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)

1. The cholinesterase inhibitors neostigmine, edrophonium and eserine (7 x 10(-7) M) reduced m.e.p.p. frequency by some 50% at the frog neuromuscular junction. Neostigmine also produced a small reduction in quantal content. 2. Tetraisopropylpyrophosphoramide, with a high specificity for non-specific cholinesterase, has a similar effect on m.e.p.p. frequency but ambenonium, with a high specificity for acetylcholinesterase, was markedly less effective in this respect. 3. Carbachol (10(-5) M) and the muscarinic agonists muscarine and metacholine (7 x 10(-7) M) also reduced the rate of spontaneous release. 4. The action of neostigmine was antagonized by atropine, but not by D-tubocurarine. Muscarine did not have any further effect when m.e.p.p. frequency was reduced with neostigmine. 5. Experiments with reduced extracellular Ca2+ concentration suggest that the cholinergic agents reduce Ca2+ permeability directly at the presynaptic terminals and that they do not act via a change in PNa or PK. It is suggested that the consequent reduction in Ca2+ entry causes a fall in both evoked release and in intracellular Ca2+ concentration, thereby reducing m.e.p.p. frequency. 6. It is concluded that non-specific cholinesterases present on the presynaptic terminals can act as inhibitory muscarinic cholinergic receptors. This form of presynaptic inhibition at the amphibian neuromuscular junction contrasts with that described in the mammalian preparation in which the sites are blocked by D-tubocurarine and are excitatory.
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PMID:Inhibitory effects of cholinergic agents on the release of transmitter at the frog neuromuscular junction. 22 16

Subacute (daily) administration of diisopropylfluorophosphate (DFP) to male swine (Yorkshire white) resulted in a 97% inhibition of cholinesterase and a decrease of [3H]quinuclidinyl benzilate [( 3H]QNB) binding sites in homogenates of striata by approximately 50% after 14 days. The maximal density of receptors (Bmax) decreased from 2.1 +/- 0.3 to 1.0 +/- 0.2 pmole/mg protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding (control: 52.6 +/- 10.7 pM; 7-day: 57 +/- 2.8 pM). Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 115 +/- 62 microM (55 +/- 3%) and KiH = 1.8 +/- 0.7 microM (45 +/- 3%), respectively, for the low- and high-affinity states. Seven-Day treatment with DFP reduced the percentage of high-affinity receptors to 22 +/- 8.6%, but affected neither the low- nor the high-affinity Kd (100 +/- 20 and 2 +/- 0.6 microM). With the addition of Mg2+, striatal homogenates had low- and high-affinity receptors in the proportion of approximately 1 to 1. In the presence of Gpp(NH)p + Mg2+ the ratio of high- to low-affinity receptors was 3:1 in homogenates of control tissue (to 26 +/- 5%). This treatment had no effect on this ratio in homogenates of tissue from 7-day DFP-treated swine (3:1) since it was already 3:1. Pirenzepine displacement of [3H]QNB binding was best described by a two-binding site model, with Ki values of 38 +/- 14 and 201 +/- 78 nM, which represent 74 and 26% of the binding sites, respectively. The high affinity Kd value was unchanged following 7 days of DFP treatment (24 +/- 5 nM). There appears to be little change in the displacement curves for pirenzepine inhibition of [3H]QNB binding. This suggests that about 75% of the receptors are of the M1 subtype. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the proportion of agonist affinity states which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.
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PMID:Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine. 238 34

Intrathecal (i.t.) injection of neostigmine was employed to activate spinal cholinergic neurons mediating a hypertensive response in freely-moving rats. Our earlier studies have demonstrated that stimulation of central alpha-adrenergic receptors inhibits the pressor response following inhibition of brain cholinesterase. Clonidine (0.5-5 micrograms) pretreatment by i.t. injection did not alter the magnitude of the pressor response to i.t. injection of neostigmine, but did significantly delay the onset of the response. Since systemic administration of clonidine abolished the pressor response to i.t. neostigmine, clonidine was administered by the intracisternal (i.c.) route to determine whether higher centers mediated the inhibitory response. In this situation, clonidine pretreatment significantly inhibited the pressor response to i.t. injection of neostigmine. I.t. injection of norepinephrine (1-10 micrograms) was more effective, but i.c. pretreatment less effective than clonidine in inhibiting the pressor response to i.t. neostigmine. In order to confirm the ascending nature of the spinal cholinergic system, hemicholinium-3 was injected i.c. to deplete medullary levels of acetylcholine. Carbachol was then injected i.t. (since carbachol is a direct-acting agonist, it is not affected by local depletion of acetylcholine). Depletion of medullary acetylcholine significantly blocked the pressor response to i.t. injection of carbachol. These findings are consistent with the concept of an ascending spinal cholinergic pressor pathway. The pressor response to activation of spinal cholinergic receptors is not sensitive to local injection of clonidine, but, the medullary cholinergic component of the system is inhibited by alpha-receptor stimulation.
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PMID:Modification of spino-bulbar autonomic cholinergic systems by activation of alpha-adrenergic receptors. 257 71

1. Strips of longitudinal muscle from guinea-pig ileum, retaining Auerbach's plexus, were superfused with oxygenated Krebs solution. Addition of 50 mM KCl led to a pronounced Ca2+-dependent increase in the activities of both acetylcholinesterase and non-specific cholinesterase (butyrylcholinesterase) in the perfusate but with no change in lactate dehydrogenase activity. 2. No release of acetylcholinesterase, either spontaneous or K+-evoked was observed in tissue freed of the nerve plexus, although release of butyrylcholinesterase still occurred. 3. Carbachol induced a marked Ca2+-dependent increase in the release of acetylcholinesterase but had no effect on the release of butyrylcholinesterase or lactate dehydrogenase. This carbachol-evoked increase in acetylcholinesterase release was blocked by hexamethonium but not by atropine. 4. Four readily soluble molecular forms of acetylcholinesterase and three soluble molecular forms of butyrylcholinesterase were present in innervated longitudinal muscle strips, but insignificant amounts of acetylcholinesterase were detected in denervated strips of muscle. Only one of the four molecular forms of acetylcholinesterase was recovered in the perfusates. 5. It is concluded that acetylcholinesterase is secreted from the nerves of Auerbach's plexus in response to depolarizing stimuli or to nicotinic cholinergic stimulation, while butyrylcholinesterase is secreted from non-neural elements, possibly the longitudinal muscle cells, of guinea-pig ileum in response to a depolarizing stimulus.
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PMID:Secretion of acetylcholinesterase and butyrylcholinesterase from the guinea-pig isolated ileum. 275 27

Tetrahydroaminoacridine (THA) is known to be a potent centrally acting cholinesterase inhibitor. In this report, the effects of THA in vivo and in vitro on the binding of muscarinic agonists and antagonists to putative M1 and M2 receptor subtypes were assessed in rat brain membranes. THA competitively inhibited labeled agonist and antagonist binding to membranes prepared from M1 and M2 enriched brain regions. The dissociation of radiolabeled antagonists from muscarinic receptors was decelerated markedly by THA. The half-time for dissociation of [3H]oxotremorine-M from the high affinity state of M1 and M2 receptors was unaffected by THA. Chronic THA administration resulted in a selective down regulation in the number of M1 receptors assayed directly with the M1-selective antagonist, [3H]pirenzepine. The decrease in the binding capacity of [3H]pirenzepine was correlated positively with the duration of drug treatment. Saturation analysis of [3H]pirenzepine binding confirmed that this loss in binding capacity was due to a reduction in the number of binding sites and not an altered affinity of the receptor for [3H]pirenzepine. Carbachol-[3H]pirenzepine competition revealed no change in the ratio of high and low affinity agonist states of the M1 receptor with chronic THA administration. In vivo studies demonstrate further that the total number of muscarinic receptors was decreased significantly, whereas putative M2 receptors, measured directly with the agonist [3H]oxotremorine-M or estimated by pirenzepine-[3H]quinuclidinyl benzilate competition, were unchanged. Thus, THA exhibits multiple actions at primary and secondary recognition sites on putative M1 and M2 subclasses of muscarinic receptors. The results suggest further that the clinical pharmacology of THA may represent a composite efficacy of THA at multiple sites on cholinergic synapses.
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PMID:Multiple in vitro interactions with and differential in vivo regulation of muscarinic receptor subtypes by tetrahydroaminoacridine. 276 Aug 41

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

The spinal cord is capable of initiating a significant and long-lasting pressor response following intrathecal injection of cholinergic agonists in freely moving rats. The magnitude of the pressor response to the cholinesterase inhibitor, neostigmine, was greatest when the site of injection was restricted to the thoracic level. Intrathecal (i.t.) injection of neostigmine (1-10 micrograms) elicited a dose-related increase in mean arterial pressure of up to 45 mm Hg which remained elevated for almost 2 h. Significant inhibition of acetylcholinesterase was localized to the spinal cord, with the thoracic region exhibiting the greatest degree of inhibition. Also, depletion of spinal acetylcholine levels following i.t. injection of hemicholinium-3 (HC-3) resulted in a significant reduction in the magnitude of the neostigmine-induced pressor response. Carbachol, a direct-acting cholinergic receptor agonist also increased mean arterial pressure following i.t. injection. However, the pressor response to carbachol was not reduced following HC-3. For both agonists, cardiovascular changes were accompanied by significant behavioral changes characterized by tremor, scratching, tail biting and chewing. The appearances of these behaviors following neostigmine injection were reduced in frequency and intensity in HC-3-pretreated animals. These findings demonstrate the ability of spinal cholinergic neurons to mediate a significant hypertensive response. The presence of marked behavioral changes accompanying the cardiovascular response suggests the possibility that cholinergic neurons may be part of an ascending spinal system.
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PMID:Hypertension following intrathecal injection of cholinergic agonists in conscious rats: role of endogenous acetylcholine. 322 83

Neuropharmacological studies of Schistosoma mansoni were conducted in vitro using visual observations of motor activity and measurements of worm length and extracellular electrical activity. The instrumentation and methodology described quantitatively measure extracellular electrical potentials associated with motor activity, and provide a highly sensitive, objective technique for studying effects of antischistosomal compounds and for evaluating schistosomes as a model for neuropharmacological investigation. The visual motor and electrical responses of schistosomes to various pharmacological agents support earlier claims for the presence of an excitatory tryptaminergic system and an inhibitory cholinergic system. The stimulation of motor activity by 5-hydroxytryptamine was blocked by the antagonists metergoline and cyproheptadine in a dose-dependent manner. The hypermotility induced by cholinergic blockade (atropine or mecamylamine) or 5-hydroxytryptamine release (p-chlorophenylethylamine) was abolished by these antagonists. The cholinomimetic agents, acetylcholine, carbachol and arecoline, and the cholinesterase inhibitors neostigmine and metrifonate, caused a flaccid paralysis of schistosomes. Carbachol-induced paralysis was reversed by both the nicotinic cholinergic blocker, mecamylamine, and the muscarinic cholinergic blocker, atropine. This reversal occurred in a dose-dependent manner. It is suggested that the cholinoceptive site in S. mansoni has unique pharmacological properties, distinctly different from those in mammals. Dopamine, apomorphine, epinephrine and norepinephrine had little effect on schistosome motility, but produced marked increases in worm length. The dopaminergic antagonist, haloperidol, completely blocked the dopamine response. A broad range of putative amino acid neurotransmitters failed to alter schistosome motor activity. The simple nervous system of the schistosome appears to have many unique pharmacological features which may make it a useful model for the study of drugs for human use, as well as providing an effective point for chemotherapeutic attack.
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PMID:Neuropharmacology of the parasitic trematode, Schistosoma mansoni. 613 Jul 10

Acetylcholine produced an elevation of the atrial pressure and decreased the systemic output dose-relatedly at 30 micrograms or more without producing any change in the heart rate. Negative chronotropic effects were observed only with doses of more than 600 micrograms. These effects of acetylcholine were enhanced by physostigmine and antagonized by atropine, while pindolol and 6-hydroxydopamine exerted no influence. Acetylcholine-induced elevation of atrial pressure and decrease of systemic output were similarly observed even when the heart was paced at a constant rate. Carbachol and methacholine produced qualitatively similar changes in the atrial pressure and systemic output. However, carbachol was unique in that it produced a dose-related negative chronotropic effect. Vagal stimulation induced an elevation of atrial pressure and a decrease of systemic output associated with bradycardia. Effects of vagal stimulation on atrial pressure and systemic output were abolished in the paced heart. These findings suggest that exogenous acetylcholine cannot reach the pacemaker site because of the abundant presence of cholinesterase in the region of the pacemaker, while acetylcholine released by vagal stimulation can reach the pacemaker site before being degraded by cholinesterase. The elevation of the atrial pressure and a decrease in the systemic output produced by exogenous acetylcholine can be ascribed to activation of the receptors in the ventricular myocardium, while the negative inotropic effects of vagal stimulation are due to an inhibition of atrial functions.
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PMID:[Cardiac effects of acetylcholine and its congeners]. 635 90

1. Human isolated pulmonary vessels were treated with cholinesterase (ChE) inhibitors to determine the role of these enzymes in regulating vascular muscle tone. In addition, kinetic parameters were determined for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in human pulmonary vessel homogenates. 2. Carbachol (CCh) and acetylcholine (ACh) were equipotent contractile agonists in human pulmonary arteries (pD2 values, 5.28 +/- 0.05 and 5.65 +/- 0.16; Emax, 0.91 +/- 0.26 and 0.98 +/- 0.30 g wt. for CCh and ACh, respectively; n = 7). In venous preparations, ACh was ineffective and CCh induced small contractions (Emax, 0.08 +/- 0.04 g wt; n = 13). 3. In human pulmonary arteries following pretreatment with tetraisopropylpyrophosphoramide (iso-OMPA, 100 microM), an increased sensitivity to the contractile agonist ACh was observed (pD2 values, 5.80 +/- 0.13 and 6.37 +/- 0.19 for control and treated preparations, respectively; n = 5). This pretreatment had no effect on the CCh concentration response curve. In contrast, human pulmonary veins pretreated with iso-OMPA failed to elicit a contractile response to ACh. 4. Neither Iso-OMPA nor neostigmine elicited concentration-dependent contractions in human isolated pulmonary arteries or veins. These results suggest the absence of sufficient spontaneous release of ACh to modulate human pulmonary vessel basal tone. 5. CCh was less potent than ACh in relaxing precontracted human isolated pulmonary arteries (pD2 value, CCh: 6.55 +/- 0.15 and ACh: 7.16 +/- 0.13, n = 4) and veins (pD2 value, CCh: 4.95 +/- 0.13; n = 5 and ACh: 5.56 +/- 0.17; n = 6). Pretreatment of vessels with either iso-OMPA or neostigmine did not modify ACh relaxant responses in either type of preparation. 6. In human pulmonary veins, the ChE activity was two fold greater than in arteries (n = 6). Vmax for AChE was 1.73 +/- 0.24 and 3.36 +/- 0.26 miu mg-1 protein in arteries and veins, respectively, whereas Vss for BChE was 1.83 +/- 0.22 and 4.71 +/- 0.17 miu mg-1 protein, in these respectively. 7. In human pulmonary arteries, BChE activity may play a role in the smooth muscle contraction but not on the smooth muscle endothelium-dependent relaxation induced by ACh. A role for ChE activity in the control of venous tone is presently difficult to observe, even though this tissue contains a greater amount of enzyme than the artery.
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PMID:Cholinesterase activity in human pulmonary arteries and veins. 922 57


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