Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adult, male rats (300-325 g) were treated with pyridostigmine bromide (n = 22) or saline (n = 22) to quantitate the effects of cholinesterase inhibition (64%) on the ability to work (9.14 m/min, level treadmill) in the heat (35 degrees C). Pyridostigmine-treated rats had a mean endurance of 23 min, whereas saline-treated animals ran for nearly 35 min (P less than 0.001). Rates of rectal and skin temperature increments were significantly higher (P less than 0.001) in pyridostigmine-treated rats as were water losses (P less than 0.001). Exercise in the heat to hyperthermic exhaustion effected anticipated increments in circulating urea nitrogen, creatinine, lactate dehydrogenase, and potassium levels, whereas pyridostigmine pretreatment had additive effects on lactate and creatine kinase concentrations. Additionally, pyridostigmine elicited a significant (P less than 0.01) hyperglycemia before exercise, an effect noted also with other organophosphate simulants. We concluded that pyridostigmine-induced cholinesterase inhibition had a variety of debilitating effects during work in the heat.
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PMID:Effects of pyridostigmine on ability of rats to work in the heat. 672 66

A single sublethal i.p. dose of lithium chloride (300 mg/kg or 7.1 meq/kg) followed 12 h later by an otherwise sublethal s.c. dose of physostigmine sulfate (1.0 mg/kg) resulted in 90% mortality among male rats following a pronounced cholinergic syndrome, including convulsions. This confirms a previous report of a lethal synergism of physostigmine after subacute dosing with lithium. Mortality could be completely prevented by 1.0 mg/kg of atropine sulfate given 30 min before physostigmine, but was incompletely, if at all, reduced by selective peripheral cholinergic blockers, methylatropine bromide (0.5, 1.5 mg/kg) or glycopyrrolate (1 mg/kg). This suggested a predominantly central site for the toxic interaction. However, a similar synergism of lethality caused by neostigmine methylsulfate (0.3 mg/kg, s.c.) after treatment with lithium, which could be eliminated by methylatropine or glycopyrrolate, indicates that lithium may also produce lethal synergism of a cholinesterase (ChE) inhibitor that does not act centrally. Ro4-1284, an agent that has reserpine-like actions, was tested in combination with physostigmine or neostigmine; it showed synergism of toxicity nearly the same as in the case of lithium plus the cholinergic agents. These findings support the hypothesis that lithium causes the toxic synergism via a reduction of adrenergic activity, leading to an imbalance between adrenergic and cholinergic influences and a consequent failure to tolerate the effects of the ChE inhibitors. A potential hazard for the clinical use of physostigmine and neostigmine, concurrently with lithium or reserpine-like agents, it suggested.
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PMID:Synergism of the toxicity of physostigmine and neostigmine by lithium or by a reserpine-like agent (Ro4-1284). 690 65

Five differential inhibitors of plasma cholinesterase have been compared using benzoylcholine as substrate. None of the inhibitors (dibucaine, NaF, NaBr, NaCl, or pancuronium dibutyryloxy bromide) could be used singly to resolve all the variants. Better resolution was obtained when two inhibitors were used in conjunction. Clear differentiation of all six genotypes was obtained only with the combined use of pancuronium dibutyryloxy bromide and sodium fluoride. The limitations of some of the parameters are discussed.
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PMID:A comparison of some methods of phenotyping the plasma cholinesterase variants using benzoylcholine as substrate. 725 66

A steroid, the dibutyrate analogue of pancuronium bromide (9.8 X 10(-8)M), has been used as differential inhibitor in the study of the plasma cholinesterase variants. Pancuronium dibutyrate numbers have been measured for 190 individuals, and the mean values for six of the known genotypes, E1uE1u, E1uE1f, E1uE1a, E1fE1a, E1aE1a, and E1fE1f, have been calculated. Evidence is presented that a combination of the pancuronium dibutyrate number and the fluoride number give better resolution of the six genotypes than the combination of the pancuronium dibutyrate and the dibucaine number. This new differential inhibitor has real potential for revealing the probable existence of new genotypes.
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PMID:Differential inhibition of plasma cholinesterase variants using the dibutyrate analogue of pancuronium bromide. 728 15

Possible mechanisms of the ability of clonidine to correct bupivacaine-induced ventricular electrophysiologic impairment were evaluated in an electrophysiologic model on closed-chest dogs. Nine groups (n = 6) of pentobarbital-anesthetized dogs were given atropine, 0.2 mg/kg intravenously (i.v.), and bupivacaine, 4 mg/kg i.v., over a 10-s period. Group 1 was then given only saline solution. Group 2 was given clonidine, 0.01 mg/kg i.v., over a 1-min period. Group 3 was given clonidine followed by i.v. administration of yohimbine, 1 mg/kg, an alpha 2-antagonist. Group 4 was given carbachol, 1 mg/kg i.v., a long-lasting cholinergic agonist, over a 1-min period. Group 5 was given electrical stimulation of the left vagus nerve. Group 6 was given physostigmine, 0.1 mg/kg i.v., known to inhibit cholinesterase degradation, 5 min before bupivacaine administration, and Group 7 received a combination of physostigmine pretreatment and electrical vagal stimulation. Group 8 was given physostigmine, 0.1 mg/kg i.v., and pancuronium bromide, 1 mg/kg i.v., known to inhibit nicotinic receptors, 5 min before bupivacaine administration. Then electrical stimulation of the left vagus nerve was performed. Group 9 was given nicotine, 0.1 mg/kg i.v., 1 min after bupivacaine injection over 1 min. Bupivacaine induced bradycardia, markedly increased the His-Purkinje conduction time (HV interval) and QRS duration. Bupivacaine decreased the peak of first derivative of left ventricle pressure (LVdP/dtmax) and increased left ventricular end-diastolic pressure (LVEDP). Clonidine improved QRS duration and HV interval. Yohimbine did not modify the effects of clonidine. QRS duration and HV interval were significantly improved in Groups 4-7. In Group 8, pancuronium pretreatment inhibited the beneficial effects of the combination of physostigmine pretreatment and electrical vagal stimulation. In contrast, in Group 9, like clonidine, nicotine improved QRS duration and HV interval. Three other groups of anesthetized dogs (n = 6) were then studied. All dogs were given hexamethonium, 10 mg/kg i.v. Then, Group 10 was given only saline solution; Group 11 was given bupivacaine, 4 mg/kg, and Group 12 was given bupivacaine and nicotine as in Group 9. In Group 11, bupivacaine induced its usual alterations. In contrast, nicotine did not modify the cardiotoxic profile of bupivacaine after hexamethonium pretreatment. We conclude that the beneficial effect of clonidine on the variables of ventricular conduction altered by bupivacaine 1) is not mediated by central alpha 2-activation, 2) is mediated by the activation of parasympathetic pathways, and 3) is indirect and not mediated by acetylcholine release but is mediated by the activation of parasympathetic ganglionic nicotinic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Receptor mechanisms for clonidine reversal of bupivacaine-induced impairment of ventricular conduction in pentobarbital-anesthetized dogs. 790 46

Effects of a peripherally active carbamate (pyridostigmine bromide) and a centrally active organophosphate (OP) nerve agent (soman) on performance by rhesus monkeys of a compensatory tracking (primate equilibrium platform, or PEP) task were measured using a balanced Latin-square design to determine the ED50 for pyridostigmine (0.66 mg/kg) and the up-and-down (titration) method to determine the ED50 for soman (2.50 micrograms/kg). We concluded that the PEP performance model is a sensitive and reliable indicator of anticholinesterase (anti-ChE) behavioral toxicity. We also found that soman, an irreversible inhibitor of acetylcholinesterase (AChE), is more than 100 times more behaviorally disruptive than the reversible peripheral inhibitor pyridostigmine, as indicated by the difference in ED50 doses expressed in molar terms. Soman's behavioral toxicity is severe at levels of serum cholinesterase inhibition (70-80%) at which pyridostigmine does not significantly affect performance. As a prophylactic treatment for OP agent poisoning, pyridostigmine has a substantial safety factor, since behavioral toxicity becomes significant only at approximately four times the proposed therapeutic dose.
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PMID:Acute behavioral toxicity of pyridostigmine or soman in primates. 820 84

Seven men participated in a double-blind study of effects of multiple-dose oral pyridostigmine bromide (PB) on physiological responses to 4-h heat stress tests (HST's) in a hot dry environment, 42 degrees C, 20% relative humidity. Subjects underwent 2 7-d series of tests, separated by 72 h, taking 30 mg PB every 8 h in one series, and placebo in the other. Each HST began right after the 0800 dose of PB or placebo. Subjects drank ad libitum during each HST, and performed two 55-min treadmill walks at about 40% VO2max during the last 2 h. Inhibition of red cell cholinesterase at the start of exercise averaged 30.0% in subjects taking PB, and did not differ significantly among HST's with PB. PB increased sweating and evaporative water loss by about 4%, and lowered chest skin temperature during exercise by 0.7 degrees C; but it had no significant effect on rectal temperature, other skin temperatures, O2 uptake, or fluid balance. PB alone had no significant effect on heart rate (HR), but had a significant interaction with day: although PB had essentially no effect on HR in the 1st HST, its effect increased progressively so that HR during exercise in the 4th HST was 8 beats.min-1 lower with PB. Multiple-dose PB had only slight effects on responses to moderate exercise-heat stress beyond those described after single-dose PB, and we found no adverse effects of multiple-dose PB administration.
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PMID:Seven-day pyridostigmine administration and thermoregulation during rest and exercise in dry heat. 824 Jan 94

Xylazine induced sedation in mice was observed as a kind of inhibition of exploratory activity. The reversible cholinesterase inhibitor cui xing ning (0.25-1.0 m.kg-1), the precursor of acetylcholine, choline bromide (100-300 mg.kg-1), and the M-receptor agonist arecoline (1.0-5.0 mg.kg-1) were shown to significantly antagonize xylazine (5.0 mg.kg-1) induced sedation. While cui xing ning (0.25 mg.kg-1) shifted the dose-response curve of xylazine induced sedation to the right, hemicholinum-3 (3 micrograms icv), which inhibits the synthesis of acetylcholine, shifted the dose-response curve to the left. These results suggest that the xylazine induced sedation may be partly due to a reduced central cholinergic function. Cui xing ning may have some value in the treatment of xylazine overdose and antagonize the anesthesia induced by anesthetics combined with xylazine.
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PMID:[Antagonistic effects of cholinergic drugs on xylazine induced sedation]. 836 75

Cholinesterase activity is detectable in the Japanese quail embryo, in the yolk and subembryonic liquid, but not in the albumen. Obviously, this enzyme is deposited by the hen into the yolk and from there it is transferred to the subembryonic liquid. In contrast, in the embryo the enzyme is synthesized by itself and the amount increases with the age of the embryo. By using BW284c51 1,5-bis-(4-allyldimethylammoniumphenyl)pentan-3-one bromide and ISO-OMPA tetraisoprophylpyrophosphoramide as inhibitors, it was found that the enzyme in the embryo is predominantly acetylcholinesterase (EC 3.1.1.7), whereas that in the yolk and subembryonic liquid is butyrylcholinesterase (EC 3.1.1.8). Both types are inhibited by dichlorphos. However, the embryonic enzyme activity is restored within 8 hr, whereas that in the subembryonic liquid remained inactive at least for 72 hr after inhibition. Enzyme inhibition leads to retardation of the development, to reduced accumulation of glucose and amino acids in the subembryonic liquid and finally to death of the embryo, suggesting that the developmental retardation is due to the restricted supply of glucose and amino acids. Surprisingly, most of the embryos die when the embryonic enzyme activity has again been restored.
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PMID:Activity of cholinesterases in the Japanese quail embryo. Effects of dichlorphos on the embryonic development. 842 27

3-Carbamyl-N-allylquinuclidinium bromide (CAB) was synthesized and evaluated for its pharmacological effects on cholinergic activity and for protection in vivo against soman toxicity in guinea pigs. This carbamylated derivative of N-allyl-3-quinuclidinol (NAQ), a potent inhibitor of high-affinity choline uptake, demonstrated stereospecific alterations of cholinergic function as well as protection against soman. The R-isomer, but not the S-isomer, of CAB inhibited erythrocyte acetylcholinesterase (AChE) and plasma pseudocholinesterase (pChE) in a concentration-response manner (IC50 = 25 and 29 microM, respectively). The R-isomer of CAB was also a more potent inhibitor of high-affinity choline uptake (IC50 = 4.8 microM) than S-CAB (IC50 = 63 microM). When R-CAB (10 mumol/kg, i.m.) was administered to guinea pigs 30 min prior to soman in conjunction with atropine (16 mg/kg, i.m.) given 1 min post-soman, the compound significantly reduced lethality up to 5 LD50S. This represents enhanced protection when compared to NAQ (up to 100 mumol/kg); the S-isomer of CAB failed to protect against soman intoxication. The results demonstrate that reversible inhibition of AChE with suppression of acetylcholine synthesis into a single compound, CAB, enhances the protection against organophosphates.
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PMID:3-Carbamyl-N-allylquinuclidinium bromide. Effects on cholinergic activity and protection against soman. 843 96


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