Disease relevance of methacholine

• To determine whether inhaled agents can alter T-cell subsets in the peripheral blood of patients with bronchial asthma, we tested six asymptomatic asthmatics who were sensitive to mixed grass (positive skin test) with mixed grass extract, methacholine, and an antigen to which they were not sensitized (negative skin test) [1].
• Six patients with chronic cough, without history of dyspnea or wheezing, had normal base-line spirometry but hyper-reactive airways, as demonstrated with methacholine [2].
• Twenty-four percent of the subjects with bronchopulmonary dysplasia in infancy had fixed airway obstruction, and 52 percent had reactive airway disease, as indicated by their responses to the administration of methacholine or a bronchodilator [3].
• At a dose of 0.03 to 0.12 nanomole, VIP produced a dose-dependent, prolonged (3 to 15 minutes) depolarization of the ganglion and enhanced the ganglionic depolarization elicited by the muscarinic agonist acetyl-beta-methylcholine [4].
• This report examines the effect of an anti-VLA-4 monoclonal antibody (mAb) HP1/2 on antigen-induced bronchial hyperreactivity to methacholine, and on eosinophil and T lymphocyte infiltration in the airways of guinea pigs sensitized and challenged by aerosolized ovalbumin and used 24 h thereafter [5].

Psychiatry related information on methacholine

• We investigated the ability of psychologic stress to modulate airway inflammation and airway hyperresponsiveness (AHR) to methacholine in a murine model of asthma [6].
• Analysis of variance showed no association of the individual differences in PC50 (methacholine) between both investigations with smoking, time from the onset of symptoms to removal, time from removal to the first or second investigation, skin sensitization to environmental allergens, or total IgE [7].
• There were no significant differences between the active and placebo groups in symptom scores, use of medication, self-assessment, or methacholine test results either before or after treatment [8].
• Forty patients with a history of alcohol abuse were treated with a 2% solution of methacholine to determine the prevalence of iridic parasympathetic denervation [9].
• AHR to methacholine and AMP improved significantly after a 1-yr smoking cessation, yet this was unrelated to changes in sputum cell counts [10].

High impact information on methacholine

• Bronchial sensitivity to methacholine (the concentration provoking a 20 percent decrease in the forced expiratory volume in one second [PC20]) was measured twice yearly [11].
• Bronchial hyperresponsiveness to cholinergic stimuli such as the inhalation of methacholine is common in patients with impaired left ventricular function [12].
• On the first treatment day, salmeterol afforded significant protection against methacholine-induced bronchoconstriction, as shown by a 10-fold increase in the PC20 as compared with the value at entry (P less than 0.001) [13].
• In contrast, there was no bronchial response to methacholine in 9 of 10 patients who had coronary artery disease but normal left ventricular function [14].
• After methacholine, there were no significant changes in neutrophil chemotactic activity or percentages of complement rosettes, despite bronchoconstriction [15].

Chemical compound and disease context of methacholine

• Thus, the vasodilator responses to methacholine and nitroprusside were blunted in patients with hypercholesterolemia [16].
• We demonstrate that the beta-adrenergic agonist isoproterenol stimulates channel activity via the alpha subunit of the stimulatory G protein of adenylyl cyclase, Gs, and that channel opening is inhibited by the action of the muscarinic agonist methacholine, acting via a pertussis toxin-sensitive G protein [17].
• The tachycardia cycle length was decreased by methacholine and increased by lidocaine [18].
• METHODS AND RESULTS: Endothelium-dependent vasodilation was assessed through brachial artery infusion of methacholine chloride both before and during 6 hours of local hyperglycemia (300 mg/dL) achieved by intra-arterial infusion of 50% dextrose [19].
• The cholinesterase inhibitor physostigmine did not restore the methacholine-induced inhibition of norepinephrine overflow after 3-minute stop-flow ischemia to normoxic level (55% vs. 17%) [20].

Biological context of methacholine

• To control for the effects of bronchoconstriction, the same studies were done after a challenge with methacholine [15].
• Again, base-line values were normal, but after methacholine one-second forced expiratory volume decreased an average of 40 per cent in the patients as compared to 30 per cent in normal controls (P less than 0.001) [2].
• The point of identical flow was increased by methacholine to 43.5 per cent of vital capacity in the patients, as compared to 6 per cent in normal controls (P less than 0.001), and the alveolar plateau was 4.8 deltaN2 per liter, as compared to 1.4 in normal controls (P less than 0.01) [2].
• Bronchial hyperresponsiveness to methacholine in patients with impaired left ventricular function [14].
• As the dose-response relationships for phosphorylation and tension should be similar if myosin phosphorylation does, in fact, regulate smooth muscle contraction, we studied myosin phosphorylation in tracheal smooth muscle stimulated with a broad range of concentrations of the cholinergic agonist, methacholine [21].

Anatomical context of methacholine

• No changes were observed in any of these T-cell subpopulations after challenge with methacholine or after the inhalation of an equal amount of an antigen to which the subjects were not sensitized [1].
• At a dose of 1.8 to 10 nanomoles, the peptide enhanced and prolonged the postganglionic discharge elicited by acetyl-beta-methylcholine, enhanced muscarinic transmission in ganglia treated with an anticholinesterase agent, and enhanced the late muscarinic discharge elicited by acetylcholine [4].
• We examined the role of a cytosolic phospholipase A2 (cPLA2) in antigen-induced eosinophil infiltration of airways and in airway hyperresponsiveness to methacholine [22].
• Antigen challenge elicited pulmonary infiltration of lymphocytes, eosinophils and neutrophils, increase in mucus-containing epithelial cells, and airway hyperresponsiveness to methacholine [23].
• This was associated with a significant blood and sputum eosinophilia and increased methacholine airway responsiveness, 24 h post-allergen [24].

Associations of methacholine with other chemical compounds

• The vasodilative response to the endothelium-dependent vasodilator, methacholine chloride, was depressed in the hypercholesterolemic group, whereas endothelium-independent vasodilation, induced by nitroprusside, was similar in each group [25].
• VAS/FEV1 slopes for bradykinin but not for methacholine correlated negatively with the magnitude of eosinophilic inflammation in airway mucosa [26].
• Superfusion with 10 muM methacholine alone had no effect on ANP secretion, but rapidly attenuated norepinephrine-stimulated secretion by 67% [27].
• To determine whether kinin production is required for the development of airway hyperresponsiveness induced by cationic proteins, dose-response curves to methacholine were constructed before and 1 h after intratracheal instillation of either MBP or poly-L-lysine (100 micrograms) [28].
• The geometric mean concentrations of arecoline and methacholine that caused 20% falls in the forced expiratory volume in 1 s (PC20 FEV1) in the asthmatic subjects were 5.2 mg/ml and 1.6 mg/ml, respectively [29].

Gene context of methacholine

• Recruitment of eosinophils to lung parenchyma and bronchoalveolar lavage (BAL) fluid was severely impaired in CCR3(-/-) mice, which failed to develop AHR to methacholine following antigen inhalation [30].
• Likewise, Penh, a measure of bronchoconstriction, was significantly enhanced in Aqp5(-/-) mice challenged with aerosolized methacholine (P < 0.05) [31].
• Although no differences in basal respiratory or lung mechanical parameters were observed, COX-1 Tr mice had increased bronchoalveolar lavage fluid PGE(2) content compared with wild-type littermates (23.0 +/- 3.6 vs 8.4 +/- 1.4 pg/ml; p < 0.05) and exhibited decreased airway responsiveness to inhaled methacholine [32].
• RESULTS: Eotaxin-2 and IL-5 cooperatively promoted eosinophil accumulation, IL-13 production, and AHR to methacholine [33].
• Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology [34].

Analytical, diagnostic and therapeutic context of methacholine

• The intravenous administration of 2.5 mg/kg of HP1/2, but not of its isotype-matched mAb 1E6, 1 h before and 4 h after antigen inhalation, markedly inhibited the increased bronchopulmonary responses to intravenous methacholine, as well as airway eosinophilia in bronchoalveolar lavage (BAL) fluid and in bronchial tissue [5].
• Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3-10 micrograms/min) [35].
• When an intravenous infusion of methacholine (3.5-12 micrograms/kg.min) was used to increase RL from 0.143 +/- 0.008 to 0.474 +/- 0.041 cmH2O/ml.s (P less than 0.05), inhalation of 5-300 ppm NO-containing gas mixtures produced a dose-related, rapid, consistent, and reversible reduction of RL and an increase of dynamic lung compliance [36].
• Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine [37].
• Sputum cell-counts were studied in 7 non-smokers with corticosteroid-responsive chronic cough productive of sputum and 8 smokers with a clinical diagnosis of chronic bronchitis, all of whom had normal lung function tests and methacholine airway responsiveness, and in 10 non-smokers with asthma, examined during an exacerbation [38].

References