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)

There is now substantial evidence that acetylcholinesterase inhibitors and muscarinic receptor agonists increase the pain threshold after both systemic and spinal administration. In rats, physostigmine gave a significant dose-dependent increase in latency times in the tail immersion test following intrathecal administration. The effect was antagonized with atropine. Neostigmine gave more prolonged latencies as did the muscarinic receptor agonist carbachol. Spinal cholinergic pathways for antinociception interacted with the spinal opioid and adrenergic nerve tracts. No cross-tolerance to the selective alpha 2-adrenoreceptor agonist guanfacine or to morphine was seen in rats tolerant of spinal carbachol antinociception. The mechanism of spinal cholinergic antinociception is not known but a muscarinic interneuron may explain the interactions with other neurotransmitters. Clinically, the centrally active cholinesterase inhibitor physostigmine has been shown to give postoperative pain relief although of short duration. Severe neurogenic pain has been successfully treated with physostigmine or distigmine.
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PMID:Cholinergic mechanisms in pain and analgesia. 269 28

The ability of physostigmine (PHY) and pyridostigmine (PYR) to protect against the segmental synaptic depression caused by sarin was examined in isolated spinal cords from neonatal rats. The monosynaptic reflex was unaffected at concentrations up to 0.1 microM PHY or 0.3 microM PYR but raising the concentrations of either drug produced a concentration-dependent depression of the monosynaptic reflex which could be completely antagonized by atropine. The monosynaptic reflex was depressed by 50% at 0.45 microM PHY and 2 microM PYR with maximal depression occurring at 1 microM PHY (to about 10% of control) and 10 microM PYR (to about 35% of control). Pretreating the cords with 0.1 microM PHY and PYR for 30 min failed to protect against the depressant effects of sarin even though they inhibited total cholinesterase (ChE) by 27 and 21%, respectively. Both PHY and PYR depressed total ChE activity of the spinal cord in a concentration-dependent manner with 50% inhibition of ChE occurring at 0.8 microM. These results suggest that the carbamates affect segmental transmission by activation of a muscarinic receptor, that protective carbamylation of ChE is ineffective against organophosphorus-induced segmental depression, and that inhibition of ChE is unrelated to both carbamate- and organophosphorus-induced depression of the monosynaptic reflex.
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PMID:Interaction of reversible and irreversible cholinesterase inhibitors on the monosynaptic reflex in neonatal rats. 272 98

Rats were given atropine for 2 weeks and a cholinesterase inhibitor, diisopropylfluorophosphate (DFP) for 4 weeks. The secretory response of the submaxillary glands to pilocarpine and the muscarinic receptor binding to [3H]quinuclidinyl benzylate (QNB) and [3H]pirenzepine (PZ) in the submaxillary glands were investigated. Experiments were performed 48 and 24 hr after the last administration of atropine and DFP, respectively. Chronic atropine treatment enhanced the secretory response and increased the number of binding sites for [3H]QNB and [3H]PZ. The increase in number of binding sites for the 2 radioligands was almost the same. Chronic DFP treatment caused a marked decrease in the secretory response to pilocarpine, without affecting [3H]PZ and [3H]QNB binding. These results suggest that the cholinergic muscarinic M1 receptors may contribute to the development of the supersensitivity of the salivary glands caused by atropine, but not to the development of subsensitivity caused by DFP.
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PMID:Muscarinic supersensitivity and subsensitivity induced by chronic treatment with atropine and diisopropylfluorophosphate in rat submaxillary glands. 273 Feb 33

1. In an experimental model of haemorrhagic shock resulting in the death of all rats within 20-30 min, the intravenous (i.v.) injection of the tertiary amine cholinesterase inhibitor physostigmine (17-70 micrograms kg-1) induced a prompt, sustained and dose-dependent improvement of cardiovascular and respiratory function, with marked increase in the volume of circulating blood and survival of all treated animals, at least for the 2 h of observation. 2. Similar results were obtained with the i.v. injection of the cholinoceptor agonist oxotremorine (5-25 micrograms kg-1), while neostigmine (54 or 70 micrograms kg-1), a quaternary cholinesterase inhibitor which cannot cross the blood-brain barrier, had negligible effects. 3. The anti-shock activities of oxotremorine and physostigmine were blocked by the intracerebroventricular injection of either of the combined nicotinic and M2-muscarinic receptor antagonists gallamine and pancuronium, or of the nicotinic antagonist mecamylamine. They were also blocked by intraperitoneal injection of the adrenergic neurone blocking agent guanethidine, but they were not antagonized by either the combined M1- and M2-muscarinic receptor antagonist atropine, the M1-muscarinic receptor antagonist pirenzepine, or the M2-muscarinic receptor 4-diphenylacetoxy-N-methylpiperidine methobromide. 4. It is concluded that cholinomimetic drugs can reverse hypovolaemic shock through central activation (seemingly mediated by nicotinic receptors) of sympathetic tone, with mobilization and redistribution of the residual blood.
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PMID:Reversal of haemorrhagic shock in rats by cholinomimetic drugs. 280 46

To examine the role of delta-opioid receptors in the modulation of striatal acetylcholine (ACh) release, the action of D-Pen2,L-Pen5-enkephalin, a selective delta-opioid receptor agonist, was tested on [3H]ACh release from slices of the rat caudate-putamen. Slices, incubated with [3H]choline, were superfused with a physiological buffer and stimulated twice by exposure to a high potassium (K+) concentration. In the absence of a cholinesterase inhibitor, 1 microM D-Pen2,L-Pen5-enkephalin produced a 46 and 35% decrease in the release of [3H]ACh evoked by 15 and 25 mM K+, respectively. The depressant action of the enkephalin analogue was concentration dependent, with a maximal effect on K+-evoked [3H]ACh release occurring at 1.0 microM, and was completely blocked in the presence of the delta-opioid receptor selective antagonist, ICI 174864 (1 microM). In the presence of the cholinesterase inhibitors physostigmine (10 microM) and neostigmine (10 microM), or the muscarinic receptor agonist oxotremorine (10 microM), D-Pen2,L-Pen5-enkephalin did not depress the K+-evoked release of [3H]ACh. Atropine (1 microM) blocked the inhibitory effect of physostigmine on the depressant action of D-Pen2,L-Pen5-enkephalin. The results of this study indicate that delta-opioid receptor activation is associated with an inhibition of striatal ACh release, but this opioid-cholinergic interaction is not apparent under conditions of presynaptic muscarinic receptor activation.
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PMID:Depression of potassium-evoked striatal acetylcholine release by delta-receptor activation: inhibition by cholinoactive agents. 285 36

The effects of acetylcholine and of the muscarinic receptor agonist carbachol on inositol phosphate production were studied in cultured rat anterior pituitary cells. In the presence of the cholinesterase inhibitor physostigmine, acetylcholine significantly (p less than 0.05-p less than 0.01) stimulated inositol phosphate formation in a concentration-related fashion: carbachol, but not oxotremorine, produced similar effects. The increase in the amount of inositol phosphates (primarily inositol trisphosphate and inositol bisphosphate) was very rapid, an effect potently antagonized by the muscarinic receptor antagonist atropine. This agent significantly attenuated the stimulatory effect of carbachol on growth hormone (GH) release. These results indicate that the effects exerted by acetylcholine on anterior pituitary function (i.e. GH release) may be mediated, at least in part, by receptor-activated polyphosphoinositide hydrolysis. In addition, acetylcholine and carbachol's relation with other intracellular pathways and with hormone release is discussed.
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PMID:Cholinergic stimulation of inositol phosphate production in cultured anterior pituitary cells. 289 Jan 15

1. Male weanling swine were injected daily for up to 14 days with the organophosphate cholinesterase inhibitors, diisopropylfluorophosphate (DFP) or sarin. The clinical signs of poisoning disappeared or were attenuated by 7 days after starting the DFP treatment, indicating the development of tolerance to DFP toxicity. 2. A significant decrease in acetylcholinesterase activity (85-98%) occurred over the course of this treatment followed by a decrease in the maximal density (Bmax) of [3H] quinuclidinyl benzilate ([3H]QNB) and [3H] N-methylscopolamine ([3H]-NMS) binding sites in isolated cells. The affinity of the muscarinic receptors (KD) for [3H]QNB and [3H]NMS binding, however, remained unaffected. 3. Dose-response curves for ACh-induced increase in isometric tension of tracheal smooth muscle (TSM) showed a leftward shift from control, 2 h after DFP injection. Twenty-four hours after the last DFP treatment, for animals receiving 1 or up to 14 daily injections of DFP, all the dose-response curves were shifted to the left to approximately the same ACh sensitivity when compared with that for control tissue. 4. In vitro treatment of the muscle with 10(-4) M DFP shifted the dose-response curves leftward, in both control and injected animals, and rendered the muscles from control, 1- and 3-day injected animals sensitive to ACh concentrations as low as 10(-10) M. Sensitivity to 10(-10) M ACh was eliminated by carefully cleaning the smooth muscle of adherent connective tissue containing nerves and ganglia and after subacute treatment of swine for 7 days with DFP. DFP-induced spontaneous contractions were also eliminated by careful cleaning. 5. Subacute DFP treatment caused a small leftward shift in the dose-response curve for bethanechol at 2 h and a rightward shift at 1,3 and 7 days, compared to controls. 6. Dose-response curves for K+ were shifted to the right after 1 and 3 days of DFP treatment, but shifted back towards the control after 7 days of treatment. The muscle cells were hyperpolarized by approximately 5 mV after 7 days of DFP or sarin injections. The membrane potential was slightly more sensitive to changes in K+ concentration after 7 days of sarin injection. 7. Subacute treatment of swine with organophosphates modifies the response of neural elements in swine TSM to ACh. Chronic cholinesterase inhibition causes a reduction in the sensitivity of the neural elements to ACh. The decrease in muscarinic receptor density which occurs with chronic cholinesterase inhibition is not sufficient to explain tolerance to organophosphates since TSM maintains an almost normal responsiveness to ACh.
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PMID:Contractile responses of tracheal smooth muscle in organophosphate-treated swine: 1. Agonist changes. 290 99

Monkeys with bilateral ibotenic-acid lesions of the nucleus basalis of Meynert, an area rich in cholinergic neurons that innervate the cerebral cortex, were compared with unoperated control monkeys on a recognition memory task. Although animals with large lesions had substantial reductions of cortical choline acetyltransferase activity, none showed impairment in the task. Lesion effects were observed, however, when performance was assessed following administration of a muscarinic receptor blocker (scopolamine) or a cholinesterase inhibitor (physostigmine). Although scopolamine produced dose-related impairments in both groups, this effect was greater in the experimental animals. Conversely, whereas physostigmine produced modest improvement in performance in the control group, no such improvement was observed in the experimental animals. The altered sensitivity to the mnemonic effects of cholinergic agents in the experimental group suggests that the cholinergic neurons of the nucleus basalis of Meynert contribute to recognition memory.
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PMID:Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert. 311 81

1. Subacute (daily) treatment of male swine with the organophosphate acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP) resulted in tolerance to the effects of DFP within 5-6 days. 2. Subacute administration of DFP resulted in a 98% inhibition of tissue cholinesterase after 7 days and in a decrease of [3H]quinuclidinyl benzilate [( 3H]QNB) binding sites in homogenates of tracheal smooth muscle by 77%. The maximal density of receptors (Bmax) decreased from 1.8 +/- 0.4 to 0.5 +/- 0.1 pmole mg-1 protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding. 3. Pirenzepine displacement of [3H]QNB binding was best described by a single binding site model, with a Ki of 230 +/- 40 nM. This value was unchanged following seven days of DFP treatment (250 +/- 30 nM). The low affinity for this M1 antagonist suggests that there is predominantly a single population of [3H]QNB binding sites of the M2 subtype in tracheal smooth muscle. 4. Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 210 +/- 60 microM (61 +/- 1%) and KiH = 1.2 +/- 0.4 microM (39 +/- 1%) respectively (n = 7) for the low and high affinity states. Seven-day treatment with DFP reduced the percent of high affinity receptors to 25 +/- 4%. 5. Addition of Mg++ to the incubation medium prevented this shift in the proportion of low and high affinity receptors. Gpp(NH)p and Mg++ together decreased the proportion of the high affinity receptors when added to the incubation medium in control tissue (to 25%), but not tissue from 7-day DFP-treated swine. NEM increased the proportion of muscarinic receptors in the high affinity state both for controls and for the DFP-treated swine, in both cases yielding receptors with identical binding properties. 6. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the affinity of the receptors for agonists which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.
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PMID:Changes in affinity states during down-regulation of muscarinic receptors in tracheal smooth muscle of organophosphate-treated swine. 317 Jun 29

Our purpose was to examine the influence of inhibition of cholinesterase at the ventral surface of the medulla on cardiorespiratory activity in the chloralose-anesthetized cat. Administration of the anticholinesterase agent, diisopropylfluorophosphate (DFP) to areas responding to acetylcholine (i.e., rostral and caudal chemosensitive areas of the ventral surface of the medulla) in doses ranging from 12.5 to 50 micrograms bilaterally had minimal effects on cardiorespiratory activity. However, similar doses applied to the intermediate area of the ventral surface of the medulla produced an increase in tidal volume and hypotension. For example, a dose of 12.5 micrograms increased tidal volume by 14 +/- 3 ml (P greater than .05). Similar responses were seen with higher doses of DFP; in addition, respiratory depression (apnea) also occurred. This depression was characterized by a slowing in respiratory rate. The organophosphate compound, soman, in doses of 0.25 and 0.5 micrograms produced effects similar to those seen with DFP with the exception that an increase in respiratory rate was observed before the decrease in respiratory rate occurred. In addition, a greater degree of hypotension was observed with soman as compared to DFP. Findings comparable to those obtained with DFP were produced by the muscarinic receptor agonist, oxotremorine (0.077-10 micrograms). The effects of DFP, soman and oxotremorine were counteracted by locally applied atropine. In addition, measurements of acetylcholinesterase activity taken from the rostral, intermediate and caudal areas indicate a relatively low activity at the rostral area but a relatively high activity at the intermediate area.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiorespiratory effects produced by activation of cholinergic muscarinic receptors on the ventral surface of the medulla. 318 70


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