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)

The effect of hemicholinium-3 (HC-3) on responses of the rat isolated bladder and ileum to acetylcholine and carbachol was investigated in the absence and presence of a number of anticholinesterases. Responses of the bladder to acetylcholine were potentiated by DFP, edrophonium, BW284C51 and physostigmine but were unaffected by the specific butyrylcholinesterase inhibitor iso-OMPA. Responses to carbachol were not potentiated by the anticholinesterases. HC-3 (1.7 X 10(-4) M) inhibited responses to carbachol without affecting those to acetylcholine. In the presence of physostigmine or DFP responses to acetylcholine were inhibited by HC-3 but no such inhibition was observed in the presence of BW284C51, edrophonium or iso-OMPA or a combination of the latter two anticholinesterases. Responses to carbachol were also inhibited to a greater extent in the presence of DFP. In the ileum, responses to acetylcholine were increased in the presence of DFP, edrophonium and physostigmine but were unaffected by iso-Ompa. responses to carbachol were not increased by any of the anticholinesterases. HC-3 (2.8 X 10(-4) M) inhibited responses to both acetylcholine and carbachol in the ileum and the degree of inhibition was not significantly altered by the presence of any of the anticholinesterases used. Although a weak anticholinesterase, HC-3 was also found to decrease the inhibitory action of physostigmine on the hydrolysis of acetylcholine by homogenates of rat ileum. A similar effect was noted with DFP but not with edrophonium. The results obtained do not support a prejunctional action for HC-3 in antagonizing responses to carbachol. It is concluded that in addition to an inhibitory action on the post-junctional muscarinic receptor HC-3 may interfere with the anticholinesterase activity of some cholinesterase inhibitors such as physostigmine and DFP but not edrophonium.
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PMID:The effect of cholinesterase inhibitors on the antimuscarinic effect of hemicholinium-3 (HC-3) in the rat. 0 55

The antiacetylcholine and anticholinesterase potencies of four 1-phenylcyclohexylamine derivatives were estimated by measuring their antagonism to the contractile response of smooth and striated muscles and their inhibition of cholinesterase activity. In addition, their affinities towards the central muscarinic receptor from mouse brain homogenate were determined by competition experiments in vitro. Relative to atropine, these drugs exerted mild antimuscarinic activity in both isolated smooth muscle and in the competition experiments. On the other hand, they were found to exert antinicotinic potencies equal to that of d-tubocurarine in the striated muscle. The concentration of (3H)-phencyclidine taken up by mouse brain in vivo could be correlated with its dissociation constants from the central muscarinic binding sites, as well as with the Ki values for acetylcholinesterase inhibition, both determined in vitro. Since these drugs have a similar rigid spatial molecular structure, it is proposed that the variations in the potency of their cholinergic interactions stemmed mainly from the structural changes in the region of the 'cationic head'.
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PMID:Anticholinesterase and antiacetylcholine activity of 1-phenylcyclohexylamine derivatives. 92 35

We administered 9-amino-1,2,3,4-tetrahydroacridine (THA, Tacrine) to mice in doses (0.3-3 mg/kg) which have been shown to enhance cognition. Animals were sacrificed at various time points and several markers of cholinergic function were measured. Following 3 mg/kg THA, drug levels in brain were sufficient to inhibit 78-80% of brain acetylcholinesterase activity, regardless of treatment duration. However, repeated administration of THA did not alter the number of muscarinic receptors or the phosphoinositide response to muscarinic receptor agonists. Thus, at therapeutically relevant doses, THA inhibits the activity of brain acetylcholinesterase substantially, but does not affect the density of muscarinic receptors on their ability to activate second messenger systems. These results are in contrast to those obtained by other investigators who found significant decreases in muscarinic receptor number following chronic administration of higher doses of THA.
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PMID:Muscarinic receptor function and acetylcholinesterase activity after chronic administration of tacrine to mice at therapeutic drug concentrations. 131 62

The effect of the muscarinic receptor antagonist AF-DX 116 on the inhibitory action of muscarinic agonists and on responses mediated by nicotinic or muscarinic ganglionic transmission was studied in the superior cervical ganglion of the anesthetized cat. The postganglionic compound action potential evoked by cervical sympathetic trunk stimulation was depressed by methacholine or acetylcholine (ACh) injected into the ganglionic arterial supply. The depression was blocked by AF-DX 116. The compound action potentials evoked by preganglionic stimulus trains were also depressed when the intratrain frequency was 2 Hz or greater. This intratrain depression was, however, insensitive to AF-DX 116. The anticholinesterase drug physostigmine markedly enhanced the intratrain depression of the compound action potential. This effect was reversed by AF-DX 116. During nicotinic receptor block with hexamethonium, preganglionic stimulus trains with intratrain frequencies of 5 Hz or greater produced nicitating membrane contractions that could be blocked by the M1 muscarinic receptor antagonist pirenzepine. The amplitude of the contractions increased with frequency and reached a maximum at 20-40 Hz. AF-DX 116 had no effect on these responses. After administration of physostigmine, the amplitude of the nictitating membrane responses decreased with increasing intratrain frequency. AF-DX 116 reversed this effect. The data suggest that, in the superior cervical ganglion, AF-DX 116 sensitive muscarinic receptors which depress synaptic transmission are activated by exogenous agonists but not by the ACh released by the preganglionic axon terminals unless cholinesterase activity is inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An AF-DX 116 sensitive inhibitory mechanism modulates nicotinic and muscarinic transmission in cat superior cervical ganglion in the presence of anticholinesterase. 133 12

The effects of the organophosphate acetylcholinesterase (AChE) inhibitor soman were investigated on different receptors coupled to phosphoinositide (PPI) breakdown on hippocampal slices in vitro. We observed that muscarinic receptor subtypes M1 and M3 are involved in the increase of intracellular inositol phosphate, which is consistent with the procholinergic effect of soman induced by inhibition of AChE. Although the M2 receptor subtypes are known to be coupled to the cAMP second messenger, we demonstrated that in vitro, under soman, they are also involved in the PPI turnover. The other receptor subtypes known to be linked to PPI hydrolysis are not involved in this model of stimulation.
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PMID:Soman-induced phosphoinositide hydrolysis in rat hippocampal slices: biochemical characterization. 133 1

To seek evidence for the involvement of acetylcholinesterase activity in the modulatory influence of the airway epithelium, we examined responses to acetylcholine (ACh), bethanechol, histamine or KCl in isolated epithelium-intact and epithelium-denuded guinea-pig trachealis preparations. The concentration-response curves to ACh were shifted 26-fold to the left by epithelial denudation but the contractile response to KCl was not altered. The response to histamine in epithelium-denuded preparations increased 4-fold with no attenuation in the presence of physostigmine (30 nM). Physostigmine (30 nM) potentiated the response to ACh in epithelium-intact tissues more (about 26-fold) than in epithelium-denuded tissues (about 3.5-fold). Thus, in the presence of physostigmine removing the epithelium had only a slight effect (not statistically significant) on the potency of ACh to contract the trachea. Removing the epithelium had no effect on the potency of bethanechol, a muscarinic receptor agonist that is not a substrate for cholinesterases. Physostigmine itself contracted the trachealis muscle but the pD2 values and maximum responses in epithelium-intact and denuded preparations were not significantly different. The frequency-response curves to electrical field-stimulated cholinergic contractions were unaffected by removing the epithelium. In conclusion, the principal mechanism by which the epithelium inhibits contraction of guinea-pig trachea to exogenously applied ACh is via epithelium-derived acetylcholinesterase activity.
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PMID:Role of acetylcholinesterase in airway epithelium-mediated inhibition of acetylcholine-induced contraction of guinea-pig isolated trachea. 135 49

A single dose of the organophosphate insecticide O,O'-diethyl-O-3,5,6- trichloro-2-pyridylphosphorothioate [chlorpyrifos (CPF), 279 mg/kg, SC] caused extensive inhibition of cortical and striatal cholinesterase (ChE) activity in adult rats at 2 (94-96%), 4 (82-83%), and 6 (58-60%) weeks after treatment. These persistent changes in ChE activity were concomitant with reductions in muscarinic receptor binding sites in cortex (34, 33, and 18% reduction in Bmax) and striatum (48, 40, and 23% reduction in Bmax) at 2, 4, and 6 weeks after exposure. Neither ChE activities nor muscarinic receptor densities were different from control levels at 12 weeks after exposure. CPF treatment caused a reduction in locomotor activity for the first 2 days after treatment, after which basal activity levels were not different from controls. CPF-treated rats showed higher activity relative to controls, however, following challenge with scopolamine (1 mg/kg, IP) at 2, 4, 6, 8, and 12 weeks after treatment. These data indicate that acute exposure to CPF in adult rats can cause long-term neurobehavioral changes that may persist following the recovery of neurochemical parameters associated with exposure and tolerance to cholinesterase inhibitors.
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PMID:Long-term neurochemical and behavioral effects induced by acute chlorpyrifos treatment. 137 35

Recent studies in this laboratory have demonstrated that intramuscular injection of the irreversible acetylcholinesterase (AChE) inhibitor, soman (pinacolylmethylphosphonofluoridate), produces a rapid (1-2 h) and profound depletion (70% of control) of norepinephrine (NE) in the olfactory bulb and forebrain. NE is decreased only in convulsing animals. As NE-containing locus coeruleus (LC) neurons provide the only NE input to the olfactory bulb and the major NE innervation of the forebrain, the reduction of NE suggests that soman may cause tonic activation of LC neurons leading to rapid depletion of NE. Activation of LC may result from: (i) facilitation of cholinergic transmission in LC; (ii) soman-induced activation of excitatory inputs to LC; or (iii) generalized activation of LC neurons due to seizures. The present experiments were designed to assess these alternatives. We examined whether LC neuronal activity, c-fos expression, and AChE staining are altered after peripheral (systemic) or direct intracoerulear injection of soman in anesthetized rats. Both modes of soman administration rapidly and potently increase the spontaneous discharge rate of LC neurons. This activation was associated with a desynchronization of the electroencephalogram, but not with seizures. The discharge of LC neurons remained elevated at all postsoman intervals examined (up to 2 h) and was rapidly and completely reversed by systemic injection of the muscarinic receptor antagonist scopolamine hydrochloride, but not by the nicotinic receptor antagonist mecamylamine. Both systemic and intracoerulear soman administration completely inhibited AChE staining in LC and rapidly induced the expression of c-fos in LC neurons. These results demonstrate that soman potently and tonically activates LC neurons. This effect appears to be mediated by direct inhibition of AChE in LC leading to a rapid accumulation of ACh. Unhydrolyzed ACh tonically activates LC neurons via muscarinic receptors. Soman-induced activation of LC neurons does not require seizures. We conclude that depletion of forebrain and olfactory bulb NE after systemic administration of soman results from tonic hypercholinergic stimulation of LC.
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PMID:Tonic activation of locus coeruleus neurons by systemic or intracoerulear microinjection of an irreversible acetylcholinesterase inhibitor: increased discharge rate and induction of C-fos. 138 4

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

In order to clarify the role of the amygdala in the working and reference memory of rats in the three-panel runway task, the effects of lesions of subnuclei of the amygdaloid complex on this behavior were studied. Rats that had been trained preoperatively, until they achieved the criterion of learning, were subjected to lesions of the amygdala. In the working memory task, lesions of the basolateral subdivision of the amygdala caused a significant increase in the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), while lesions of the corticomedial amygdala had no effect on working memory errors. The increase in working errors, observed in basolateral amygdaloid-lesioned rats, declined gradually as retraining sessions were given once each day, reverting to control levels on and after the sixth session. In the reference memory task, the number of errors was not affected by lesions of the basolateral or corticomedial amygdala. The increase in working memory errors, induced by lesions of the basolateral amygdala was significantly reduced by intraperitoneal administration of the inhibitors of cholinesterase, tetrahydroaminoacridine (0.32-1.0 mg/kg) and physostigmine (0.032-0.1 mg/kg), and the muscarinic receptor agonist, oxotremorine (0.1 mg/kg), before the runway test. These findings suggest that the basolateral amygdala is selectively involved in working memory but not in reference memory and that the lowering of central cholinergic function may account for the impairment of working memory, induced by lesions of the basolateral amygdala.
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PMID:Involvement of cholinergic mechanisms in impairment of working memory in rats following basolateral amygdaloid lesions. 143 98


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