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)

The present study examined the role of spinal cholinergic modulation of spinal mechanical and thermal transmission. Intrathecal administration of the cholinergic muscarinic receptor antagonists atropine or scopolamine in awake rats produced a dose-dependent decrease in the nociceptive mechanical withdrawal threshold of the rat tail. Pirenzepine, a selective muscarinic receptor type 1 antagonist, produced a similar effect at greater doses while mecamylamine, a nicotinic receptor antagonist, was without effect. The nociceptive tail flick (TF) reflex evoked by noxious heating was unaffected by the above drugs. Intrathecal administration of the cholinesterase inhibitor physostigmine produced a rapid, reversible and significant increase in the mechanical withdrawal threshold; TF latency was increased slightly but not significantly. Intrathecal administration of morphine, carbachol or clonidine all produced dose-dependent increases in TF latency; morphine and carbachol, but not clonidine, also increased the mechanical withdrawal threshold significantly. Intrathecal pretreatment with atropine reversed carbachol-produced increases in TF latency and the mechanical withdrawal threshold but did not affect increases in TF latency produced by intrathecal morphine or clonidine. The morphine-produced increase in the mechanical withdrawal threshold, however, was shifted rightward in a parallel fashion by intrathecal pretreatment with atropine. Intrathecal pretreatment with yohimbine did not affect the inhibitory effect of carbachol on either TF latency or the mechanical withdrawal threshold. These results suggest that a tonic, endogenous cholinergic muscarinic influence in the spinal cord, independent of spinal adrenergic mechanisms, modulates spinal mechanical transmission.
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PMID:Tonic cholinergic inhibition of spinal mechanical transmission. 166 Oct

An impairment of cholinergic and somatostatinergic neurotransmission have been reported in dementia. Both acetylcholine and somatostatin are involved in the regulation of growth hormone (GH) secretion. The effects of GH-releasing hormone (GHRH) 1-44 on GH release have been studied before and after the pretreatment with pyridostigmine or pirenzepine in subjects with senile dementia of the Alzheimer type, multi-infarct dementia and mixed dementia. The data have been compared with those obtained in an age-matched healthy control group. The GH response to GHRH is similar in the patients and in the controls, though the peak occurrence is significantly delayed in dementia. The cholinesterase inhibitor pyridostigmine enhances significantly the GH response to GHRH in both groups. The responses obtained in demented subjects are significantly larger than those found in the controls. Pirenzepine, a muscarinic receptor blocker, inhibits the GHRH effect on GH secretion in both groups. The findings may be interpreted in terms of an underlying impairment of the hypothalamic cholinergic neurotransmission, with an acetylcholine receptor supersensitivity that becomes apparent when the cholinergic tonus is enhanced by the inhibition of cholinesterase by pyridostigmine. No significant differences, due to the type of dementia, have been observed.
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PMID:Cholinergic modulation of growth hormone-releasing hormone effects on growth hormone secretion in dementia. 198 29

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

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

Radioimmunoassay for acetylcholine (ACh) with a sensitivity of 10 pg/tube was applied to the direct determination of ACh output from the nerve endings in longitudinal muscle strips of guinea pig ileum. The strips were preincubated with an irreversible cholinesterase inhibitor and superfused with Krebs' solution under various experimental conditions. Pirenzepine (0.1-10 microM) and atropine (10-100 nM) produced an increase in electrically evoked ACh output through the inhibition of presynaptic muscarinic receptors. Contractile response to endogenous ACh released by electrical stimulation was enhanced by pirenzepine and atropine at lower concentrations, whereas the highest concentrations of pirenzepine (10 microM) and atropine (100 nM) caused a reduction in the enhanced contractile response and a significantly diminished response, respectively. These results demonstrate that the concentrations of pirenzepine and atropine, effective in inhibiting presynaptic muscarinic receptors, differ from those inhibiting postsynaptic muscarinic receptors and suggest the possibility that presynaptic M1 muscarinic receptors regulating ACh output may be present in the guinea pig ileum.
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PMID:Direct determination of acetylcholine release by radioimmunoassay and presence of presynaptic M1 muscarinic receptors in guinea pig ileum. 325 21

Pirenzepine, a muscarinic antagonist probably acting via stimulation of hypothalamic somatostatin release, abolishes the growth hormone releasing hormone (GHRH)-stimulated growth hormone (GH) rise in normal subjects but only blunts it in patients with anorexia nervosa (AN). This finding suggested the existence in AN of an alteration of cholinergic system and/or somatostatinergic tone. To further investigate these mechanisms, in 11 AN women patients (age 18.8 +/- 0.9 years; BMI 13.4 +/- 0.4) we studied the GH response alone (1 microgram/Kg IV as a bolus at 0 min) and combined with pyridostigmine (PD, 120 mg orally, 60 min before GHRH administration), a cholinesterase inhibitor, or arginine (ARG 30 g infused over 30 min starting at 0 min), two compounds probably acting via inhibition of hypothalamic somatostatin (SS) release. The GH response to GHRH preceded by a previous (120 min before) neurohormone administration also was studied. All these tests also were performed in 20 normal age-matched women (age 22.0 +/- 1.8 yrs; BMI20.1 +/- 2.4). Basal serum GH levels were higher in AN patients than in normal volunteers (NV) (10.3 +/- 3.4 versus 2.8 +/- 0.3 microgram/L; p < 0.001), whereas plasma IGF-I levels were lower in AN patients than in NV (43.3 +/- 10.6 versus 172.4 +/- 13.9 micrograms/L; p < 0.00001). In AN patients, GHRH administration induced a GH rise higher, though not significantly, than that in NV [delta area under the curve (AUC) 1173.6 +/- 167.6 versus 834.6 +/- 188.1 micrograms/L/h]. The GH response to the second of two consecutive GHRH boluses was lower (p < 0.01) than that of the first one either in AN patients or in NV (67.6 +/- 27.4 and 53.1 +/- 25.7 micrograms/L/h, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Arginine but not pyridostigmine, a cholinesterase inhibitor, enhances the GHRH-induced GH rise in patients with anorexia nervosa. 788 Sep 38

1. The present study was designed to examine the effects of intracerebroventricular injection of several cholinergic drugs on the impairment of spontaneous alternation performance induced by the M1-selective muscarinic receptor antagonist pirenzepine. 2. Pirenzepine (3 and 10 micrograms) significantly reduced spontaneous alteration performance related to working memory without producing any marked increase in total arm entries, which are considered to reflect locomotor activity. 3. Physostigmine (3.47 micrograms), a cholinesterase inhibitor, and McN-A-343 (20 micrograms), and M1-selective muscarinic receptor agonist, significantly improved the pirenzepine (3 micrograms)-induced impairment of spontaneous alternation performance, although oxotremorine (0.68 microgram), a nonselective muscarinic receptor agonist, showed a tendency to reverse the pirenzepine (3 micrograms)-induced impairment. 4. These findings suggest that the blockade of muscarinic M1 but not M2 receptors results in the impairment of spontaneous alternation performance associated with working memory.
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PMID:Cholinergic receptor agonists inhibit pirenzepine-induced dysfunction of spontaneous alternation performance in the mouse. 869 Feb 40

The cataleptogenic effects of haloperidol, a dopamine D2 receptor antagonist; SCH23390, a D1 receptor antagonist; physostigmine, a cholinesterase inhibitor; and pilocarpine, a muscarinic M1 receptor agonist, were challenged by pretreatment of mice with SKF38393, a dopamine D1 receptor agonist; apomorphine, a dopamine D1/D2 receptor agonist (mainly D2 receptor); pirenzepine, a muscarinic M1 receptor antagonist; and scopolamine, a muscarinic M1/M2 receptor antagonist. The effect of physostigmine and pilocarpine on haloperidol and SCH23390 cataleptic responses was also examined. Each of the challenging agents blocked one or more of the cataleptogenic agents, but only scopolamine blocked all four. Pirenzepine blocked cataleptic responses induced by SCH23390 and pilocarpine, but not those by haloperidol and physostigmine. The results of this study suggest that the action of physostigmine (endogenous acetylcholine) on M2 receptors might be more potent than that on muscarinic M1 receptors. A further interesting observation was that the haloperidol-induced catalepsy was enhanced by physostigmine pretreatment, but not by pilocarpine pretreatment, whereas the SCH23390-induced catalepsy showed the opposite spectrum of enhancement by the two cholinergic agonists. We conclude that, although the four cataleptogenic agents act via the dopaminergic-cholinergic systems, their pharmacological differences may be due largely to the different receptor subtypes that are involved in the mediation of catalepsy produced by each agent. Thus, dopamine receptors not only influence the cholinergic muscarinic receptors, but muscarinic M1 and M2 receptors also might mediate dopamine D1 and D2 receptor responses, respectively. The results suggest that there are, at the least, relationships between muscarinic M1 receptors and dopaminergic D1 receptors, and between muscarinic M2 receptors and dopaminergic D2 receptors. Dopamine D1 and D2 receptors may interact in a synergistic fashion on dopaminergic systems, but act independently of each other in influencing other system such as cholinergic neurons.
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PMID:Dopaminergic and cholinergic interaction in cataleptic responses in mice. 926 77

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