Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms by which the epithelium affects reactivity of guinea pig trachealis to agonists were examined using the isolated, perfused trachea preparation. Contractile agonists (acetylcholine, methacholine, carbachol or histamine) were more potent when applied to the serosal (extraluminal, EL) surface compared to the mucosal (intraluminal, IL) surface, and the IL maximum responses to these agents were smaller. In epithelium-denuded tracheae, IL reactivity to the agonists was increased to the EL level. Physostigmine (10(-7) M) increased the EL and IL potency of acetylcholine to that of carbachol (+/- epithelium), and elevated the IL acetylcholine maximum response (+ epithelium); the relative role of epithelial acetylcholinesterase could not be defined. Indomethacin (3 x 10(-6) M) increased, in an epithelium-dependent manner, the IL acetylcholine, carbachol and histamine maximum responses to the EL level. Phentolamine plus propranolol (both 10(-6) M) potentiated the IL maximum response to methacholine, Isoproterenol also was more potent extraluminally than intraluminally, and the EL and IL maximum responses were similar. IL isoproterenol reactivity was elevated to the EL level in rubbed tracheae. Corticosterone (5 x 10(-5) M) potentiated EL and IL responses to isoproterenol (+/- epithelium); the relative role of epithelial extraneuronal uptake could not be delineated. The epithelium reduces reactivity to mucosally applied drugs by acting as a diffusion barrier. In addition, responses to mucosally administered contractile agonists are inhibited by a physiological antagonism caused by modulatory prostanoids, catecholamines and, possibly, epithelium-derived relaxing factor.
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PMID:Influence of epithelium on the reactivity of guinea pig isolated, perfused trachea to bronchoactive drugs. 150 Nov 19

The vascular effects of fasciculin and physostigmine, two acetylcholinesterase inhibitors, were studied with radioactively labelled microspheres in the rabbit eye. In addition, the effects on the intraocular pressure, pupil size and the aqueous humor protein concentration were determined. Both drugs were injected intracamerally in pentobarbital anesthetized and indomethacin pretreated animals. Fasciculin injected in a dose of 0.5 micrograms (0.7 x 10(-10)M) reduced blood flow in the anterior uvea as determined 30 and 60 min after injection. Higher doses had inconsistent effects. Physostigmine injected in a dose of 3 micrograms (1.1 x 10(-8)M) also reduced blood flow in the anterior uvea. The effect was most pronounced in the iris. Neither drug had any appreciable effect on choroidal or retinal blood flow. Both drugs caused pupillary constriction but the reduction in blood flow was not secondary to miosis. The effects on the intraocular pressure and aqueous humor protein concentration were inconsistent. The reduction in blood flow of the anterior uvea after intracameral injection of acetylcholinesterase inhibitors is consistent with a cholinergic vasoconstriction previously described in the eye during electrical stimulation of the oculomotor nerve.
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PMID:Vascular effects of acetylcholinesterase inhibitors in the rabbit eye: a study with fasciculin and physostigmine. 150 54

Physostigmine (PHYSO), in doses as low as 0.003 mg/kg IP, antagonized scopolamine (SCOP, 3 mg/kg) induced amnesia of step-through passive avoidance in mice. The peripherally acting acetylcholinesterase (AChE) inhibitor neostigmine (NEO) was also found to reliably, though less strongly, antagonize the SCOP induced amnesia at a dose of 0.03 mg/kg. The NEO antagonism of the SCOP amnesia could be reversed with SCOP (0.3, 1, and 3 mg/kg) and mecamylamine (MECA, 1, 3, and 10 mg/kg), muscarinic and nicotinic antagonists, respectively, which are active both peripherally and centrally, as well as with M-SCOP (0.3 and 1 mg/kg) and hexamethonium (HEX, 1 and 3 mg/kg), muscarinic and nicotinic antagonists, respectively, which are active only in the periphery. In contrast to the ability of these four compounds to attenuate the SCOP amnesia, only the centrally acting compounds SCOP (3 mg/kg) and MECA (10 mg/kg) induced an amnesia when administered alone. These findings suggest that the induction of amnesia of passive avoidance involves central cholinergic systems, whereas the NEO, and possibly PHYSO, reversal of the SCOP induced amnesia is mediated peripherally by both muscarinic and nicotinic receptors. It is hypothesized that the release of adrenal catecholamines, the influence of which on memory processes is well known, and secondarily glucose, may be responsible for the NEO antagonism of the SCOP amnesia.
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PMID:Memory modulation with peripherally acting cholinergic drugs. 157 Mar 86

Physostigmine was originally isolated from the Calabar Bean, which was used for ordeal by poison in West Africa. The main alkaloid was isolated in 1864. It acts through inhibition of acetylcholinesterase, and has been of major importance in elucidating the kinetics and configuration of the enzyme. Physostigmine has been important for our understanding of neurohumoral chemical transmission, and in mapping the cholinergic nerves. It was the first antagonist to curare, and has been widely used for various therapeutic purposes. Today it has been largely replaced by more efficient and safe drugs. It is still used as an antidote to poisoning from various psychopharmacological drugs, and to treat postoperative somnolence and respiratory depression. It is considered a potent antidote to organophosphorous poisoning and is used experimentally to treat Alzheimer's disease.
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PMID:[Development of physostigmine from a poisonous plant to an antidote. One of the most important drugs in the development of modern medicine?]. 157 14

Inhibition of acetylcholinesterase (AChE) activity by physostigmine (PHY) is reversible due to spontaneous decarbamylation. Physostigmine has been shown to be effective as a pretreatment against potent anticholinesterase poisons (e.g., soman) in experimental animals, yet it is short acting and causes undesirable side effects in mammals. The two-fold purpose of this study was 1) to determine whether extension of the N-substituted alkyl chain (N-SAC) of PHY from N-methyl to N-ethyl (I), N-propyl (II), N-isopropyl (III), N-butyl (IV) or N-heptyl (V) affects anti-AChE potency and spontaneous decarbamylation of inhibited AChE of guinea pig blood in vitro and in vivo, and 2) to see whether chain extension affects efficacy as pretreatment in poisoning by soman. The in vitro AChE inhibition studies were done using whole blood incubated at 37 degrees C for 30 min. All 5 homologs possessed anti-AChE activity with I50s ranging from 1.1 to 27.6 x 10(-7)M; compound III was the least potent in vitro and in vivo. Lengthening of the N-SAC of PHY markedly extended the duration of anti-AChE activity when compared to PHY, but rendered the modified compounds ineffective as pretreatments against soman. These data support the premise that the decrease in decarbamylation rates observed upon extending the N-SAC of PHY is responsible for the loss of effectiveness of pretreatment regimens against soman. Perhaps, these homologs of PHY may have potential use in instances where sustained action of acetylcholine is required at cholinergic junctions because of disease conditions or drug overdosage.
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PMID:Acetylcholinesterase inhibition and anti-soman efficacy of homologs of physostigmine. 159 27

Physostigmine and other centrally-acting acetylcholinesterase inhibitors are currently being examined for their potential in the treatment of Alzheimer's Disease. The ability to employ this class of agents is limited by the potential for debilitating and dangerous side effects. Clonidine and related drugs have recently been demonstrated to enhance memory performance in monkeys. Clonidine also inhibits the function of cholinergic neurons in specific brain regions and reduces certain side effects of physostigmine. Seven adult macaque monkeys performing a delayed matching-to-sample (DMTS) task received regimens of increasing doses of clonidine and physostigmine on separate occasions to determine the 'best dose' of each agent in terms of enhanced memory performance. The best doses were combined as a single administration and performance compared to that using the two drugs alone. The combination regimen of clonidine and physostigmine was more effective than either drug alone in enhancing memory performance. Part of the benefit may have been due to the ability to employ significantly higher doses of physostigmine in the combination regimen. A single injection of the combination resulted in enhanced performance both on the day of administration as well as on the following day. These results are consistent with the ability of clonidine to limit the expression or intensity of certain physostigmine-induced autonomic side effects, while allowing the cognitive beneficial effects of the cholinesterase inhibitor.
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PMID:Effects of concomitant cholinergic and adrenergic stimulation on learning and memory performance by primates. 161 76

1. Homogenates of tissues from females of the nematode Heterodera glycines were clarified by centrifugation and used to initiate characterization of soluble esterases using p-nitrophenyl acetate as the substrate. 2. Optimum temperature and pH were 40 degrees C and 7.2 respectively. 3. Acetazolamide (a carbonic anhydrase inhibitor) at 10(-3) M did not inhibit enzyme activity, indicating that carbonic anhydrase was not present. 4. Phenamiphos (an organophosphate) at 10(-6) M reduced activity by 38%, whereas eserine hemisulfate (a cholinesterase inhibitor) and aldicarb (a carbamate) were not inhibitory at that concentration, indicating that there was no cholinesterase activity. 5. Eserine hemisulfate, aldicarb, and phenamiphos inhibited enzyme activity by 50% (I50) at 5 x 10(-3) M, 7.5 x 10(-4) M, and 6 x 10(-6) M, respectively. 6. Approximately 25% of the activity detected appeared due to A- and/or C-esterases. 7. The data demonstrated that aldicarb and phenamiphos were active against esterases other than acetylcholinesterase.
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PMID:Partial characterization of soluble esterase from Heterodera glycines and inhibition by aldicarb and phenamiphos. 168 31

The effect of physostigmine, a cholinesterase inhibitor, on the loss of consciousness induced by three different intravenous induction anesthetics, namely midazolam, etomidate and althesin at ED50, was studied in three comparable groups of patients. Ten min before induction, the first and second groups received physostigmine 8 micrograms/kg and 16 micrograms/kg, respectively, and the third group received 2 ml of saline solution. Physostigmine 16 micrograms/kg resulted in a significant decrease in the percentage of unconscious patients with midazolam (from 50% to 10%), but it did not modify the incidence with etomidate or althesin. Physostigmine at doses of 8 micrograms/kg and 16 micrograms/kg could cause 6.7% and 10% nausea, respectively. Although the mechanism of the drug interaction of physostigmine and midazolam is unclear, physostigmine could be used clinically to reverse post-anesthetic somnolence induced by midazolam.
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PMID:Effect of physostigmine on the loss of consciousness induced by midazolam, etomidate and althesin. 175 60

Physostigmine, an acetyl cholinesterase inhibitor, and arecoline, a muscarinic agonist, have been shown to improve Alzheimer presenile dementia in some patients when administered parenterally. Both of these compounds are ineffective orally due to first-pass metabolism. The nasal route was examined as an alternative route of administration for both drugs. Nasal bioavailabilities and dispositions for both drugs were determined in rats. Physostigmine nasal bioavailability was 100% as compared with iv bioavailability, and that of arecoline was 85% when compared with bioavailability following im administration.
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PMID:Intranasal absorption of physostigmine and arecoline. 179 34

To determine the roles of oxidants in airway responsiveness, we studied the effects of the chemical oxidant N-chlorosuccinimide (NCS) on the contractile responses to electrical field stimulation (EFS) and acetylcholine (ACh) in isolated rat tracheal smooth muscle segments. Effects of NCS on the contractile response to EFS (5 Hz, 20 sec of duration, 50 V) reached the maximum with a 60-min incubation time. NCS potentiated the contractile response to EFS, with a maximum effect at 3 x 10(-7) M and to ACh, with a maximum effect at 3 x 10(-6) M. Thus, at a concentration of 3 x 10(-6) M, NCS significantly decreased log ED50 concentration of ACh from a control value of -5.56 +/- 0.05 to -6.24 +/- 0.06. Physostigmine (10(-7) M), at a concentration that did not alter resting tension, mimicked NCS-induced effects on contractile responses to ACh and EFS with the greater degree of shift in the respective dose-response curves. However, NCS failed to alter dose-response curves to carbachol. Removal of the epithelium shifted the dose-response curves to ACh to lower concentrations, but NCS showed similar effects on dose-response curves to ACh with and without the epithelium. Active staining showed that both acetylcholinesterase (EC 3.1.1.7) and butyrylcholinesterase (EC 3.1.1.8) activities were found in the smooth muscle of the rat trachea. NCS inhibited both enzyme activities from rat tracheal homogenates in a concentration-dependent fashion. These results suggest that NCS potentiates cholinergically induced contraction by decreasing cholinesterase activity and that the oxidation of cholinesterase may cause hyperresponsiveness of airway smooth muscle by inhibition of the enzyme activity.
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PMID:Chemical oxidant potentiates electrically and acetylcholine-induced contraction in rat trachea: possible involvement of cholinesterase inhibition. 192 Jan 23


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