Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

1. The neuromuscular blocking action of suxamethonium, given by intravenous injection, and the effect upon it of iso-OMPA (tetraisopropyl pyrophosphoramide) in doses which produced marked selective inhibition of cholinesterase in blood were studied in anaesthetized rats and cats, and in mice.2. In cats experiments were also carried out in which suxamethonium was given by intravenous infusion until an effect which remained constant with time was achieved. From the degree of neuromuscular block (under equilibrium conditions) obtained with different infusion rates the infusion rate for 50% reduction in twitch tension of the indirectly stimulated soleus and gastrocnemius muscles (IR50) was calculated. The effect on it of raising the suxamethonium hydrolysing capacity of blood and of selectively reducing the level of cholinesterase in blood by various doses of iso-OMPA was then investigated.3. At relevant stages of each experiment cholinesterase activity in blood was determined with butyrylcholine or benzoylcholine and where appropriate with suxamethonium as substrate.4. The results obtained show that in rats and cats the effectiveness of suxamethonium is unrelated to the level of cholinesterase activity in blood and that raising the suxamethonium hydrolysing capacity in the blood up to 22-fold (in cats) only reduces the IR50 by a factor of 1.6.5. The enhancement of the effectiveness of suxamethonium in the three species (2- to 3-fold in rats, 2- to 4-fold in mice and 7- to 8-fold in cats under the conditions used for comparison) which follows the administration of iso-OMPA is attributable to inhibition of cholinesterase in the tissues.6. It is concluded that the results obtained clearly indicate that the species studied do not give information as regards suxamethonium and its metabolism which is applicable to man.
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PMID:The relationship between the level of cholinesterase in plasma and the action of suxamethonium in animals. 432 43

1. Contractions of the isolated taenia of the guinea-pig caecum produced by acetylcholine and TMA were examined in the presence of various antagonists and anticholinesterases.2. Hemicholinium-3 (HC-3) (50-400 mug/ml) inhibited contractions or relaxations produced by TMA but not contractions produced by acetylcholine. The inhibition was rapid in onset and readily reversible. Contractions produced by transmural stimulation were unaffected by HC-3 but responses produced by nicotine were inhibited.3. Low concentrations of hyoscine and benzhexol inhibited responses to acetylcholine to a greater extent than those to TMA.4. Morphine, raised concentrations of Mg(++) or reduced concentrations of Ca(++) inhibited contractions produced by TMA and by acetylcholine to a similar extent.5. Edrophonium, in concentrations which preferentially inhibit acetylcholinesterase, increased contractions produced by acetylcholine and converted responses to nicotine or transmural stimulation into contractions or biphasic responses with a marked contraction phase but did not increase contractions produced by TMA.6. Iso-OMPA, in concentrations which preferentially inhibit butyrylcholinesterase, had no effect on responses to acetylcholine, nicotine, transmural stimulation or TMA.7. HC-3 inhibited contractions produced by TMA in the presence of anticholinesterases but had little effect on contractions produced by acetylcholine.8. These results suggest that TMA produces contractions by acting directly on receptors of the smooth muscle. An analysis of possible reasons for HC-3 (in the concentrations used) acting as an antagonist of TMA but not of acetylcholine indicates that the findings do not necessarily contradict the interpretation that both agonists act on the same receptor.
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PMID:Differentiation between the actions of acetylcholine and tetramethylammonium on the isolated taenia of the guinea-pig caecum by hemicholinium-3. 432 8

1. The effects of intravenous infusions of suxamethonium on the twitch tension of the indirectly stimulated tibialis and gastrocnemius muscles of anaesthetized cats were recorded. From these data the infusion rate giving a 50% reduction in twitch tension after 15 min (IR50), was calculated.2. Marked inhibition of cholinesterase activity in plasma with less inhibition of cholinesterase activity in tissues, obtained by repeatedly withdrawing blood samples, incubating them with DFP and reinjecting them, had only a small effect on the IR50 of suxamethonium.3. Injection of iso-OMPA produced marked inhibition of cholinesterase activity in plasma and tissues, and lowered the IR50 to 10% of that in controls. The IR50 in cats treated with iso-OMPA could be restored to normal only by raising the suxamethonium hydrolysing capacity of plasma 10-50 times above normal by the intravenous injection of purified cholinesterase of human plasma.4. Exchange blood transfusion between normal cats and cats treated with iso-OMPA failed to affect the IR50 of suxamethonium in either of the two.5. It is concluded that in cats, unlike in man, the effectiveness of suxamethonium is not determined by the cholinesterase activity in plasma but by the cholinesterase activity in tissue. The role in this of cholinesterase at the neuromuscular junction and other sites is discussed.
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PMID:Relative importance of the enzymic hydrolysis of suxamethonium in plasma and tissues: studies in cats. 433 3

1. Tetramonoisopropyl pyrophosphortetramide (iso-OMPA) added for 15 min to the rat isolated phrenic nerve-diaphragm in a concentration of 30 muM, produced a complete selective and stable inhibition of cholinesterase. A concentration of 3 muM produced near complete inhibition of cholinesterase, and a concentration of 300 muM also inhibited acetylcholinesterase marginally.2. Inhibition of cholinesterase was associated with a sustained increase in the neuromuscular blocking action of exogenous butyrylcholine but not of exogenous acetylcholine. Iso-OMPA, 300 muM, in addition caused transient increases in the sensitivity of the rat diaphragm to exogenous acetylcholine and butyrylcholine. In the same concentration, it had a curare-like action on the frog rectus abdominis muscle preparation.3. Iso-OMPA, 30 muM, caused reversible increases in the amplitude of the twitch response and tetanic responses, which were of a similar magnitude in the indirectly stimulated preparation and the directly stimulated curarized preparation. Caffeine had a similar effect on the twitch response and its effectiveness was increased by iso-OMPA, and vice-versa. Amongst anticholinesterases, octamethyl pyrophosphortetramide and tetraethylpyrophosphate also enhanced the amplitude of the tetanic response, but paraoxon, dyflos, and mipafox did not.4. It is concluded that iso-OMPA, in concentrations (3 and 30 muM) which in 15 min give near maximal or maximal selective inhibition of cholinesterase, has no effect on the transmission of nerve impulses at the neuromuscular junction, but enhances reversibly the amplitude of the contractile response to stimulation by a direct action upon the muscle fibre, which involves a mechanism related to but not identical with that by which caffeine potentiates twitch tension. In higher concentrations, iso-OMPA has a curare-like action at the neuromuscular junction.
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PMID:Actions of the selective inhibitor of cholinesterase tetramonoisopropyl pyrophosphortetramide on the rat phrenic nerve-diaphragm preparation. 434 8

1. Suxamethonium was given by intravenous infusion to anaesthetized Rhesus monkeys and the infusion rate required to produce after 10 min a 50% reduction in twitch tension of the indirectly stimulated gastrocnemius or tibialis anterior muscle (IR50) was calculated from results obtained with paired infusions of two concentrations, repeated at intervals. The IR50 values in three monkeys were (388, 958 and 1,010 nmol/kg)/minute.2. In one experiment the cholinesterase activity in plasma was increased to 125 and then to 182% of the initial value by infusions of purified human cholinesterase (usual enzyme). This increased the IR50 by 34 and then by 60%, respectively.3. Inhibition by iso-OMPA of cholinesterase activity in plasma and tissues (four monkeys) by more than 90% lowered the mean IR50 value to (69 +/- 11 (S.E.M.) nmol/kg)/minute. Restoration of cholinesterase activity in the plasma of these animals by infusion of purified human cholinesterase raised the IR50's to values within the normal range.4. It is concluded that in the Rhesus monkey most of the infused suxamethonium is hydrolyzed by the cholinesterase in plasma before reaching the motor endplates. This agrees with observations in man with usual cholinesterase and contrasts with experiments in the cat where the hydrolysis of suxamethonium by cholinesterase in tissues was found to be more important than the hydrolysis by cholinesterase in plasma.
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PMID:Relative importance of the enzymic hydrolysis of sexamethonium in plasma and tissues: studies in Rhesus monkeys. 462 72

Acetylcholinesterase (AChE) activity was measured in the presence of the specific inhibitor of pseudocholinesterase, iso-OMPA, in plasma from patients with amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), neuromuscular disease controls, and normal controls. Both AChE and Na-K ATPase activities were measured in erythrocyte ghost membranes from ALS and normal controls. Activities of erythrocyte ghost AChE and Na-K ATPase did not differ between ALS and control patients, suggesting that erythrocyte membranes were normal in ALS. However, the activity of plasma AChE in patients with ALS and PMA was increased significantly over plasma activity in disease controls and normal controls. In addition, in an animal model of human PMA, the Wobbler mouse, plasma AChE activity was increased significantly over littermate controls. The explanation for the increase in plasma acetylcholinesterase was not clear; however, a number of potentially useful clinical points followed from this study. First, there was no relationship between a specific subtype of motor neuron disease and the level of AChE activity. Second, AChE activity appeared to vary directly with the duration of PMA but not with the severity of PMA. This did not correlate with either the duration or severity of ALS. Last, plasma AChE activity was normal in about 30% of patients who had motor neuron disease; therefore, AChE assay had limited use in the diagnosis of ALS or PMA.
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PMID:Acetylcholinesterase and ATPases in motor neuron degenerative diseases. 613 69

The regeneration of cholinesterase positive nerves into segments of the supradiaphragmatic inferior vena cava transplanted from one rat into the abdominal aorta of another rat of the same inbred strain and sex were studied, using a histochemical thiocholine method for the demonstration of cholinesterase. Iso-OMPA and BW-284 C 51 were used as inhibitors for nonspecific cholinesterase (nsChE) and acetylcholinesterase (AChE), respectively. A total of 12 grafts were examined 3, 5, 8, 16, 27 and 32 weeks after transplantation. One single regenerating nsChE reactive nerve was seen near the suture line in a 3-week-old graft. Some solitary regenerating nerves were regularly seen in the grafts at 5 weeks. Eight weeks after grafting some solitary sparsely distributed nerves were found in the outer layers of the graft. In the 16-, 27-, and 32-week-old grafts, nsChE reactive nerves and small nerve bundles were running either solitary or forming nerve plexa in addition to nerves in the vicinity of vasa vasorum. These regenerated nsChE reactive nerves are probably vasomotor in nature. The AChE reaction showed a clear activity in the intimal layer of the grafted veins. No AChE reactive nerves were seen in the 3-, 5-, and 8-week-old grafts. Only occasional AChE positive nerves were observed 16, 28 and 32 weeks after transplantation. These nerves are probably sympathetic cholinergic nerves.
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PMID:Innervation of syngeneic vein grafts in the rat. The regeneration of cholinesterase positive nerves. 633 19

CBDP (2-/O-cresyl/4H:1:2-benzodioxaphosphorin-2-oxide) pretreatment produced a dramatic increase in the toxicity of soman in mice following the subcutaneous (s.c.) or intraperitoneal (i.p.) route of administration. This increase in soman toxicity was very highly correlated with inhibition of plasma aliesterase activity. Other enzymes (e.g. liver aliesterase and plasma cholinesterase) were inhibited by CBDP pretreatment; however, they did not appear to play a significant role in the potentiation of soman toxicity by CBDP. Liver aliesterase was not inhibited by doses of CBDP which produced significant increases in soman toxicity. Similarly, doses of Iso-OMPA, a selective inhibitor of pseudocholinesterase, which completely inhibited plasma cholinesterase, had no effect on soman toxicity. Pyridostigmine pretreatment which inhibited brain, diaphragm and plasma acetylcholinesterase 27, 57 and 60%, respectively, while not inhibiting plasma aliesterase, did not affect soman toxicity. The results of this study demonstrate that, in mice, plasma aliesterase is an extremely important detoxification route for soman.
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PMID:Importance of aliesterase as a detoxification mechanism for soman (Pinacolyl methylphosphonofluoridate) in mice. 650 35

The effect of chronic administration of diisopropylphosphorofluoridate (DFP) on the levels and forms of plasma cholinesterase (ChE), were studied in male Wistar albino rats sacrificed at different time intervals after various schedules of treatment. In particular the inhibition and recovery rate of the enzymatic activity was evaluated for butyrylcholinesterase (BuChE), determined using butyrylthiocholine (BuThCh) as substrate and for acetylcholinesterase (AChE), measured using acetylthiocholine (AcThCh) in the presence of iso-OMPA 0.1 mM. At 1 1/2 and 24 hr after the DFP treatments, BuChE was considerably more depressed than was the case for AChE. Moreover, the recovery of BuChE proceeded more slowly, its activity being restored only seven days after the last treatment, while the recovery of AChE was completed 72 hr after the end of the treatments. Plasma molecular forms were separated by polyacrylamide gel electrophoresis and were revealed by enzymatic reaction with BuThCh or AcThCh as substrates. By using selective inhibitors, five main molecular forms of BuChE and two of AChE were found to exist in control plasma samples. A differential inhibition and recovery rate was observed among these forms after DFP intoxication. At 1 1/2 hr after the treatments, the BuChE activity was too low to be detected on the gels, but 24 hr thereafter, the quantitative determination of the different forms, performed by scanning densitometry, showed a significant increase of the two faster migrating ones. At the following time intervals, the electrophoretic pattern returned progressively towards normality. The faster migrating forms are therefore probably the first synthesized in the process of recovery of BuChE activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in the levels and forms of rat plasma cholinesterases during chronic diisopropylphosphorofluoridate intoxication. 670 81

Various doses of CBDP (2-(2- methylphenoxy )-4H-1,3,2- benzodioxaphosphorin -2-oxide), a metabolite of tri-o-cresyl phosphate, increased dramatically the acute toxicity of soman ( pinacolyl methylphosphonofluoridate ) in mice. CBDP (5 mg/kg; iv) reduced the soman LD50 value from 136 micrograms/kg in control to 6.95 micrograms/kg. The potentiation of soman toxicity following CBDP pretreatment appeared to be due primarily to inhibition of plasma aliesterase activity. Inhibition of liver aliesterase was not of primary importance in the potentiation of soman toxicity following CBDP pretreatment. In addition pretreatment with ISO-OMPA ( tetraisopropyl pyrophosphoramide ), a selective inhibitor of pseudocholinesterase, had no effect on the acute toxicity of soman. Similarly pretreatment of mice with pyridostigmine, a quaternary carbamate anticholinesterase which does not inhibit aliesterase , resulted in marked inhibition of diaphragm, plasma, and brain acetylcholinesterase had no effect on the acute toxicity of soman. Plasma aliesterase may be a depot for soman poisoning. The acute toxicity of soman by the ip, sc, and iv routes of administration was reduced following pretreatment of mice with phenobarbital (100 mg/kg) for 4 days. The reduced toxicity of soman following phenobarbital pretreatment was due to induction of liver aliesterase activity which subsequently resulted in an increase in plasma aliesterase activity. Thus more soman was probably bound to plasma aliesterase activity resulting in a reduction in acute toxicity of soman. Conversely pretreatment of mice with pentobarbital (70 mg/kg; ip) increased the toxicity of soman. This was probably the result of inhibition of plasma aliesterase by pentobarbital pretreatment combined with the central respiratory depression following pentobarbital administration. Following pentobarbital pretreatment soman inhibition of brain acetylcholinesterase was increased suggesting that plasma aliesterase inhibition alters the distribution of free soman in vivo. In summary, in mice plasma aliesterase appears to be an extremely important detoxification route for soman in vivo.
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PMID:Role of aliesterase in organophosphate poisoning. 672 16


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