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:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enzymatic hydrolysis of acetylcholine (ACh) was determined in intact frog sartorius muscles or their homogenates. The Vmax was 29 nmol min-1 in intact muscles and 46 nmol min-1 per muscle in homogenates, and the Km was 6 and 0.2 mM, respectively. The muscle was divided into small segments, which were homogenized; the junctional cholinesterase (ChE) accounted for 60% of total enzyme activity. At low substrate concentrations the rate of hydrolysis was up to 30 times higher in homogenates than in intact muscles. This difference was greatly reduced at very high substrate concentrations. It appears that most of the ChE in intact muscle is 'occluded' to external ACh, mainly because the ChE at the edges of the synaptic cleft prevents the ACh from reaching the enzyme situated further inwards, which consequently does not contribute to its hydrolysis; homogenization makes all synaptic ChE accessible to added ACh. Incubation of sartorius muscles with collagenase caused an 80% decrease in ChE activity (determined in homogenates) of end-plate-containing parts which became similar to that in end-plate-free parts on which collagenase had little effect. Histochemistry showed that the tendon-muscle junction contained folds which were stained intensively for ChE. Diethyldimethylpyrophosphonate , neostigmine, eserine, and di-isopropyl fluorophosphonate inhibited ChE activity in this order of potency. The I50 values (i.e. the concentrations of the drugs which caused a 50% inhibition) were about 5 times higher in intact than in homogenized tissue. Neostigmine, 0.15 and 0.4 microM, increased the time constant of miniature end-plate currents 1.3- and 1.8-fold, and slowed down ChE activity of muscle homogenates by 1.4 and 2.1 times, respectively, without significantly affecting ACh hydrolysis by intact muscles. This indicates that synaptic ChE is not present in large excess. It is concluded that ChE activity measured in homogenates presents a better picture of in situ ChE activity than that measured in whole muscles especially for evaluating the effect of ChE inhibitors. A mathematical model for ChE-hindered diffusion of ACh is presented in an Appendix.
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PMID:Acetylcholinesterase activity in intact and homogenized skeletal muscle of the frog. 661 Jul 44

Cerebral blood flow (CBF) was estimated from measurements of internal carotid blood flow and sagittal sinus blood flow in mechanically ventilated rabbits under 70% N2O-30% O2. Intravenously administered physostigmine, a cholinesterase inhibitor, increased CBF under normocapnia and enhanced the cerebral vasodilatation of hypercapnia, but did not alter the cerebral metabolic rate of oxygen (CMRO2). The cerebrovascular effects of physostigmine were antagonized by atropine but not by dihydro-beta-erythroidine, a nicotinic blocker. Neostigmine, a quaternary cholinesterase inhibitor that does not cross the blood-brain barrier, showed no cerebrovascular effects. It is concluded that the cholinergic cerebral vasodilatation does not depend on cerebral metabolic activation, and that the cholinergic receptors involved are muscarinic and located beyond the blood-brain barrier.
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PMID:Cholinergic cerebral vasodilatation in the rabbit: absence of concomitant metabolic activation. 680 71

1 The effects of antimuscarinic agents alone and in the presence of neostigmine on the contractile responses to exogenously applied cholinomimetics or (-)-noradrenaline were studied in the rat anococcygeus muscle.2 Atropine (1 x 10(-9) -1 x 10(-6)M) alone, in the presence of hexamethonium (1 x 10(-4)M), or phentolamine (1 x 10(-6)M), inhibited responses to acetylcholine but not to (-)-noradrenaline. The inhibitory effect with the higher concentrations of atropine (1 x 10(-8) - x 10(-6)M), was seen as an increase in the slopes of the concentration-response curves. Atropine (1 x 10(-8)M) alone inhibited the responses to methacholine and carbachol without altering the slopes of the concentration-response curves.3 Homatropine (1 x 10(-6)M) alone had no effect on responses to (-)-noradrenaline and inhibited responses to acetylcholine and methacholine. The inhibitory effect on responses to acetylcholine but not to methacholine, included an increase in the slopes of the concentration-response curves.4 Neostigmine (1 x 10(-6)M) alone had no effect on responses to (-)-noradrenaline and potentiated responses to acetylcholine and methacholine. The potentiating effect included an increase in the slopes of the concentration-response curves.5 In the presence of neostigmine (1 x 10(-6)M), atropine (1 x 10(-9)M - 1 x 10(-6)M) caused a parallel concentration-dependent shift of the concentration-response curves to acetylcholine. The pA(2) values, in the presence of neostigmine, were independent of the concentration of atropine and of the agonist (acetylcholine, methacholine, or carbachol) used. In the presence of neostigmine (1 x 10(-6)M), homatropine (1 x 10(-6)M) also failed to alter the slopes of the concentration-response curves to acetylcholine and was approximately 100 times less potent than atropine as an antimuscarinic agent.6 These results illustrate that, in the rat anococcygeus muscle, it is necessary to inhibit acetylcholinesterase before determining the relative potencies of antagonists at muscarinic receptors.
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PMID:Effect of antimuscarinic agents on the contractile responses to cholinomimetics in the rat anococcygeus muscle. 689 42

Excitatory postsynaptic currents (EPSCs) have been studied in voltage-clamped bullfrog sympathetic ganglion B cells. The EPSC was small, rose to a peak within 1-3 ms, and then decayed exponentially over most of its time-course. For 36 cells at --50 mV (21-23 degrees C), peak EPSC size was --6.5 +/- 3.5 nA (mean +/- SD), and the mean decay time constant tau was 5.3 +/- 0.9 ms. tau showed a small negative voltage dependence, which appeared independent of temperature, over the range --90 to --30 mV; the coefficient of voltage dependence was --0.0039 +/-0.0014 mV-1 (n = 29). The peak current-voltage relationship was linear between --120 and --30 mV but often deviated from linearity at more positive potentials. The reversal potential determined by interpolation was approximately --5 mV. EPSC decay tau had a Q10 = 3. The commonly used cholinesterase inhibitors, neostigmine and physostigmine, exhibited complex actions at the ganglia. Neostigmine (1 X 10(-5)M) produced a time-dependent slowing of EPSC decay without consistent change in EPSC size. In addition, the decay phase often deviated from a single exponential function, although it retained its negative voltage dependence. With 1 x 10(-6) M physostigmine, EPSC decay was slowed by the decay phase remained exponential. At higher concentrations of physostigmine, EPSC decay was markedly prolonged and was composed of at least two decay components. High concentrations of atropine (10(-5) to 10(-4) M) produced complex alterations in EPSC decay, creating two or more exponential components; one decay component was faster and the other was slower than that observed in untreated cells. These results suggest that the time-course of ganglionic EPSC decay is primarily determined by the kinetics of the receptor-channel complex rather than hydrolysis or diffusion of transmitter away from the postsynaptic receptors.
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PMID:Voltage clamp study of fast excitatory synaptic currents in bullfrog sympathetic ganglion cells. 696 7

Bilateral occlusion of the common carotid arteries of urethane-anesthetized rats evoked a pressor response of 14 +/- 1 mm Hg. Injection into the lateral cerebral ventricle of neostigmine (0.2-1.0 microgram) or physostigmine (10-15 microgram) caused a dose-dependent increase in basal blood pressure and in the magnitude of the carotid artery occlusion (CAO) pressor reflex. Neostigmine (1 microgram) and physostigmine (15 microgram) caused nearly maximal and approximately equal degrees of cholinesterase inhibition in several brain regions. The recovery of the cardiovascular parameters and of brain cholinesterase activity was significantly faster following physostigmine compared to neostigmine. Prior intracerebroventricular injection of atropine (0.3 microgram) or hemicholinium-3 (20 microgram) prevented the increases in basal pressure and the CAO pressor response. Potentiation of the CAO reflex also followed injection of physostigmine or neostigmine into the posterior hypothalamic nucleus and of injection of physostigmine intravenously. Injection of atropine bilaterally into ther posterior hypothalamic nucleus prior to intravenous injection of physostigmine prevented the potentiation of the CAO reflex but not the increase in basal blood pressure. These results indicate that acetylcholine in the posterior hypothalamic nucleus serves as a neurotransmitter in a pathway which can potentiate the pressor response to carotid artery occlusion and thus modulate baroreceptor reflexes.
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PMID:Potentiation of the carotid artery occlusion reflex by a cholinergic system in the posterior hypothalamic nucleus. 707 Feb 15

1. Two fractions of aryl acylamidase (EC 3.5.1.13) were further separated from rat brain extracts at pH 7.5 by ammonium sulfate precipitation and Bio-Gel chromatography. 2. 1,2,3,4-Tetrahydro-beta-carboline competitively inhibited (67%) fraction-1 but slightly inhibited (13%) fraction-2. Tetrahydroharman, 6-hydroxy-tetrahydroharman and harminic acid slightly inhibited both fractions. Harmalol inhibited fraction-1 but enhanced fraction-2. 6-Methoxy-harman, 6-methoxy-harmalan and harmaline enhanced both fractions. 3. Pargyline did not affect either fraction. Methiothepin, cyproheptadine and chlorimipramine inhibited fraction-1 but stimulated fraction-2. 4. Neostigmine moderately (30%) inhibited AAA-2 but did not have any significant effect on AAA-1. 5. These results indicate that the beta-carboline compounds might play a role in regulating activity of AAA-1 and 2 in brain. 6. Both fractions might be related to serotonergic neurons but only AAA-2 might be associated with acetylcholinesterase.
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PMID:Rat brain aryl acylamidase: further characterization of multiple forms. 710 57

1 Physostigmine (0.1-1 mM) induced dose-dependent negative and neostigmine (0.1-1 mM) positive inotropic effects on driven guinea-pig isolated atria. Physostigmine decreased and neostigmine increased cardiac frequency of spontaneously beating atria. 2 The depression of amplitude of contraction by physostigmine cannot be attributed to its inhibitory effect on tissue cholinesterase. The negative inotropic action of physostigmine is not influenced by preincubation with atropine. 3 The positive inotropic effect of neostigmine is not caused by a nicotine-like action of the drug. Neostigmine (1 mM) counteracts the negative inotropic effect of acetylcholine. The possible mechanisms of action are discussed.
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PMID:The inotropic and chronotropic effects of physostigmine and neostigmine on guinea-pig isolated atria. 711 61

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) propulsion in rats. KW-5092 at 1 to 30 mg/kg, p.o. dose-dependently enhanced the gastric emptying, small intestinal propulsion and the proximal and distal colonic propulsion. Metoclopramide, a dopamine D2-receptor antagonist with ACh release facilitatory activity, dose-dependently enhanced the gastric emptying at 0.03 to 1 mg/kg, p.o., whereas this drug did not affect the small intestinal propulsion, or the proximal and distal colonic propulsion. Neostigmine, an AChE inhibitor, dose-dependently enhanced the small intestinal propulsion and the proximal and the distal colonic propulsion at 0.3 to 10 mg/kg, p.o., whereas it delayed the gastric emptying at 10 mg/kg, p.o. The present results demonstrate that KW-5092 enhances the GI propulsion from the stomach to the colon and that metoclopramide or neostigmine enhances only the upper or the lower GI propulsion, respectively. Thus, KW-5092 may be a gastroprokinetic drug of a novel type for the treatment of GI motility dysfunctions in a wide range from the stomach to the colon.
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PMID:Stimulating effects of KW-5092, a novel gastroprokinetic agent, on the gastric emptying, small intestinal propulsion and colonic propulsion in rats. 774 44

Serum adrenocorticotropic hormone (ACTH) and growth hormone (GH) concentrations were assessed simultaneously with hypothalamic neuronal activities of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) 60 min after the third cerebroventricular administration of neostigmine (a cholinesterase inhibitor) in awake rats. Serum ACTH and GH concentrations were significantly increased and decreased, respectively. Neostigmine caused significant increases in hypothalamic NE and DA activities and a significant decrease in hypothalamic 5-HT activity. The reciprocal changes of serum ACTH and GH concentrations were similar to those of hypothalamic NE and 5-HT activities. Multiple regression analyses with stepwise procedure revealed that hypothalamic NE and 5-HT activities were respectively significant determinants of serum ACTH and GH concentrations. Apart from the direct influence of neostigmine on ACTH and GH secretions, it is suggested that the changes in hypothalamic monoaminergic activities play an important role in modulating ACTH and GH secretions following the administration of neostigmine.
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PMID:Adrenocorticotropin and growth hormone secretions after intracerebroventricular administration of neostigmine in rats: their relationships to hypothalamic monoaminergic neuronal activities. 782 Jun 71

This study evaluated the effect of stimulating the central nervous system (CNS) with neostigmine, an inhibitor of acetylcholinesterase, on the blood lactate concentration in fed rats and in rats fasted for 48 hours. After the rat was anesthetized with pentobarbital, neostigmine was stereotaxically injected into the third cerebral ventricle. In fed rats, the central injection of neostigmine significantly increased the blood lactate level, while concomitantly increasing plasma glucagon, epinephrine and norepinephrine concentrations. Constant infusion of somatostatin throughout the experiments, to inhibit glucagon secretion from the pancreas, did not affect alterations in blood lactate by central injection of neostigmine. In adreno-medullated rats, CNS-stimulation by neostigmine still increased plasma norepinephrine significantly, however, the alteration in blood lactate was only one-third of that in intact rats. Intraperitoneal propranolol, but not phentolamine, prevented the rise in lactate. Neostigmine increased lactate in fasted rats as well as in fed rats. We conclude that in anesthetized rats, stimulation of the CNS by neostigmine increases blood lactate mainly through circulating epinephrine and partially through circulating norepinephrine or direct sympathetic nervous stimulation; glucagon does not appear to be involved in the increase in blood lactate.
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PMID:CNS regulation of blood lactate concentration in anesthetized rats. 791 Jun 51


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