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)

In the rat diaphragm muscle, nitric oxide (NO)--sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP), as well as substrate for the NO synthesis L-arginine, decrease the level of hyperpolarization of the muscle fibre membrane after acetylcholine receptor blockade by the d-TC and irreversible acetylcholinesterase inhibition by armin (H-effect). Contrary to that, disruption of the NO synthesis in the muscle fibres by the NO-synthase inhibitor NG-nitrol-L-arginine methyl ester (L-NAME) results in enhancement of the H-effect both in vitro and in vivo. Inactivated SNP and inactive forms of arginine and NAME did not affect the H-effect magnitude. Haemoglobin, effectively binding the NO molecules, abolishes the suppressing effects of the SNP, SNAP and L-arginine upon the H-effect. The findings suggest that the NO could be acting as a modulator of nonquantal transmitter release at the mammalian neuromuscular junction.
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PMID:[Modulation of the intensity of the non-quantal transmitter release by nitric oxide (NO) at the neuromuscular junction]. 1080 31

We have described recently an acetylcholinesterase (AChE) knockout mouse. While comparing the tissue distribution of AChE and butyrylcholinesterase (BChE), we found that extraction buffers containing Triton X-100 strongly inhibited mouse BChE activity. In contrast, buffers with Tween 20 caused no inhibition of BChE. Conventional techniques grossly underestimated BChE activity by up to 15-fold. In Tween 20 buffer, the intestine, serum, lung, liver, and heart had higher BChE than AChE activity. Only brain had higher AChE than BChE activity in AChE +/+ mice. These findings contradict the dogma, based mainly on observations in Triton X-100 extracts, that BChE is a minor cholinesterase in animal tissues. AChE +/- mice had 50% of normal AChE activity and AChE -/- mice had none, but all mice had similar levels of BChE activity. BChE was inhibited by Triton X-100 in all species tested, except rat and chicken. Inhibition was reversible and competitive with substrate binding. The active site of rat BChE was unique, having an arginine in place of leucine at position 286 (human BChE numbering) in the acyl-binding pocket of the active site, thus explaining the lack of inhibition of rat BChE by Triton X-100. The generally high levels of BChE activity in tissues, including the motor endplate, and the observation that mice live without AChE, suggest that BChE has an essential function in nullizygous mice and probably in wild-type mice as well.
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PMID:Abundant tissue butyrylcholinesterase and its possible function in the acetylcholinesterase knockout mouse. 1093 16

Excess activation of muscle nicotinic acetylcholine receptors due to genetic mutations, as seen in slow channel congenital myasthenic syndrome, or acetylcholinesterase (AChE) inhibition results in muscle cell degeneration. Our recent work showed that nitric oxide synthase (NOS) inhibitors prevent nicotine-induced muscle cell death in culture. In the present study, we examined the effects of NOS inhibition on nicotinic receptor-mediated myopathy in vivo. Rats injected with the AChE inhibitor paraoxon demonstrate a 90-fold increase in the number of dying muscle cells compared with control as evidenced histologically by centralized nuclei and the presence of degenerating profiles. Coadministration of the nonspecific NOS inhibitor nitro-L-arginine methyl ester or the neuronal NOS-specific inhibitor 7-nitroindazole dramatically reduced the presence of such degenerating profiles to approximately 20% of that seen with paraoxon alone. These results show that inhibition of NOS, as well as neuronal NOS, significantly reduces AChE inhibitor-induced muscle cell degeneration, suggesting that increased nitric oxide production mediates such myopathy.
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PMID:Nitric oxide is involved in acetylcholinesterase inhibitor-induced myopathy in rats. 1099 96

Pulmonary arteries from the Madison (M) strain relax more in response to acetylcholine (ACh) than those from the Hilltop (H) strain of Sprague-Dawley rats. We hypothesized that differences in endothelial nitric oxide (NO) synthase (eNOS) expression and function, metabolism of ACh by cholinesterases, release of prostacyclin, or endothelium-derived hyperpolarizing factor(s) (EDHF) from the endothelium would explain the differences in the relaxation response to ACh in isolated pulmonary arteries. eNOS mRNA and protein levels as well as the NO-dependent relaxation responses to thapsigargin in phenylephrine (10(-6) M)-precontracted pulmonary arteries from the M and H strains were identical. The greater relaxation response to ACh in M compared with H rats was also observed with carbachol, a cholinesterase-resistant analog of ACh, a response that was not modified by pretreatment with meclofenamate (10(-5) M). N(omega)-nitro-L-arginine (10(-4) M) completely abolished carbachol-induced relaxation in H rat pulmonary arteries but not in M rat pulmonary arteries. Precontraction with KCl (20 mM) blunted the relaxation response to carbachol in M rat pulmonary arteries and eliminated differences between the M and H rat pulmonary arteries. NO-independent relaxation present in the M rat pulmonary arteries was significantly reduced by 17-octadecynoic acid (2 microM) and was completely abolished by charybdotoxin plus apamin (100 nM each). These findings suggest that EDHF, but not NO, contributes to the strain-related differences in pulmonary artery reactivity. Also, EDHF may be a metabolite of cytochrome P-450 that activates Ca(2+)-dependent K(+) channels.
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PMID:EDHF contributes to strain-related differences in pulmonary arterial relaxation in rats. 1115 29

Human paraoxonase (PON1) is a polymorphic, high-density lipoprotein (HDL)-associated esterase that hydrolyzes the toxic metabolites of several organophosphorus (OP) insecticides and nerve agents. The activity polymorphism is determined by a Gln/Arg (Q/R) substitution at position 192. Injection of purified PON1 protects animals from OP poisoning. In the present study, we investigated the in-vivo function of PON1 for detoxifying organophosphorus insecticides in PON1-knockout mice that were challenged via dermal exposure with diazoxon, diazinon and paraoxon. PON1-knockout mice were extremely sensitive to diazoxon. Doses (2 and 4 mg/kg) that caused no cholinesterase (ChE) inhibition in wild-type mice were lethal to the knockout mice, which also showed slightly increased sensitivity to the parent compound diazinon. Surprisingly, these knockout mice did not show increased sensitivity to paraoxon. In-vitro assays indicated that the PON1R192 isoform hydrolyzed diazoxon less rapidly than did the PON1Q192 isoform. In-vivo analysis, where PON1-knockout mice received the same amount of either PON1(192) isoform via intraperitoneal (i.p.) injection 4 h prior to exposure, showed that both isoforms provided a similar degree of protection against diazoxon, while PON1R192 conferred better protection against chlorpyrifos-oxon than PON1Q192. Injection of purified rabbit PON1 or either human PON1(192) isoform did not protect PONI-knockout mice from paraoxon toxicity, nor did over-expression of the human PON1R192 transgene in wild-type mice. Kinetic analysis of the two human PON1(192) isoforms revealed that the catalytic efficiency (Vmax/Km) determines the in-vivo efficacy of PON1 for organophosphorus detoxication. The results indicate that PON1 plays a major role in the detoxication of diazoxon and chlorpyrifos oxon but not paraoxon.
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PMID:Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds. 1119 81

1. The present study was undertaken to investigate the influence of the airway epithelium on the release of acetylcholine (ACh) from parasympathetic nerves of the rat trachea. Epithelium-intact and epithelium-denuded preparations of rat trachea were incubated with [3H]-choline to incorporate [3H]-ACh into the cholinergic transmitter stores. Release of radiolabelled transmitter ACh was evoked by electrical field stimulation (60 s trains of 1 ms pulses, 5 Hz, 15 V). 2. Field stimulation both of epithelium-intact and epithelium-denuded radiolabelled tracheal preparations evoked an increase in the efflux of radioactivity; however, the mean stimulation-induced (S-I) efflux from epithelium-denuded preparations (2932 +/- 190 d.p.m., n = 9) was approximately 60% of that from epithelium-intact preparations (4802 +/- 820 d.p.m., n = 11). We have shown previously that, in epithelium-intact (but not epithelium-denuded) tracheal preparations, a substantial proportion of the S-I efflux is resistant to tetrodotoxin (1 microM) and to the removal of extracellular Ca2+, indicating that much of the S-I efflux is not caused by exocytotic release of neuronal [3H]-ACh. In epithelium-denuded tracheal preparations, superfused individually, phosphorylcholine (1 and 100 microM) did not alter S-I efflux. In epithelium-intact tracheal preparations, both in the absence and in the presence of atropine (1 microM), neither N(G)-nitro-L-arginine (100 microM), superoxide dismutase (100 units ml(-1)), indomethacin (10 microM), capsaicin (30 microM) nor alpha-chymotrypsin (1 unit ml(-1)) altered S-I efflux. 3. Experiments were also performed using two tracheal preparations superfused in series. When unlabelled epithelium-intact preparations were present in the upper chamber (superfused first), the S-I efflux from radiolabelled epithelium-denuded preparations in the lower chamber (superfused second) did not differ significantly from radiolabelled epithelium-denuded preparations superfused individually. Moreover, there was no significant difference in the S-I efflux from radiolabelled epithelium-denuded preparations in the lower chamber between experiments in which the upper chamber contained epithelium-intact or epithelium-denuded preparations. 4. Field stimulation of epithelium-intact tracheal preparations in the upper chamber with 90, 120 and 300-s periods (trains of 1 ms pulses, 5 Hz, 15 V) did not significantly alter the S-I efflux from radiolabelled epithelium-denuded tracheal preparations in the lower chamber. 5. When introduced into the upper (unlabelled epithelium-intact) and subsequently allowed to superfuse the lower (radiolabelled epithelium-denuded) tracheal preparations, the stable cholinomimetic carbachol (3 microM) markedly reduced the S-I efflux whereas ACh (0.1 and 1 microM) had no significant effect. However, in the presence of the anti-cholinesterase neostigmine (1 microM), ACh (1 microM) significantly reduced S-I efflux, indicating that ACh is subject to rapid hydrolysis by cholinesterase enzymes. When atropine (10 microM) was only exposed to radiolabelled epithelium-denuded preparations in the lower chamber, the inhibitory effects of ACh (1 microM) and carbachol (3 microM) on S-I efflux were prevented. 6. In conclusion, the findings of the present study do not support the notion that the airway epithelium exerts an inhibitory influence on ACh release from parasympathetic nerves of the rat trachea. Alternatively, if epithelium-dependent modulation of cholinergic transmission does occur in the rat trachea, then the mechanism does not appear to involve phosphorylcholine, nitric oxide, superoxide radicals, cyclo-oxygenase products of arachadonic acid, capsaicin-sensitive neuropeptides or vasoactive intestinal peptide. Moreover, the inhibitory effect of carbachol and ACh on transmitter ACh release in the rat trachea appears to be due solely to activation of prejunctional inhibitory muscarinic cholinoceptors on parasympathetic nerves and does not involve the liberation of a putative epithelium-derived inhibitory factor.
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PMID:Influence of the epithelium on acetylcholine release from parasympathetic nerves of the rat trachea. 1126 Mar 62

Acetylcholine administered to the inside of epithelium-denuded tracheal tubes did cause a potent contraction (2486+/-120 mg). In contrast, a response was hardly observed in tissues with an intact epithelial layer (674+/-81 mg), which was due to both the synthesis of nitric oxide and the activity of acetylcholinesterase, since the contractions to acetylcholine were significantly enhanced after preincubation with N(omega)-nitro-L-arginine methyl ester (L-NAME) or physostigmine (1374+/-65 and 1120+/-65 mg, respectively). In addition, the suppressive effect was caused by the barrier function of the epithelial layer, since preincubation of epithelium-denuded tissues with physostigmine significantly increased the pD2 value for acetylcholine (7.48+/-0.04) compared to intact tissues preincubated with physostigmine (6.32+/-0.10) and epithelium-denuded preparations without physostigmine (6.37+/-0.06). Increasing concentrations of physostigmine administered to the inside of tissues with epithelium did induce a potent spontaneous contraction (1440+/-350 mg) that was prevented by atropine. In contrast to what was expected, the contractile response was diminished in tracheal tubes without epithelium (665+/-221 mg). It is concluded that contractions of epithelium-denuded tissues are more pronounced to exogenous than to endogenous acetylcholine, and that the production and breakdown of this neurotransmitter is very rapid in intact guinea pig airways. Moreover, the release of nitric oxide and the barrier function of the epithelium did suppress the responsiveness to acetylcholine.
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PMID:Factors that determine acetylcholine responsiveness of guinea pig tracheal tubes. 1140 37

The effects of oral ENA713 and CHF2819 (0.5, 1.5 and 4.5 mg/kg), two novel acetylcholinesterase inhibitors, on extracellular concentrations of amino acids in rat hippocampus, were evaluated using in vivo microdialysis. ENA713, at 4.5 mg/kg, but not CHF2819, significantly decreased glutamate, taurine, arginine and citrulline levels, without affecting aspartate concentrations. These results suggest that the modulation of amino acidergic transmission could represent an additional mechanism of action in Alzheimer's disease for some acetylcholinesterase inhibitors.
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PMID:Effects of ENA713 and CHF2819, two anti-Alzheimer's disease drugs, on rat amino acid levels. 1148 69

Experiments on rat diaphragm muscle showed that the nitric oxide (NO) donors sodium nitroprusside SNP) and S-nitroso-N-acetylpenicillamine (SNAP). as well as L-arginine. a substrate for NO synthesis. decreased the level of muscle fiber hyperpolarization (the H effect) after blockade of cholinoceptors on the postsynaptic membrane by d-tubocurarine in conditions of irreversible inhibition of acetylcholinesterase with armine. Conversely, disruptions to NO synthesis in muscle fibers by the NO synthase blocker NG-nitro-L-arginine methyl ester (L-NAME) led to increases in the H effect both in vitro and in vivo. Inactivated solutions of sodium nitroprusside and inactive forms of arginine and NAME (D-arginine. D-NAME) had no effect on the magnitude of the H effect, while hemoglobin, which efficiently binds NO molecules, blocked the inhibitory effects of sodium nitroprusside. SNAP, and L-arginine on the magnitude of the H effect. All these points provide evidence that NO can function as a modulator of non-quantum mediator release in the neuromuscular junctions of warm-blooded animals.
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PMID:Modulation by nitric oxide (NO) of the intensity of non-quantum mediator secretion in neuromuscular junctions in rats. 1150 98

Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor used for treatment of myasthenia gravis and for prophylactic protection against organophosphate nerve agent. We previously showed PB can induce apoptotic death in rat brain following systemic treatment. To study mechanisms by which PB induces brain cell death, cultured rat cerebellar granule cells were used. Cytotoxicity was determined after exposure to PB (10-1000 microM) for 24 h; a high concentration of PB (>500 microM) significantly increased lactate dehydrogenase release, which was reduced by pretreatment with the antioxidant, N-t-butyl-alpha-phenyl-nitrone (PBN). Apoptosis, as determined by TUNEL staining, was concentration dependent (10-250 microM) after a 24-h exposure and cytotoxicity was confirmed by gel electrophoresis of DNA, release of cytochrome c from mitochondria, elevation of caspase activity, and electron microscopy. The oxidant-sensitive fluorescent dye 2',7'-dichlorofluorescin diacetate was used to detect reactive oxidative species (ROS) generation. Pretreatment with PBN, superoxide dismutase, catalase, or the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) blocked PB-induced ROS generation and apoptotic cell death. Pretreatment with atropine or MK-801 blocked ROS generation and the subsequent neurotoxicity, showing that both muscarinic and NMDA receptors mediate the response. DNA extracted from PB-treated cells revealed oligonucleosomal fragmentation on gel electrophoresis and antioxidants attenuated the DNA fragmentation, providing further evidence for a link of ROS generation and apoptosis. These results indicate that muscarinic receptor-mediated ROS generation is an initiating factor in PB-induced apoptotic cell death and activation of the NMDA glutamate receptor is directly linked to the response.
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PMID:Reactive oxygen species mediate pyridostigmine-induced neuronal apoptosis: involvement of muscarinic and NMDA receptors. 1170 96


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