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 denervation and tetrodotoxin-induced muscle disuse on endplate structure was investigated in rat hind-limb muscles. The endplate was visualized by light microscopic cholinesterase staining and by scanning electron microscopy. Denervation resulted in a reduction in histochemically determined endplate dimensions proportionate to the decrease in muscle fiber circumference. Scanning electron microscopy, on the other hand, revealed a flattening or more often collapse of primary grooves with a reduction in the width of the endplate but no longitudinal shrinkage. Primary groove area per se was not measurable due to the loss of primary groove structural integrity. Thus, the apparent histochemical diminution of endplate length after denervation was artefactual, probably due to loss of cholinesterase activity and impeded access of substrate. In disuse, cholinesterase staining revealed a similar reduction in endplate girth with fiber atrophy but with a corresponding increase in endplate length. Scanning electron microscopy of disused muscle fibers confirmed these histochemical findings and the overall preservation of primary groove area. Disuse also resulted in an increase in the number of intrasynaptic primary groove branches as visualized by scanning electron microscopy. Finally, a specialized endplate "raised area", prominent in soleus muscle, was greatly reduced after disuse but much less so after denervation. Thus, after denervation, primary groove structural integrity is lost and the shape of the endplate passively follows that dictated by circumferential loss of surface membrane. In disused muscle, presence of an intact axon preserves the structure and area but not the orientation of the primary grooves which are distorted by fiber atrophy. Disuse also strongly affects other endplate surface structures visualized by scanning electron microscopy.
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PMID:Endplate topography of denervated and disused rat neuromuscular junctions: comparison by scanning and light microscopy. 673 62

Inhibition of cholinesterase activity in the blood has been proposed as an index of ChE activity in tissues targeted by ChE-inhibiting pesticides, including the muscle end-plate region and the central nervous system (CNS). While opinions vary regarding the utility of blood ChE activity in predicting ChE activity in the target tissues, there appear to be no comprehensive studies designed to assess this possible correlation in a time- and dose-dependent manner. We undertook this type of study by administering a single dose of an organophosphate, chlorpyrifos (0, 30, 60 or 125 mg/kg in corn oil, s.c.) to rats and then sacrificing animals at 1, 4, 7, 21 or 35 days after dosing. Whole blood, plasma, erythrocytes, frontal cortex, hippocampus, striatum, hypothalamus and diaphragm tissue were collected and assayed for ChE activity. Collapsed across dosages, optimal correlations of blood ChE activity with brain or muscle activity occurred 7-21 days after dosing (when ChE inhibition was maximal and most stable). At all times after dosing, there was a high correlation among ChE activity in the hippocampus, striatum and frontal cortex. Generally, ChE activity in whole blood and erythrocytes correlated better with the activity in brain and muscle than did activity in the plasma (whole blood > or = erythrocytes >> plasma). Similar relationships were also observed in a more abbreviated study using a direct acting organophosphate, paraoxon. ChE activity was determined in blood components, brain and muscle at the time of maximal inhibition (4 h after injection) and during recovery (24 hrs after injection) using two dosage levels (0.17 or 0.34 mg/kg, s.c.). Taken together, these data indicate that the level of ChE activity in the blood may accurately reflect activity in other tissues, but that this correlation is tissue- and time-specific.
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PMID:Studies on the correlation between blood cholinesterase inhibition and 'target tissue' inhibition in pesticide-treated rats. 752 96

KW-5092 ([1-[2-[[[5-(piperidinomethyl)-2- furanyl]methyl]amino]ethyl]-2-imidazolidinylidene) propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase (AChE) inhibitory activity and acetylcholine (ACh) release facilitatory activity. The present study examined the effects of KW-5092 on gastrointestinal (GI) motor activity in dogs. In anesthetized dogs, KW-5092 at 0.03 to 1 mg/kg, i.v. dose-dependently enhanced the gastric antral and the colonic motor activity. Neostigmine, an AChE inhibitor, enhanced the motor activity at 0.03 and 0.1 mg/kg, i.v. Ranitidine, a histamine H2-receptor antagonist with AChE inhibitory activity and ACh release facilitatory activity, enhanced the motor activity but decreased blood pressure at 1 to 10 mg/kg, i.v. In conscious dogs, KW-5092 at 0.03 to 1 mg/kg, i.v. or 1 to 10 mg/kg, p.o. dose-dependently enhanced the gastric antral, duodenal, ileal and the colonic motor activities. Neostigmine at 0.1 mg/kg, i.v. or 3 mg/kg, p.o. enhanced the duodenal, ileal and colonic motor activities, but induced excitement, slavering, vomiting and diarrhea. Ranitidine at 3 mg/kg, i.v. enhanced the gastric antral and colonic motor activities, but induced collapse or akinesia. The present results suggest that KW-5092 enhances the GI motor activity in a wide range from the gastric antrum to the colon and does not induce behavioral and cardiovascular side effects. KW-5092 may be a useful drug for the treatment of GI motility dysfunctions.
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PMID:Enhancement by KW-5092, a novel gastroprokinetic agent, of the gastrointestinal motor activity in dogs. 796 26

This study was undertaken to investigate the possibility that non-cholinergic mechanism accounts for acute lethality of cholinesterase (ChE) inhibitor. Physostigmine and carbamate insecticides (2-s-butylphenyl methylcarbamate (BPMC); isoprocarb, 2-isopropylphenyl methylcarbamate (MIPC); and propoxur, 2-isopropoxyphenyl methylcarbamate (PHC)) were employed as ChE inhibitors. Rabbits intravenously given any of the ChE inhibitors showed typical signs of anti-ChE poisoning, a marked inhibition of systemic ChE activity, and an increase in RR interval on an ECG. Injection of physostigmine or PHC at a lethal dose produced a pressor response before cessation of spontaneous breathing. In contrast, injection of MIPC or BPMC primarily elicited a cardiovascular collapse, characterized by a rapid and progressive decrease in blood pressure and a decrease in QRS amplitude of ECG, before cessation of spontaneous breathing. The atropine pretreatment inhibited the pressor response, but not the depressor response and the QRS change. The pretreatment antagonized acute lethality of the ChE inhibitors except BPMC. It is suggested that the mode of lethality for intravenous ChE inhibitor could be determined by a balance between anti-ChE activity and some mechanism other than ChE inhibition. BPMC produced acute lethality through the latter mechanism rather than the former one.
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PMID:Non-cholinergic lethality following intravenous injection of carbamate insecticide in rabbits. 797 14

Fiber diameter variability, acetylcholinesterase staining properties, and average fiber diameter were determined 5 weeks after varying doses of botulinum A toxin were administered into albino rabbit longissimus dorsi muscle. The average fiber diameter within the muscle appeared to be a function of the dose of botulinum toxin injected. Fiber diameter variability correlated with the dose of botulinum toxin administered. Both fiber diameter variability and acetylcholinesterase spread characteristics showed a distinct diffusion gradient over a defined field within a muscle. At lower doses (1 IU), collapse of the diffusion gradient occurred over a 15-30-mm segment of muscle. At higher doses (5-10 IU), diffusion of botulinum A toxin effect occurred throughout the entire muscle with no apparent end point. This study demonstrated that botulinum A toxin produces a gradient of denervation in a given muscle and that both the magnitude of denervation and the extent of the gradient are dose dependent. Furthermore, both muscle fiber diameter variability and acetylcholinesterase staining were useful as measures of chemodenervation.
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PMID:Histologic assessment of dose-related diffusion and muscle fiber response after therapeutic botulinum A toxin injections. 813 3

The objective of this study was to test our hypothesis that pregnancy modifies the central nervous and cardiovascular toxicity of cocaine. Ten chronically catheterized term pregnant rats and 13 chronically catheterized nonpregnant female rats were infused with cocaine (2 mg/kg/min) intravenously to observe the sequential toxic manifestation of cocaine from mild central nervous stimulation (hyper-locomotor activities) to fatal cardiovascular collapse. Arterial blood samples were withdrawn at the onset of major toxic signs or symptoms--namely convulsion, hypotension, and circulatory collapse--for determination of cocaine concentrations and plasma cholinesterase activity. The dosage and plasma concentrations of cocaine associated with the onset of convulsions and cardiovascular depression were significantly lower in pregnant rats when compared with the nonpregnant animals. The mean time required to develop convulsions in the pregnant rat was significantly shorter (21 minutes) than that in the nonpregnant animal (33 minutes). However, once convulsive activity had developed, the time interval to achieve circulatory collapse was similar in both groups. Although the baseline plasma cholinesterase activity was higher in the pregnant rats than in the nonpregnant ones, the values in the samples obtained from the pregnant group at the onset of circulatory collapse were similar to the baseline values for the nonpregnant group. These findings suggest that a higher enzyme activity does not protect the development of toxic manifestations in the pregnant rat as compared to the nonpregnant animal when cocaine was administered at the same infusion rate.
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PMID:Pregnancy decreases the threshold for cocaine-induced convulsions in the rat. 824 93

To test our hypotheses that gender-related differences in cocaine toxicity exist in the rat, cocaine (2 mg/kg/min) was infused intravenously in chronically catheterized male and ovariectomized or intact female rats until the onset of circulatory collapse. Sequential manifestations of cocaine toxicity from mild central nervous stimulation to fatal cardiovascular collapse were observed. Arterial blood was withdrawn at the onset of the toxic signs or symptoms for determination of cocaine concentrations. Dosages and plasma concentrations of cocaine required to produce cardiovascular toxic manifestations were significantly lower in male and ovariectomized rats than in intact females. Plasma cholinesterase activity was lowest in the male animals and highest in intact females. These data suggest that systemic toxicity of cocaine is enhanced in male rats, because lower doses and plasma concentrations are required to induce toxic signs and symptoms.
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PMID:Gender-related differences in cocaine toxicity in the rat. 834 Jun 97

The data of long-standing research allowed to establish correlation between oxygen consumption different at various age and catecholamine (CA) content and acetylcholinesterase (AChE) activity in blood. Early postnatal age is characterised by adrenergic indexes of homeostasis manifesting in high CA content and AChE activity in blood and high quantities of consumed oxygen. After complete realisation of antigravitation reactions cholinergic indexes of homeostasis are revealed in the organism. They appear as essential decrease of AChE activity and CA content in blood and reduction of oxygen consumption. As a result negentropy tendencies of organism development increase and hence the adaptive and working capacities of the organism enhance. In the old age because of the decrease of skeletal musculature mass repeated and essential decrease of oxygen consumption takes place and it is due to the decrease of AChE activity in blood and the increase rather than decrease of CA content in blood. The organism converts to hypobiotic state with entropy tendencies of protracted and prolonged collapse.
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PMID:[A comparative ontogenic analysis of the correlative characteristics between oxygen consumption and the catecholamine level of the blood and its cholinesterase activity at different age periods]. 876 34

The neurotoxicity of organophosphorus (OP) compounds involves the inhibition of acetylcholinesterase (AChE), causing accumulation of acetylcholine (ACh) at synapses. However, cholinergic crisis may not be the sole mechanism of OP toxicity. Adverse drug reactions caused by synergistic toxicity between drugs with distinct pharmacological mechanisms are a common problem. Likewise, the multiple pharmacological activities of a single molecule might also contribute to either toxicity or efficacy. For example, certain OP compounds (e.g. soman) exhibit anti-AChE activity and also act as secretagogues by inducing mast cell degranulation with associated autacoid release and anaphylactoid reactions. Anaphylactoid shock can produce a lethal syndrome with symptoms of respiratory failure and circulatory collapse similar to the physiological sequelae observed for OP poisoning. Moreover, the major classes of drugs used as antidotes for OP intoxication can affect anaphylaxis. Acetylcholine can act as an agonist of autacoid release, and autacoids such as histamine can augment soman-induced bronchial spasm. In concert with the demonstrably critical role of cholinergic crisis in OP toxicity, the precepts of neuroimmunology indicate that secondary adverse reactions encompassing anaphylactoid reactions may complicate OP toxicity.
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PMID:Hypothesis for synergistic toxicity of organophosphorus poisoning-induced cholinergic crisis and anaphylactoid reactions. 882 72

This study was undertaken to investigate whether cholinesterase (ChE) inhibitor exerts cardiovascular collapse through non-cholinergic mechanism in halothane-anesthetized rabbits. Physostigmine and N-methylcarbamate insecticides (BPMC = 2-sec-butylphenyl methylcarbamate and PHC = propoxur = 2-isopropoxyphenyl methylcarbamate) were employed as ChE inhibitors. Intravenous injection of physostigmine produced a dose-related pressor response a few minutes after the injection. In contrast, the injection of BPMC elicited a dose-related depressor response during the injection. PHC produced a slight depressor response during the injection followed by a dose-dependent pressor response. Norepinephrine (NE)-induced pressor response was inhibited by the ChE inhibitors with the same order and magnitude as the depressor response. ECG of physostigmine or PHC was characterized by an increase in QRS voltage and a sinus bradycardia, and that of BPMC by a decrease in QRS voltage. Atropine pretreatment inhibited the pressor response, the increase in QRS voltage and the sinus bradycardia, but not the depressor response and the decrease in QRS voltage. From these observations, it is suggested that the pressor response is ascribed to the cholinergic mechanism (acetylcholine accumulation through ChE inhibition), but the depressor response may result from a non-cholinergic mechanism. It is also suggested that the difference in the cardiovascular response is determined by a balance between cholinergic and non-cholinergic activity of each ChE inhibitor.
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PMID:Cardiovascular collapse through non-cholinergic mechanism after intravenous injection of N-methylcarbamate insecticide in rabbits. 905 95


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