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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of muscarinic receptor antagonists on ACh release were studied in the absence or presence of cholinesterase (ChE) inhibition using the isolated perfused chicken heart. Presynaptic inhibitory muscarinic autoreceptor were characterized by determining the potency of various antagonists to enhance [3H]-ACh release evoked by field stimulation (3 Hz, 1 min). The order of potencies was: (+/-)-telenzepine > atropine > 4-DAMP > silahexocyclium > pirenzepine > hexahydro-siladifenid-ol > AF-DX 116. The comparison with known pA2 values for M1-, M2- and M3-receptors revealed that the presynaptic autoreceptor meets the criteria of an M1-receptor. Basal, not electrically evoked overflow of unlabelled ACh into the perfusate was caused by 'leakage' release (non-exocytotic), as it was independent of extracellular Ca2+. Muscarinic receptor antagonists failed to enhance basel overflow. In contrast, when ChE activity was inhibited by 10(-6) M tacrine or pretreatment with 10(-4) M DFP, the ACh overflow was partially Ca(2+)-dependent and was reduced by tetrodotoxine. Moreover, block of the inhibitory muscarinic autoreceptors by (+/-)-telenzepine or pirenzepine caused a several-fold enhancement of the ACh release. The potencies of these antagonists were identical to those found for the electrically evoked [3H]-ACh release. The rate of ACh release enhanced by ChE inhibition plus telenzepine corresponds to about 12% of the total ACh pool per min, which is about the maximum amount of ACh that is available for any kind of stimuli. The release was dependent on the presence of exogenous choline. Hence elevation of ACh release led to a correspondingly enhanced ACh synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitory and excitatory muscarinic receptors modulating the release of acetylcholine from the postganglionic parasympathetic neuron of the chicken heart. 143 22

Cholinomimetic agents increase blood pressure and heart rate via central muscarinic cholinoceptors in various species. It was reported that i.c.v. injection of the muscarinic M1 and M3 cholinoceptor selective antagonist, 4-DAMP (4-diphenylacetoxy-N-methyl-piperidine methiodide), inhibited the pressor response to physostigmine, while the M1 selective antagonist, pirenzepine, was ineffective. In the present study, the involvement of muscarinic M2 cholinoceptors in central cholinergic hypertension and tachycardia was investigated. Physostigmine (10-80 micrograms/kg i.v.), a cholinesterase inhibitor, and oxotremorine (20-40 micrograms/kg i.v.), a direct muscarinic cholinoceptor agonist, caused a dose-dependent increase in blood pressure. Additionally, physostigmine induced dose-dependent tachycardiac responses. I.c.v. administration of the muscarinic M2 cholinoceptor antagonists, AF-DX 116 and methoctramine, inhibited both physostigmine (60 micrograms/kg) and oxotremorine (20 micrograms/kg)-induced pressor responses at their lower doses used in this study (100 nmol/rat and 10 nmol/rat, respectively). These findings indicate the partial involvement of postsynaptic muscarinic M2 cholinoceptors. The higher doses of the antagonists (AF-DX 116,300 nmol/rat and methoctramine 30 nmol/rat) potentiated the blood pressure increase due to physostigmine but did not affect that due to oxotremorine. The physostigmine-induced tachycardiac responses were influenced similarly by these antagonists. These results suggest the presence and tonic influence of presynaptic inhibitory muscarinic M2 cholinoceptors.
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PMID:Central muscarinic M2 cholinoceptors involved in cholinergic hypertension. 811 94

The direct effect of acetylcholine on the activation of the corpora allata (CA) was investigated in the adult male loreyi leafworm, Mythimna loreyi. Acetylcholine, in the presence of the choline esterase inhibitor physostigmine (50 microM), elicited a stimulatory effect on juvenile hormone acids (JHAs) release from the CA. Maximum effect was obtained at concentrations of 10 and 50 microM. Repeated administration of 10 microM acetylcholine on the same CA did not elicit similar stimulatory effect. Since JHA release can be significantly activated by carbachol and not by nicotine, this cholinergic effect is likely to belong to the muscarinic type. The effect of acetylcholine was significantly antagonized by gallamine triethiodide (M(2) antagonist) and 4-DAMP (M(3) antagonist), pirenzepine (M(1) antagonist), and tropicamide (M(4) antagonist) were ineffective. It is concluded that in the adult male M. loreyi, the cholinergic regulation of CA is most likely via M(2) and M(3) muscarinic receptors.
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PMID:Cholinergic regulation of the corpora allata in adult male loreyi leafworm Mythimna loreyi. 1192 Oct 79

In the course of examining the actions of major human bile acids on cholinergic receptors, we discovered that conjugates of lithocholic acid are partial muscarinic agonists. In the present communication, we report that conjugates of deoxycholic acid (DC) act as cholinergic muscarinic receptor antagonists. Chinese hamster ovary (CHO) cells expressing rat M3-muscarinic receptors were used to test bile acids for inhibition of radioligand [N- (3)H-methylscopolamine ((3)H-NMS)] binding; alteration of inositol phosphate (IP) formation; mitogen-activated protein (MAP) kinase phosphorylation and cell toxicity. We observed approximately 18.8, 30.3 and 37.1% inhibition of (3)H-NMS binding with DC and its glycine (DCG) and taurine (DCT) conjugates, respectively (all 100 micromol/l, p < 0.01). DCT and DCG inhibited acetylcholine-induced increases in IP formation and MAP kinase phosphorylation (p44 and p42 ERK). DCG and DCT did not alter trypan blue exclusion or lactate dehydrogenase release from CHO-M3 cells. We observed the following rank order of potency (IC(50) micromol/l) for inhibition of (3)H-NMS by muscarinic antagonists and bile acids: NMS (0.0004) > 4-DAMP (0.009) > atropine (0.012) > DCT (170) > DCG (250). None of the bile acids tested were hydrolyzed by recombinant cholinesterase. At concentrations achieved in human bile, DC derivatives are natural muscarinic antagonists.
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PMID:Deoxycholic acid conjugates are muscarinic cholinergic receptor antagonists. 1211 52

The neurochemical effects in developing rats exposed during gestation to the anticholinesterase organophosphorus insecticide chlorpyrifos (CPS) were determined. Pregnant rats were dosed daily with CPS (0, 3, or 7 mg/kg) in corn oil from gestation days (GD) 6-20. Pups were euthanized on postnatal days (PND) 1, 3, 6, 9, 12, and 30 for the determination of brain cholinesterase (ChE) and choline acetyltransferase (ChAT) activities, along with muscarinic receptor (mAChR) densities, the levels of the high-affinity choline uptake (HACU) system, and the vesicular acetylcholine transporter (VAChT). ChE activities were inhibited about 15 and 30% on PND 1, in the low- and high-dosage groups, respectively, and were not different from control values by PND 6. mAChR densities on PND 1 were reduced in the high-dosage group by about 18, 21, and 17%, using 3H-N-methylscopolamine, 3H-quinuclidinyl benzilate, and 3H-4-DAMP, respectively, as ligands, and were not different from control levels by PND 6. ChAT activity was decreased by approximately 12% in the high-dosage group on PND 9, 12, and 30. HACU levels, using 3H-hemicholinium-3 as the ligand, were reduced by approximately 25% on PND 6 in the low- and high-dosage groups, and by approximately 14 and 21% on PND 12 and 30, only in the high-dosage group. Levels of the VAChT were reduced by a range of 13-31% on PND 3 through 30 in the high-dosage group, using 3H-AH5183 (vesamicol) as the ligand. These data suggest that gestational exposure to 7 mg/kg/day CPS results in long-term alterations of presynaptic cholinergic neurochemistry.
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PMID:Neurochemical effects of repeated gestational exposure to chlorpyrifos in developing rats. 1460 Feb 74

Intrathecal (IT) injection of neostigmine (a cholinesterase inhibitor) has been reported to produce a significant anti-nociceptive effect in a number of inflammatory pain models. However, a potential anti-inflammatory effect of IT neostigmine in these models has not been investigated. In the present study, we have examined the 'anti-inflammatory effect of IT injection of neostigmine' (AI-NEO) using a standard mouse air pouch model by evaluating the effect of AI-NEO on zymosan-induced leukocyte migration and myeloperoxidase (MPO) release. IT neostigmine was found to suppress both leukocyte migration and MPO degranulation in a dose dependent manner. We then established which subtypes of cholinergic receptors were involved in this AI-NEO. IT pretreatment with atropine (a muscarinic receptor antagonist) but not hexamethonium (a nicotinic receptor antagonist) completely blocked the IT neostigmine anti-inflammatory effect. Subsequent experiments showed that IT pretreatment with methoctramine (a muscarinic type 2 (M2) receptor antagonist), but not pirenzepine (M1 receptor antagonist) or 4-DAMP (M3 receptor antagonist), suppressed the AI-NEO. We then evaluated whether adrenal glandular activity was important in the AI-NEO. Adrenalectomy significantly blocked the AI-NEO, while intraperitoneal pretreatment with the beta-adrenoceptor antagonist (propranolol), but not the corticosteroid antagonist (RU486) reversed AI-NEO. In conclusion, these results indicate that IT neostigmine facilitates the activation of spinal M2 receptors and this activation ultimately leads to release of adrenal catecholamines which contribute to the anti-inflammatory effect observed at the site of tissue inflammation.
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PMID:Intrathecal neostigmine reduces the zymosan-induced inflammatory response in a mouse air pouch model via adrenomedullary activity: involvement of spinal muscarinic type 2 receptors. 1592 70

The neurodevelopmental effects of two organophosphorus (OP) insecticides, chlorpyrifos (CPS) and methyl parathion (MPS), on cholinesterase (ChE) activity and muscarinic acetylcholine receptor (mAChR) binding were investigated in neonatal rat brain. Animals were orally gavaged using an incremental dosing regimen from postnatal day 1 (PND1) until PND8 with a low, medium, and high dosage for both CPS and MPS. On PND4 and PND8, ChE activity was measured in whole brain while the total and subtype densities of mAChRs were measured in three brain sections: area anterior to optic chiasma (anterior forebrain), area from the optic chiasma to the medulla/pons (posterior forebrain); and the medulla/pons excluding the cerebellum. The ligands 3H-pirenzepine, 3H-AF-DX 384, 3H-4-DAMP, and 3H-QNB were used to measure the maximal binding of the M1, M2/M4, and M3 subtypes and total mAChR receptors, respectively. In the anterior and the posterior forebrain, the levels of all mAChRs nearly doubled from PND4 to PND8, while in the medulla/pons, M1- and M3-subtype mAChR densities were low and did not increase and M2/M4 subtype and total mAChR slightly increased from PND4 to PND8. Reduction of ChE activity and mAChR binding by CPS or MPS was more evident in rats at PND8 than at PND4. With respect to mAChR binding, the greatest effects were observed in the medulla/pons and the least effects were observed in the posterior region of the forebrain. These results demonstrate that OPs exert adverse effects on rat central nervous system development through the cholinergic system in an age- and region-dependent manner.
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PMID:Altered muscarinic acetylcholine receptor subtype binding in neonatal rat brain following exposure to chlorpyrifos or methyl parathion. 1766 26

Recently, a cholinergic neurogenic component of contraction has been characterised in the aganglionic mouse vas deferens. In this paper, a cholinergic component of contraction in the guinea-pig vas deferens is characterised pharmacologically. A residual, tetrodotoxin-sensitive (TTX, 0.3 microM), neurogenic contraction was revealed after prolonged exposure (5 h) to the adrenergic neurone blocker bretylium (20 microM) or in the presence of prazosin (100 nM) and alpha,beta-methylene ATP (1 microM), a purinergic agonist which desensitizes P2X receptors. The bretylium-resistant component was potentiated by the acetylcholinesterase (AChE) inhibitor neostigmine (10 microM) and inhibited by the muscarinic-receptor (mAChR) antagonist cyclopentolate (1 microM). Nicotine (30 microM) enhanced the bretylium-resistant component. Neostigmine increased the second component of contraction in the presence of prazosin and alpha,beta-methylene ATP, whilst yohimbine (1 microM), an alpha(2) adrenergic receptor antagonist, enhanced both the first and second components of the electrically evoked contraction. These enhanced contractions were blocked by cyclopentolate in both cases. Nicotine enhanced the cholinergic component of contraction revealed by neostigmine but failed to have any detectable effects in the presence of cyclopentolate. Neostigmine alone increased the slow component of contraction which was reversed by cyclopentolate to control levels. The M(3) receptor-antagonist 4-DAMP (10 nM) markedly inhibited the cholinergic component of contraction to a level comparable with cyclopentolate. Laser microscopy has shown that neostigmine also increased the frequency of spontaneous Ca(2+) transients remaining in smooth muscle cells after perfusion with prazosin and alpha,beta-methylene ATP, an effect blocked by 4-DAMP. These experimental data show that there is a functional cholinergic innervation in the guinea-pig vas deferens whose action is limited by acetylcholinesterase, blocked by cyclopentolate and mediated through M3 receptors. Moreover, by blocking the cholinesterase, the increased amount of ACh generates spontaneous Ca(2+) transients in smooth muscle cells.
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PMID:Cholinergic innervation of the guinea-pig isolated vas deferens. 1799 17

In the present study, the plasticity of the non-adrenergic non-cholinergic (NANC) response was investigated. Isolated rat bladder strips were electrically stimulated and the evoked contractions were isometrically recorded. The NANC part of the contractions were unmasked by applying 500 nM 4-DAMP, a potent muscarinic antagonist. Treatment of the bladder strips with 10 microM carbachol (a cholinergic agonist) increased the muscle tone but did not alter the neurally evoked contractions. However, carbachol decreased: (1) the NANC response from 74.6% to 33.3% of control and (2) the purinergic contractile response to alpha,beta-methylene ATP (alpha,beta-mATP) (10 microM) from 97.0% to 43.4% (p<0.05). Treatment with the cholinesterase inhibitor eserine (10 microM) also significantly decreased the NANC response to 21.1% (p<0.0001). The purinergic receptor antagonist suramin (100 microM) did not affect the neurally evoked contractions, however; subsequent addition of 4-DAMP decreased the contractions to 31%. Activation of the smooth muscle cholinergic receptors (with carbachol or eserine) and purinergic receptors (with alpha,beta-mATP) decreased the NANC contractions and the direct contractile response to alpha,beta-mATP. When the electrically evoked contractions were facilitated by the L-type Ca2+ channel activator, Bay-K 8644 the subsequent application of 4-DAMP did not unmask inhibited NANC contractions. We conclude that activation of muscarinic receptors by cholinergic agonist, carbachol or by endogenous acetylcholine (ACh) induce a cascade of events that leads to diminished purinergic response and consequently an inhibition of the bladder NANC response.
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PMID:Activation of cholinergic receptors blocks non-adrenergic non-cholinergic contractions in the rat urinary bladder. 1875 52

We have investigated the muscarinic receptor subtype(s) mediating the release of urinary bladder-derived relaxant factor that is demonstrated by a coaxial bioassay system. Acetylcholine-induced relaxation of a precontracted anococcygeus muscle mounted within the bladder was considered as an evidence for the release of this factor. M(1)-muscarinic agonist McN-A-343 and the cholinesterase inhibitor physostigmine also elicited relaxation responses in the coaxial bioassay besides acetylcholine. Acetylcholine-induced relaxation was antagonized by the subtype-selective muscarinic antagonists (pK(B)): M(3)-antagonist darifenacin (9.36+/-0.11), M(3)/M(1)-antagonist 4-DAMP (9.30+/-0.11), M(1)-antagonist telenzepine (8.56+/-0.21), M(4)-antagonist tropicamide (6.63+/-0.17) and M(2)-antagonist AF-DX 116 (6.01+/-0.21). The pK(B) values of these antagonists have suggested that stimulation of M(1)- and M(3)-muscarinic receptors in the bladder wall mediates the release of urinary bladder-derived relaxant factor. In addition, McN-A-343, by activating the facilitatory M(1) receptors and physostigmine by inhibiting the acetylcholinesterase may induce the release of this factor through endogenous acetylcholine in the coaxial bioassay system.
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PMID:M(1) and M(3) muscarinic receptors are involved in the release of urinary bladder-derived relaxant factor. 1941 29


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