following suxamethonium, c) on the need for more muscle relaxant, d) on the reversal of muscle paralysis by a cholinesterase inhibiting agent, and finally e) on the differential diagnosis of prolonged postoperative apnoea. By employing a nerve stimulator, the neuromuscular blocking agents can be titrated according to the surgical requirements and overdosage can be avoided. The clinical judgement of muscle relaxation by the anaesthesiologist should be accompanied by a more quantitative and objective evaluation, making use of the nerve stimulator.
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PMID:[On the monitoring of neuromuscular blockade during anaesthesia (author's transl)]. 85 89

In concentrations above 20 microM, (+/-)-meptazinol produced a contraction of the guinea-pig isolated ileum and this effect was antagonized by atropine (0.01 to 0.3 microM) in a manner which was not competitive. Cooling the preparation to 15 degrees C blocked the contractile action of meptazinol and of dimethylphenylpiperazinium (DMPP) but did not affect the action of carbachol. Twitch responses of the rat phrenic nerve-diaphragm preparation induced by indirect electrical stimulation in the presence of naloxone (20 nM) were potentiated by meptazinol (1 to 40 microM) which also reversed a partial blockade of the twitch induced by tubocurarine. Neither of these effects was seen in tissues which had been pretreated with the cholinesterase inhibitor BW284C51 (0.2 microM) though tetraethylammonium iodide (40 microM) was still able to enhance the responses to stimulation. In the presence of naloxone (20 nM) electrically induced responses of the rat isolated rectum were abolished by cinchocaine (10 microM), partially blocked by atropine (0.1 to 0.4 microM) and potentiated by meptazinol (1 to 30 microM). The latter action was not seen when meptazinol was administered in the presence of BW284C51. It is concluded that the cholinergic action of meptazinol in these tissues is due to an indirect effect, probably involving inhibition of cholinesterase and that no evidence was seen of any ability to increase the release of acetylcholine itself.
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PMID:An investigation of the mechanism involved in the cholinergic action of meptazinol. 288 82

Mivacurium chloride (BW B1090U), a bis-benzylisoquinolinium diester compound, was found to undergo hydrolysis in vitro by purified human plasma cholinesterase in a pH-stat titrator at 88% of the rate of succinylcholine at pH 7.4, 37 degrees C and 5 microM substrate concentration. In 72 consenting ASA Physical Status I-II patients receiving nitrous oxide/oxygen-narcotic-thiopental anesthesia, the neuromuscular blocking effect of mivacurium was assessed following bolus doses from 0.03 to 0.30 mg/kg, as well as during and following continuous infusions from 35 to 324 min in length. The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.08 mg/kg. At 0.1 mg/kg, 96% block developed, onset to maximum block required 3.8 +/- 0.5 min, and recovery to 95% twitch height occurred 24.5 +/- 1.6 (SE) min after injection. At 0.25 mg/kg, onset was 2.3 +/- 0.3 min; 95% recovery developed within 30.4 +/- 2.2 min, an increase in duration of action of only 24% versus 150% higher dosage. Comparative recovery indices from 5 to 95% or from 25 to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.3 mg/kg (range 12.9 to 14.7 and 6.6 to 7.2 min, respectively). In 38 patients who received mivacurium by continuous infusion (duration 88.1 +/- 7.1/47.1 min, SE/SD) for maintenance of 95 +/- 4% twitch inhibition, the mean 5-95% and 25-75% recovery indices after discontinuation of infusion were 14.4 +/- 0.6 and 6.5 +/- 0.3 min (P greater than 0.5 vs. all single bolus doses). The train-of-four (T4) ratio, within 2.6 +/- 0.5 min after 95% twitch recovery following bolus doses, averaged 79.5 +/- 1.8% (n = 32). Similarly, after discontinuation of infusions, the T4 ratio reached 73.4 +/- 1.9% within 3.4 +/- 1.9 min after 95% twitch recovery (n = 33). Antagonism of residual block was seldom indicated, but, to test ease of reversal, eight patients electively received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at 67 to 93 (76.6 +/- 3.5) % block. Twitch returned to 95% of control within 4.5 to 9.5 (6.3 +/- 0.5) min after neostigmine. Mivacurium may offer increased versatility in providing clinical muscle relaxation in a variety of situations. Further studies seem appropriate.
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PMID:The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). A short-acting nondepolarizing ester neuromuscular blocking drug. 296 39

Anatoxin-a(s) [antx-a(s)] is produced by Anabaena flos-aquae clone NRC 525-17 and is different from anatoxin-a, a known depolarizing agent produced by A. flos-aquae NRC 44-1. Purification of antx-a(s) from lyophilized cells involved extraction with 1.0 M acetic acid: ethanol (80:20), column chromatography (Sephadex G-15 and CM-Sephadex C-25) and high performance liquid chromatography. Purified toxin has an LD50 (i.p., mouse) of approximately 50 micrograms/kg. Gross pharmacological tests of antx-a(s) on isolated chick biventer cervicis and frog rectus abdominis muscles showed no direct agonistic effect. Instead, antx-a(s) augments the acetylcholine response and antagonizes the actions of d-tubocurarine. Twitch potentiation and tetanic fade were observed on isolated rat phrenic nerve--diaphragm muscle when stimulated indirectly at different frequencies. In acute toxicity tests with mice and rats the signs of poisoning were indicative of excessive cholinergic stimulation. Mice pretreated with atropine sulfate showed longer survival times and no parasympathomimetic signs of toxicity. The mice still died of respiratory arrest with convulsions, which indicated that toxicity is due to more than just the peripheral muscarinic action of antx-a(s). Assays of serum cholinesterase of rats in acute toxicity tests showed complete inactivation of the enzyme at doses of 350 and 600 micrograms/kg. It was concluded that antx-a(s) may be acting as an anticholinesterase, thereby causing toxicity.
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PMID:The pharmacology of anatoxin-a(s), a neurotoxin produced by the freshwater cyanobacterium Anabaena flos-aquae NRC 525-17. 308 30

Toxic manifestations of acetylcholinesterase inhibitors (AChE-I) include muscle twitching and muscle fiber necrosis, in addition to muscarinic manifestations of acetylcholine excess. The AChE-Is pinacolyl methylphosphonofluoridate (soman) or diisopropylphosphorofluoridate (DFP) were administered to rats to produce spontaneous muscle fiber discharges. Soman produced discharges that arose primarily from the central nervous system (CNS), while those due to DFP were generated from the peripheral nerves as well as the CNS. Three drugs were tested for their potential to reduce muscle fiber discharges: atropine methyl nitrate (AMN), ketamine, and phenytoin. Ketamine caused a significant decrease in discharges of CNS origin, while AMN and phenytoin had no effect. For muscle fiber discharges of peripheral origin, all three drugs produced a significant drop in muscle fiber discharges, but phenytoin showed slightly more efficacy than the others. AChE-I-induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different AChE-Is. Treatment for the toxicity of AChE-Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system (PNS) where AChE-Is exert their effects. By attenuating the effects of AChE-Is at specific CNS or PNS sites, the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each AChE-I.
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PMID:Effects of phenytoin, ketamine, and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate. 341 30

The fast-twitch posterior latissimus dorsi muscle of normal and genetically dystrophic chickens was subjected to continuous indirect electrical stimulation at 10 Hz for periods of 4-8 weeks. To sustain this in vivo nerve stimulation an internally implantable miniature stimulator device was designed. This regime of stimulation caused complete fatigue of the normal muscle within 5 min of its initiation. The dystrophic muscles maintained a very small degree of contractile activity during this initial phase. Tangible twitching of the muscle returned in 5 week birds between 3 and 5 days and in 10 week birds between 11 and 16 days after implantation. After 4 weeks of stimulation, no significant change was measured in the time-to-peak of the isometric twitch response, nor in the half-relaxation time. The resistance to fatigue was significantly increased in the stimulated muscles when tested with a series of tetani at 40 Hz. The mean fibre area was decreased, in all muscles stimulated for longer than 3 weeks, in comparison to their contralateral controls, except where fibre splitting in dystrophic birds abnormally reduced the control value. The majority fibre type of the muscle was changed from type IIB to IIA. The histochemical reactions for both NADH-linked oxidation and phosphorylase were distinctly increased in the stimulated muscles. In normal muscle, stimulation increased somewhat the number of nuclei per unit area and changed their intracellular distribution, so that a greater proportion was found adjacent to the sarcolemma. The normal posterior latissimus dorsi muscle responded to chronic stimulation with increases of 3-6-fold in its acetylcholinesterase (AChE) activity. The maximum change in AChE occurred after 2 weeks stimulation; a steady level, 3 times that of the control unstimulated muscle, persisted at later times. Chronic stimulation suppressed the over-production of AChE that is characteristic of dystrophic chicken fast-twitch muscle, to attain a level comparable to the AChE activity in a stimulated normal muscle. Stimulation exerted a strong normalizing influence on dystrophic muscle, as assessed morphologically. The characteristic fibre rounding, fibre hypertrophy and myonuclear proliferation were reduced. This influence was most marked where the stimulation was initiated before the major pathological changes had occurred, but was also significant when commenced in strongly affected birds of 10-11 weeks.
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PMID:Low frequency chronic electrical stimulation of normal and dystrophic chicken muscle. 379 78

1 Isolated, desheathed preparations of the rabbit rectococcygeus muscle were relatively insensitive to spasmogens other than muscarinic drugs. Transmural stimulation with 1-50 pulses (0.2-0.4 ms at 10 Hz) elicited graded twitches which were abolished by tetrodotoxin and were therefore neurogenic; longer pulses sometimes triggered tetrodotoxin-resistant myogenic contractions.2 Twitches elicited by 0.2-0.4 ms pulses were due to post-ganglionic excitation because they were not reduced by hexamethonium, pentolinium or dimethyltubocurarine, or by ganglion-paralyzing concentrations of nicotine.3 The acetyl- and butyryl-cholinesterase activities of the rectococcygeus were determined manometrically and could be selectively inhibited by BW 284C51 (1:5-bis-(4-allyl-dimethylammonium-phenyl)-pentan-3-one dibromide) and iso-OMPA (tetramonoisopropylpyrophosphortetramide), respectively. Single-pulse twitches were greatly potentiated in amplitude and duration only when both cholinesterases were inhibited.4 The preparations could not be made to contract by nicotine (2.1-21 muM) even after cholinesterase inhibition, suggesting an absence of ganglion-cells; with nicotine (105-210 muM) small, atropine-susceptible responses were elicited, which were non-ganglionic because they were not reduced by tetrodotoxin.5 Rectococcygeus preparations that had been treated with physostigmine released acetylcholine into the bath fluid on electrical stimulation.6 The motor transmission was paralyzed by botulinum toxin (Type A) and abolished by atropine; the block of muscarinic receptors by atropine was effective against both endogenous and exogenous acetylcholine.7 Inhibitory adrenoceptors and scanty motor alpha-adrenoceptors were detected in the smooth muscle.8 Strong inhibitions of motor transmission and of rhythmic activity were produced by noradrenaline (but not by tyramine), by isoprenaline, and, after phentolamine, also by adrenaline and phenylephrine. These inhibitions were only slightly reduced by propranolol and rather more by pindolol.9 Experiments on preparations retaining their extrinsic nerve supply suggest an absence of ganglionic relays in the last 1-2 cm of the motor nerve pathway to this muscle.10 Some contrasting properties of the adjacent caudo-anal muscle, including the poor motor responses to transmural stimulation, are described.
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PMID:The rabbit rectococcygeus: a ganglion-free parasympathetically innervated preparation. 415 88

The irreversible inhibitor of acetylcholinesterase (AChE), paraoxon, when given in vivo to rats in a single injection (0.23 mg/kg s.c.) raised the miniature endplate potential (MEPP) frequency to values greater than 3 times control levels in 34% of the fibers in the rat phrenic nerve-hemidiaphragm preparation. The elevated MEPP frequencies were observed in areas of extensive muscle twitching and were associated with high frequencies of giant MEPPs. Following 3 daily injections of paraoxon; the overall MEPP frequency was reduced below control levels, the frequency of giant MEPPs returned to normal, and a greater percentage of fibers showed no spontaneous activity. This depressant effect of chronic AChE inhibition on the overall MEPP frequency diminished during 1-2 weeks of daily paraoxon treatment (0.12 mg/kg s.c. paraoxon/day). After one week of recovery from 14 daily paraoxon injections (0.12 mg/kg, 1 injection/day), the original response to a single injection (0.23 mg/kg) was restored. In an attempt to determine whether paraoxon exerts its effects on spontaneous release by depolarizing the presynaptic terminal, the effect of increases in the potassium concentration on the MEPP and giant potential frequency were examined in control (saline injection) preparations, and preparations treated with 1 or 3 daily injections of paraoxon. The results suggest that paraoxon does not act by reducing the presynaptic membrane potential, but may interact more directly with the mechanism(s) responsible for regulating the release of MEPPs and giant MEPPs.
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PMID:A comparison of the effects of acute and chronic cholinesterase inactivation on spontaneous transmitter release. 613 84

The actions of pyridostigmine (Pyr), an anticholinesterase agent, were studied on the acetylcholine (ACh) receptor-ion channel complex and on the electrically excitable membrane of the frog cutaneous pectoris and sartorius muscles and the chronically denervated soleus muscle of the rat. Pyr at concentrations of 0.2-0.4 mM potentiated the indirect evoked muscle twitch and at concentrations greater than or equal to 0.8 mM depressed the indirect twitch with an IC50 of about 2 mM. Twitch depression produced by Pyr was reversed slowly, and after a 60-min wash only 59% of the control muscle twitch had returned. Pyr did not affect either the membrane potential or the muscle action potential. Pyr had several effects at the neuromuscular junction of the frog and rat. It decreased the peak amplitude of the end-plate current (EPC) in a voltage- and concentration-dependent manner. In contrast to diisopropylfluorophosphate, which depresses the EPC amplitude and induces a double exponential decay of the EPC and miniature end-plate current (MEPC), Pyr produced a marked prolongation of the time constants of EPC and MEPC decay while maintaining a single exponential decay. The decrease caused by Pyr of indirect twitch tension, EPC amplitude, and ACh sensitivity indicates mechanisms which limit the number and/or properties of conducting channels. The drug decreased channel conductance and prolonged channel lifetime as revealed by Fourier analysis of ACh-induced end-plate current fluctuations. An altered form of the conducting species induced by Pyr appears to be responsible for either the apparent agonist-induced depolarization or its ability to increase the affinity of ACh for its recognition site. Pyr was also found to inhibit the binding of ACh and alpha-bungarotoxin to receptor-rich membrane from the electric organ of Torpedo nobiliana, and to have a higher affinity for the receptor than for the ion channel binding sites. These actions are distinct from acetylcholinesterase inhibition caused by the agent. Strong evidence suggests that the direct influences of the agent on neuromuscular transmission involve at least three distinct, although possibly interacting, mechanisms: (a) a weak agonist action, (b) the formation of desensitized receptor-complex intermediates, and (c) the alteration of the conductance properties of active channels.
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PMID:The nature of the interactions of pyridostigmine with the nicotinic acetylcholine receptor-ionic channel complex. I. Agonist, desensitizing, and binding properties. 632 55

The neuromuscular junction of the buffalo sculpin (Enophrys bison) was characterized in situ by examining the effects of various neuromuscular blocking agents and acetylcholinesterase inhibitors (ACHE-I) on pectoral muscle response to indirect stimulation. The injection of either d-tubocurarine (350 micrograms/kg) or alpha-bungarotoxin (alpha-Butx) (1 mg/kg) resulted in a flaccid paralysis. The depolarizing agents, succinylcholine (11 micrograms/kg) and decamethonium (42 micrograms/kg), produced a spontaneous contraction. The administration of the ACHE-I, diisopropyl fluorophosphate (DFP), and eserine resulted in responses which were contrary to those expected based on similar experiments using mammalian skeletal muscle. Twitch potentiation did not occur and the ability to maintain a tetanic response was not abolished even after the administration of clearly lethal concentrations of ACHE-I.
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PMID:Effects of neuromuscular blocking agents and acetylcholinesterase inhibitors on the response of pectoral fin muscle of the sculpin (Enophrys bison) to indirect stimulation. 647 51


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