Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a survey of 21 patients with myasthenia gravis receiving regular acetylcholinesterase inhibitor therapy, 8 were found to have air-flow limitation associated with their antimyasthenic therapy. In 6 of these subjects, detailed assessments were made of the effect of antimyasthenic therapy on airways function. Pyridostigmine was given together with either placebo or the anticholinergic bronchodilator ipratropium bromide (72 micrograms) by inhalation administered double blind on 2 consecutive days. Airways resistance (Raw) increased significantly after pyridostigmine and placebo inhaler (0.49 +/- 0.13 kPa/L/s basal versus 0.60 +/- 0.13 kPa/L/s at 2 h; mean +/- SEM, p less than 0.05), whereas a significant decrease in Raw followed the combination of pyridostigmine with ipratropium bromide (0.57 +/- 0.08 kPa/L/s basal versus 0.41 +/- 0.07 kPa/L/s at 2 h, p less than 0.05). Thus, acetylcholinesterase inhibitor therapy in subjects with myasthenia gravis with airflow limitation led to significant increase in airways resistance that could be completely reversed by the inhalation of the muscarinic receptor blocker ipratropium bromide.
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PMID:Air-flow limitation in myasthenia gravis. The effect of acetylcholinesterase inhibitor therapy on air-flow limitation. 622 24

Muscarinic cholinergic receptors were identified and partially characterized in crude membrane fractions of rat lung and trachea from day 17 of gestation to adulthood using (-)-[3H]quinuclidinyl benzilate (QNB). (-)-[3H]QNB binding to rat lung membrane was characteristic of muscarinic cholinergic receptor sites. Binding capacity of muscarinic receptors sites was relatively low in rat lung compared to that in other tissues. The number of (-)-[3H]QNB-binding sites (binding capacity) decreased progressively and significantly from 79 +/- 8 fmol X mg-1 protein on days 17-18 of gestation to 21 +/- 3 fmol X mg-1 mean +/- SEM on days 21-22 of gestation, p less than 0.01. Binding capacity did not vary thereafter from birth to adulthood. Affinity of (-)-[3H]QNB binding for lung membranes did not change with age (KD approximately 70 pM). (-)-[3H] QNB-binding sites were significantly higher in membrane preparations of trachea or tracheal-bronchial tissue than in lung parenchyma from both the adult and newborn rats. (-)-[3H]QNB binding was undetectable in crude membrane preparations of cultured purified type II epithelial cells isolated from the adult rat lung. Muscarinic cholinergic receptor sites are present in rat lung as early as day 17 of gestation. Since preparations of proximal portions of the lung are relatively enriched in (-)-[3H]QNB binding compared to more peripheral portions of the lung, ontogenic decreases in (-)-[3H]QNB binding may result from the higher contribution of tracheal-bronchial tissue compared to alveolar tissue in the preparations of early fetal lung, rather than to a specific regulation of muscarinic receptor sites.
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PMID:Muscarinic cholinergic receptors in developing rat lung. 651 39

Low Km high affinity GTPase activity, with and without muscarinic receptor stimulation with 1 mM carbachol, was measured in membrane preparations of mouse hippocampus prenatally exposed to phenobarbital or heroin. Basal and carbachol-stimulated low Km GTPase activities after prenatal exposure to phenobarbital exhibited a statistically significant (P < 0.05) decrease both in Km and Vmax values. Basal Vmax values were reduced from 152 +/- 10 in controls to 112 +/- 13 (pmol/mg protein/min, mean +/- SEM) in exposed mice. The Km values in the offspring of mice treated with phenobarbital were reduced from 1.55 +/- 0.21 to 0.96 +/- 0.11 (microM, mean +/- SEM); Vmax and Km values after carbachol stimulation were similarly affected. Prenatal exposure to heroin did not change the GTPase activities, basal or carbachol-stimulated, with only a non-significant increase in both Vmax and Km values. It is postulated that these changes in G alpha protein activity may be related to the teratogenic effect of these drugs.
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PMID:GTPase activity in mouse hippocampus membranes following prenatal exposure to heroin and phenobarbital. 760 38

Histamine release has been implicated in the pathogenesis of exercise-induced asthma (EIA), and is believed to be partly mediated by vagal stimulation. Our aim was to determine the relationship between the contributions of vagal stimulation (determined by the use of the muscarinic receptor antagonist, ipratropium bromide) and histamine release (determined by the use of the histamine H1-receptor antagonist terfenadine) in EIA. Ten stable asthmatic subjects with documented EIA took part in a randomized double-blind study. Each undertook four identical treadmill exercise tests, following drug therapy with one of the following: nebulized ipratropium bromide, 0.5 mg, terfenadine, 180 mg, by mouth, both active drugs together, and placebo preparations by mouth and by nebulizer. The mean +/- SEM maximum percentage fall in forced expiratory volume in one second (FEV1) after exercise following placebo therapy was 33.6 +/- 3.8%, which significantly decreased to 27.2 +/- 3.6% after terfenadine, to 21.8 +/- 3.9% after ipratropium bromide, and to 15.1 +/- 4.1% after the combination of both drugs. The addition of ipratropium bromide to terfenadine treatment improved on the protection offered by terfenadine alone. We conclude that both histamine release and vagal stimulation contribute independently and additively to EIA.
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PMID:The contribution of histamine release and vagal reflexes, alone and in combination, to exercise-induced asthma. 822 21

The effects of muscarinic cholinergic neurotransmission on fetal breathing was determined by administration of carbachol or carbachol plus a muscarinic receptor antagonist into the cerebrospinal fluid of the fourth ventricle in unanesthetized fetal sheep. In the hour following the instillation of carbachol (1.0 microgram), the incidence of fetal breathing in high voltage electrocortical state (ECoG) increased to 63 +/- 11.7 (SEM) percent compared to 1.2 +/- 0.9 after instillation of vehicle (Ringer solution). The cholinergic agonist increased breath amplitude from 4.5 +/- 0.4 to 10.6 +/- 1.4 mmHg. These effects were eliminated when the M1 receptor antagonist pirenzepine (50-100 micrograms) was administered with carbachol but not by antagonists which are relatively selective for M2 or M3 receptors. When administered alone, muscarinic receptor antagonists did not effect the incidence or amplitude of fetal breathing in low voltage. These data indicate that the apnea which occurs during high voltage in the sheep fetus involves an inhibition of acetylcholine acting at M1 muscarinic receptor bearing neurons.
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PMID:A cholinergic mechanism involved in fetal breathing during the high voltage ECoG state. 805 81

The maturation of the cholinergic innervation of the rat cochlea is associated with a transient increase in the muscarinic-receptor activated inositol phosphate synthesis. In order to investigate the mechanisms involved in this transient enhancement of the inositol phosphate response, the binding properties of the cochlear muscarinic receptors were studied during rat cochlear development. Incubating the membranes from 4-day-old, 12-day-old and adult cochleas with [3H]quinuclidinyl benzylate indicates that their respective, mean concentrations of cholinoceptors are 454 +/- 51 (+/- SEM), 39 +/- 2 and 42 +/- 3 fmol/mg of protein. The dissociation constants at equilibrium are 207 +/- 80, 42 +/- 7 and 28 +/- 3 pM for the binding sites of the 4-day-old, 12-day-old and adult cochleas, respectively. Pharmacological characterization of the binding, using selective antagonists, shows that M3 cholinoceptors are expressed in developing and adult cochleas. The data demonstrate that changes in muscarinic receptor affinity and number do not correlate with the previously observed peak of the inositol phosphate metabolism. The transient enhanced inositol phosphate response is therefore not due to changes in cholinoceptors, but probably due to alterations involving the intrinsic activity of the phospholipase C and/or the efficacy of coupling of the transduction system.
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PMID:Characterization of muscarinic binding sites in the adult and developing rat cochlea. 825 26

The effect of the muscarinic antagonist on carbachol-induced increase in spontaneous activity of neurons of the subthalamic nucleus was examined by recording the extracellular unitary activity in an in vitro slice preparation. Carbachol produced (98% of the 263 neurons tested) an increase (twofold of the basal at 500 nM) of the discharge frequency. The EC50 for the carbachol-induced effect was 375 +/- 8.7 nM (mean +/- SEM). The response was blocked by muscarinic antagonists in a dose dependent manner. However, the IC50 (94 +/- 3 nM) for the M3 antagonist 4-diphenyl acetoxy-N-methyl piperidine methobromide (4-DAMP) was considerably less than the other muscarinic antagonists (M1 antagonist pirenzepine, IC50 1340 +/- 110 nM; M2 antagonist AF-DX-116, IC50 6780 +/- 690 nM). These results suggest that the cholinergic input to the rat subthalamic nucleus exerts a postsynaptic excitatory action and this effect is likely mediated via muscarinic receptor type 3.
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PMID:M3 muscarinic receptors mediate cholinergic excitation of the spontaneous activity of subthalamic neurons in the rat. 874 28

Carbachol increased ventricular automaticity in a concentration-dependent fashion from a control rate of 72 +/- 5 (mean +/- SEM) to 86 +/- 4 beats per minute at 10(-4) M carbachol. Pirenzepine, an M1-selective antagonist, and AFDX 116, an M2-selective antagonist, both at 10(-7) M, did not block the carbachol-induced positive chronotropic response. In contrast, 10(-7) M HHSiD, an M3-selective antagonist, completely blocked the positive chronotropic effect of carbachol. Carbachol stimulated the accumulation of IP1 in a concentration-dependent manner at concentrations > or = 3 x 10(-6) M. AFDX 116 had no effect on carbachol-induced IP1 accumulation. HHSiD significantly inhibited IP1 accumulation at concentrations > or = 3 x 10(-8) M, while pirenzepine inhibited IP1 accumulation only at concentrations > or = 10(-5) M. McN A343 and methacholine, two muscarinic receptor agonists with minimal M2 activities, and carbachol did not alter basal cAMP concentration, but all three agonists significantly attenuated the increase in cAMP accumulation in response to isoproterenol. Carbachol inhibited isoproterenol-mediated cAMP accumulation at concentrations > or = 10(-7) M. AFDX 116, HHSiD, and pirenzepine blocked the carbachol-induced inhibition of isoproterenol-stimulated cAMP accumulation. At equimolar concentrations, the inhibitory effects of HHSiD and AFDX-116 were similar, while that of pirenzepine was much less. Pretreatment with pertussis toxin for 24 h did not prevent the carbachol-mediated positive chronotropic response or accumulation of IP1 but completely abolished the inhibition of isoproterenol-stimulated cAMP accumulation. These results indicate that (a) neonatal ventricular myocytes in culture have a heterogeneous population of muscarinic (M2 and M3) receptors, (b) the M3 receptor is coupled to pertussis toxin-sensitive and pertussis toxin-insensitive G proteins, (c) M3 receptor stimulation activates phosphoinositide hydrolysis and increases automaticity via a pertussis toxin-insensitive G protein-dependent pathway, and (d) both M2 and M3 receptors couple to pertussis toxin-sensitive G protein(s) to mediate the inhibition of intracellular cAMP accumulation in response to isoproterenol stimulation.
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PMID:Muscarinic receptor heterogeneity in neonatal rat ventricular myocytes in culture. 884 59

The purpose of this study was to visualize muscarinic receptors and their distribution on cardiomyocytes and to examine the effects of muscarinic cholinergic receptor (mACh-R) stimulation with carbachol on phosphatidylcholine hydrolysis. Cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts. Cardiomyocytes, grown on cover slips, were labelled with BODIPY PZ, a fluorescent analog of the muscarinic receptor antagonist pirenzepine, and examined with a laser scanning confocal microscope, mACh-R clusters were visualized and were fairly homogeneous in size with diameters ranging from 0.5 to 1.0 micron. The number of receptor clusters per cell was 83.5 +/- 6.8 (mean +/- SEM) and clusters were found at the periphery of the cell. Cardiomyocytes, grown as a monolayer in dishes, were treated with the 10(-4) M carbachol, a mACh-R agonist, and the effects on phosphatidylcholine hydrolysis were ascertained in cells preincubated with [methyl-3H]choline for 18 h. Cells were washed, lysed, and subjected to thin-layer chromatography to separate [3H]choline in various metabolites of phosphatidylcholine. Carbachol significantly (p < 0.05) increased intracellular free choline and decreased cellular phospholipid consistent with phosphatidylcholine hydrolysis. Carbachol increased the amount of [3H]choline that effluxed out of the cardiomyocyte into the medium. Carbachol-induced choline efflux was not prevented by pretreatment with n-butanol, a phospholipase D inhibitor, suggesting that other lipases such as phospholipase C are the major enzyme involved in phosphatidylcholine hydrolysis. Pertussis toxin prevented carbachol-induced choline efflux and the changes in intracellular free choline and phospholipid. An action of carbachol through G proteins was supported by the ability of pertussis toxin to antagonize the carbachol-induced reduction in cAMP generation from isoproterenol. In summary, mACh-Rs, visualized in living cardiomyocytes, were peripheral to the nucleus. Phosphatidylcholine hydrolysis induced by mACh-R stimulation may be a signal transduction pathway for mACh-R in the cardiomyocyte, operating through inhibitory G proteins sensitive to pertussis toxin.
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PMID:Visualization of muscarinic cholinergic receptors on chick cardiomyocytes and their involvement in phosphatidylcholine hydrolysis. 925 Mar 60

Drug delivery to the receptor sites and receptor affinity could be determinant factors for increased bronchial responsiveness seen in asthma. Competitive antagonism blockade which is measured as dose ratio - 1 (DR-1) depends only on these two factors. Therefore, in this study we examined the muscarinic receptor blockade by atropine on isolated tracheal chains of sensitized compared to control guinea pigs. An experimental model of asthma was induced in guinea pigs by sensitization of animals with injection and inhalation of ovalbumin (OA). The responses of tracheal chains of sensitized and control animals (for each group n = 10) to cumulative concentrations of methacholine in the absence and presence of 5 nmol/l atropine were measured, and the effective concentrations of methacholine causing 50% of maximum response (EC50 M) were obtained. The atropine blockade (DR-1) was calculated by: (post-atropine EC50 M/EC50 M) - 1. The responses of tracheal chains to 0.1% OA, relative to contraction obtained by 10 mmol/l methacholine, were also measured. The tracheal responses of sensitized guinea pigs were significantly higher than those of control animals to both OA (mean +/- SEM, 55.94 +/- 5.22 vs. 2.59 +/- 0.85%, p < 0.001) and methacholine (EC50 M for asthmatic and control animals were 0.88 +/- 0.27 and 2.00 +/- 0.26 micromol, respectively, p < 0.01). The muscarinic receptor blockade by atropine (DR-1) was also significantly higher in tracheas of asthmatic compared to that of control animals (131.12 +/- 19.82 vs. 24.50 +/- 3.19, p < 0.001). There were significant correlations between tracheal response to OA and EC50 M (r = -0.644, p = 0.002) and also between DR-1 and tracheal responses to both OA (r = 0.738, p < 0.001) and EC50 M (r = -0.679, p < 0.001). This enhanced muscarinic receptor blockade in tracheal chains of sensitized animals confirms our previous findings which was predicted to be due to the increased drug delivery to the receptors. Drug delivery could also be a determinant factor for bronchial responsiveness to stimuli in asthma.
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PMID:Increased muscarinic receptor blockade by atropine in tracheal chains of ovalbumin-sensitized guinea pigs. 1032 75


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