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Journal of Applied Physiology... Mar 2016Regional differences in large equine pulmonary artery reactivity exist. It is not known if this heterogeneity extends into small vessels. The hypothesis that there is...
Regional differences in large equine pulmonary artery reactivity exist. It is not known if this heterogeneity extends into small vessels. The hypothesis that there is regional heterogeneity in small pulmonary artery and vein reactivity to sympathomimetics (phenylephrine and isoproterenol) and a parasympathomimetic (methacholine) was tested using wire myography on small vessels from caudodorsal (CD) and cranioventral (CV) lung of 12 horses [9 mares, 3 geldings, 8.67 ± 0.81 (age ± SE) yr, of various breeds that had never raced]. To study relaxation, vessels were precontracted with U46619 (10(-6) M). Methacholine mechanism of action was investigated using L-nitroarginine methylester (L-NAME, 100 μM) and indomethacin (10 μM). Phenylephrine did not contract any vessels. Isoproterenol relaxed CD arteries more than CV arteries (maximum relaxation 28.18% and 48.67%; Log IC50 ± SE -7.975 ± 0.1327 and -8.033 ± 0.1635 for CD and CV, respectively, P < 0.0001), but not veins. Methacholine caused contraction of CD arteries (maximum contraction 245.4%, Log EC50 ± SE -6.475 ± 0.3341), and relaxation of CV arteries (maximum relaxation 40.14%, Log IC50 ± SE -6.791 ± 0.1954) and all veins (maximum relaxation 50.62%, Log IC50 ± SE -6.932 ± 0.1986) in a nonregion-dependent manner. L-NAME (n = 8, P < 0.0001) and indomethacin (n = 7, P < 0.0001) inhibited methacholine-induced relaxation of CV arteries, whereas indomethacin augmented CD artery contraction (n = 8, P < 0.0001). Our data demonstrate significant regional heterogeneity in small blood vessel reactivity when comparing the CD to the CV region of the equine lung.
Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Endothelium, Vascular; Female; Horses; Indomethacin; Isoproterenol; Lung; Male; Methacholine Chloride; Myography; NG-Nitroarginine Methyl Ester; Phenylephrine; Pulmonary Artery; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Veins
PubMed: 26769957
DOI: 10.1152/japplphysiol.00975.2015 -
Respiratory Care Mar 2021A 20% reduction in the FEV is routinely used as an end point for methacholine challenge testing (MCT). Measurement of FEV is effort dependent, and some patients are not...
BACKGROUND
A 20% reduction in the FEV is routinely used as an end point for methacholine challenge testing (MCT). Measurement of FEV is effort dependent, and some patients are not able to perform acceptable and repeatable forced expiration maneuvers. The goal of the present study was to investigate the diagnostic value of airway resistance measurement by forced oscillation technique (FOT), body plethysmography, and interrupter technique compared with the traditionally accepted standard FEV measurement in evaluating the responsiveness to methacholine during MCT.
METHODS
We included in the study adult subjects referred for MCT because of asthma-like symptoms and with normal baseline spirometry. We modified routine MCT protocol by adding the assessment of airway resistance to the measurement of FEV at each step of MCT.
RESULTS
We observed, in the subjects with airway hyper-responsiveness versus those with normal airway responsiveness, a significantly greater percentage change in median (interquartile range) FOT resistance at 10 Hz (25.9% [13.7%-35.4%] vs 16% [15.7%-27.2%]), plethysmographic resistance (70.2% [39.5%-116.3%] vs 37.1% [23.9%-81.9%]), and mean ± SD conductance (-41.3 ± 15.4% vs -29.6 ± 15.9%); and a significantly greater change in mean ± SD FOT reactance at 10 Hz (-0.41 ± 0.48 cm HO/L/s vs -0.09 ± 0.32 cm HO/L/s) and at 15 Hz (-0.29 ± 0.2 cm HO/L/s vs -0.1 ± 0.19 cm HO/L/s). We also recorded significant differences in airway resistance parameters (FOT resistance at 10 Hz, FOT reactance at 15 Hz, plethysmographic airway resistance, and conductance indices as well as interrupter resistance) in FEV non-responders at the onset of respiratory symptoms during MCT compared with baseline.
CONCLUSIONS
Measurements of airway resistance could possibly be used as an alternative method to spirometry in airway challenge. Significant changes in airway mechanics during MCT are detectable by airway resistance measurement in FEV non-responders with methacholine-induced asthma-like symptoms. (ClinicalTrials.gov registration NCT02343419.).
Topics: Adult; Airway Resistance; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Methacholine Chloride; Spirometry
PubMed: 33203723
DOI: 10.4187/respcare.08331 -
Journal of Applied Physiology... Nov 2014Cholinergic agents (e.g., methacholine) induce cutaneous vasodilation and sweating. Reports indicate that either nitric oxide (NO), cyclooxygenase (COX), or both can...
Cholinergic agents (e.g., methacholine) induce cutaneous vasodilation and sweating. Reports indicate that either nitric oxide (NO), cyclooxygenase (COX), or both can contribute to cholinergic cutaneous vasodilation. Also, NO is reportedly involved in cholinergic sweating; however, whether COX contributes to cholinergic sweating is unclear. Forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser-Doppler perfusion units/mean arterial pressure) were evaluated in 10 healthy young (24 ± 4 yr) adults (7 men, 3 women) at four skin sites that were continuously perfused via intradermal microdialysis with 1) lactated Ringer (control), 2) 10 mM ketorolac (a nonselective COX inhibitor), 3) 10 mM N(G)-nitro-l-arginine methyl ester (l-NAME, a nonselective NO synthase inhibitor), or 4) a combination of 10 mM ketorolac + 10 mM l-NAME. At the four skin sites, methacholine was simultaneously infused in a dose-dependent manner (1, 10, 100, 1,000, 2,000 mM). Relative to the control site, forearm CVC was not influenced by ketorolac throughout the protocol (all P > 0.05), whereas l-NAME and ketorolac + l-NAME reduced forearm CVC at and above 10 mM methacholine (all P < 0.05). Conversely, there was no main effect of treatment site (P = 0.488) and no interaction of methacholine dose and treatment site (P = 0.711) on forearm sweating. Thus forearm sweating (in mg·min(-1)·cm(-2)) from baseline up to the maximal dose of methacholine was not different between the four sites (at 2,000 mM, control 0.50 ± 0.23, ketorolac 0.44 ± 0.23, l-NAME 0.51 ± 0.22, and ketorolac + l-NAME 0.51 ± 0.23). We show that both NO synthase and COX inhibition do not influence cholinergic sweating induced by 1-2,000 mM methacholine.
Topics: Adult; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Forearm; Humans; Ketorolac; Male; Methacholine Chloride; Muscarinic Agonists; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Regional Blood Flow; Skin; Sweating; Young Adult
PubMed: 25213633
DOI: 10.1152/japplphysiol.00644.2014 -
Tuberkuloz Ve Toraks Mar 2021Airway hyper-responsiveness (AHR) is a characteristic feature of asthma. The aim of this study was to compare the impulse oscillometry (IOS) and spirometry to... (Comparative Study)
Comparative Study
INTRODUCTION
Airway hyper-responsiveness (AHR) is a characteristic feature of asthma. The aim of this study was to compare the impulse oscillometry (IOS) and spirometry to methacholine for AHR detection among individuals with clinically hyper-reactive airway disease suggestive of bronchial asthma and baseline spirometry were normal.
MATERIALS AND METHODS
Adults with symptoms suggestive of AHR and normal baseline spirometry test were selected. The short protocol of methacholine challenge test (MCT) was performed for all subjects using IOS and spirometry simultaneously. The primary endpoint was to compare the methacholine dosage causing a 20% drop in forced expiratory volume in one second (FEV1), with methacholine dosage that causing 40% increasing the baseline respiratory resistance at 5 hertz (R5), as measured by IOS.
RESULT
A total of 235 participants were analyzed, 184 (78.2%) had positive test results with R5, while 81 (34.4%) had positive MCT results with FEV1.The sensitivity and specificity of MCT with R5were 87.3%, 64.6%, and MCT with FEV1 were 39.1%, 85.4%, respectively. The area under the receiver operating characteristic (ROC) curve was greater at lower doses of MCT at R5, (AUROC: 0.653; p= 0.01).
CONCLUSIONS
The results showed higher sensitivity, negative predictive value, and earlier response of the short protocol of MCT with IOS, compared to MCT with spirometry. Our study suggested the utility of IOS in addition to conventional spirometry as a method of choice in MCT for detection of AHR.
Topics: Adult; Airway Obstruction; Airway Resistance; Asthma; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Oscillometry; ROC Curve; Respiratory Function Tests; Respiratory Hypersensitivity; Sensitivity and Specificity; Spirometry
PubMed: 33853300
DOI: 10.5578/tt.20219901 -
Respiration; International Review of... 2016In a post-hoc analysis of a pediatric asthma study, we identified the predictors of asthma exacerbations (AEs) and related them to forced expiratory volume (FEV1), the... (Clinical Trial)
Clinical Trial
BACKGROUND
In a post-hoc analysis of a pediatric asthma study, we identified the predictors of asthma exacerbations (AEs) and related them to forced expiratory volume (FEV1), the FEV1/FVC ratio, and bronchial hyperresponsiveness (BHR).
OBJECTIVES
We sought to detect predictors of AEs in a prospective study that utilizes impulse oscillometry (IOS) and to compare the results to previously determined predictors.
METHODS
A moderate AE was defined as an increased use of salbutamol during coughing episodes. Pulmonary function and BHR were measured during symptom- and medication-free periods. Additionally, allergen testing and IOS were included. To calculate the sensitivity and specificity of AE detection, a receiver-operating characteristic (ROC) curve was plotted, and accuracy was measured with the area under the ROC curve (AUC). A logistic regression analysis was used to predict the probability of an exacerbation.
RESULTS
Seventy-five pediatric patients (4-7 years of age) with intermittent asthma were included. In 69 patients, the following cut-off values demonstrated the best sensitivity and specificity combination for predicting an AE: FEV1 103.2% (AUC 0.62), BHR (PD20methacholine) 0.13 mg (AUC 0.61), and, in 54 children, Rrs5 0.78 kPa × l-1 × s (AUC 0.80). Logistic regression analysis demonstrated that the combination of all parameters predicted the individual risk of AEs with an accuracy of 86%.
CONCLUSIONS
IOS, a simple method, predicted the probability of AEs in young children. Airway resistance, measured by IOS, was superior to FEV1 and methacholine testing. The current data suggest that peripheral airway obstruction is present during symptom-free periods and that these children more likely experience AEs.
Topics: Asthma; Child; Child, Preschool; Cross-Sectional Studies; Female; Forced Expiratory Volume; Humans; Logistic Models; Male; Methacholine Chloride; Oscillometry; Predictive Value of Tests; Prospective Studies; Skin Tests; Symptom Flare Up; Vital Capacity
PubMed: 26756585
DOI: 10.1159/000442448 -
Respiratory Medicine Jan 2020Although the methacholine challenge test is useful in the diagnosis of asthma, it is time-consuming in children. While protocols that quadruple methacholine...
RATIONALE
Although the methacholine challenge test is useful in the diagnosis of asthma, it is time-consuming in children. While protocols that quadruple methacholine concentrations are widely used in adults to shorten testing time, this has not been evaluated in children. Studies have not identified predictors associated with the safe use of a quadrupled concentration protocol.
OBJECTIVES
To identify clinical predictors associated with the preclusion of a quadrupled concentration protocol in children.
METHODS
We included subjects <18 years who performed a methacholine challenge tests between April 2016 to February 2017 (derivation cohort) and March 2017 to September 2017 (validation cohort). We determined the eligibility of a subject to omit the 0.5 mg/ml and 2.0 mg/ml concentrations based on their PC20 and identified baseline characteristics that are associated with the preclusion of the quadrupled protocol using bivariate analysis. The derived algorithm was applied to the validation cohort.
RESULTS
We included 399 and 195 patients in the derivation and validation cohorts, respectively. A baseline FEV ≤90% predicted, FEV/FVC ≤0.8, FEF ≤70% predicted, and a decrease in FEV ≥10% with the previous concentration significantly precluded the omission of the 0.5 mg/ml concentration. A baseline FEF ≤70% predicted and a drop in FEV ≥10% with the previous concentration significantly precluded the omission of the 2.0 mg/ml concentration. Applying these 4 criteria to the validation cohort resulted in an overall sensitivity and specificity of 74.0% and 84.6%, respectively.
CONCLUSIONS
We identified objective pulmonary function measures that may personalize and shorten the methacholine challenge protocol in children by quadrupling concentrations.
Topics: Adolescent; Asthma; Child; Cohort Studies; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Predictive Value of Tests; Retrospective Studies; Time Factors
PubMed: 31756408
DOI: 10.1016/j.rmed.2019.105823 -
The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices.American Journal of Physiology. Lung... Sep 2017Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to...
Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β-induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction.
Topics: Airway Remodeling; Aminopyridines; Animals; Benzamides; Bronchoconstriction; Cholinergic Antagonists; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Drug Interactions; Glycopyrrolate; Guinea Pigs; Lung; Male; Methacholine Chloride; Phosphodiesterase 4 Inhibitors; Sulfonamides; Tiotropium Bromide; Transforming Growth Factor beta; para-Aminobenzoates
PubMed: 28596292
DOI: 10.1152/ajplung.00069.2017 -
American Journal of Physiology. Lung... Dec 2021Increased insulin is associated with obesity-related airway hyperreactivity and asthma. We tested whether the use of metformin, an antidiabetic drug used to reduce...
Increased insulin is associated with obesity-related airway hyperreactivity and asthma. We tested whether the use of metformin, an antidiabetic drug used to reduce insulin resistance, can reduce circulating insulin, thereby preventing airway hyperreactivity in rats with dietary obesity. Male and female rats were fed a high- or low-fat diet for 5 wk. Some male rats were simultaneously treated with metformin (100 mg/kg orally). In separate experiments, after 5 wk of a high-fat diet, some rats were switched to a low-fat diet, whereas others continued a high-fat diet for an additional 5 wk. Bronchoconstriction and bradycardia in response to bilateral electrical vagus nerve stimulation or to inhaled methacholine were measured in anesthetized and vagotomized rats. Body weight, body fat, caloric intake, fasting glucose, and insulin were measured. Vagally induced bronchoconstriction was potentiated only in male rats on a high-fat diet. Males gained more body weight, body fat, and had increased levels of fasting insulin compared with females. Metformin prevented development of vagally induced airway hyperreactivity in male rats on high-fat diet, in addition to inhibiting weight gain, fat gain, and increased insulin. In contrast, switching rats to a low-fat diet for 5 wk reduced body weight and body fat, but it did not reverse fasting glucose, fasting insulin, or potentiation of vagally induced airway hyperreactivity. These data suggest that medications that target insulin may be effective treatment for obesity-related asthma.
Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Bronchoconstrictor Agents; Diet, High-Fat; Female; Glucose; Hyperinsulinism; Hypoglycemic Agents; Male; Metformin; Methacholine Chloride; Obesity; Rats; Rats, Sprague-Dawley; Vagus Nerve; Weight Gain
PubMed: 34668415
DOI: 10.1152/ajplung.00202.2021 -
Scientific Reports Oct 2022Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral...
Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral angioedema (CholU-PA), 3) CholU with acquired anhidrosis and/or hypohidrosis (CholU-Anhd); 1) and 2) include SAT based on pathogenesis. There have been no studies on differences in the prevalence of bronchial asthma among the subtypes. We analyzed bronchial responsiveness using the methacholine dose indicator D, respiratory symptoms, and exhaled nitric oxide (FeNO). Median log10 D (interquartile range) of patients with conventional SAT-CholU (n = 11), CholU-PA (n = 11), and CholU-Anhd (n = 11) was 0.381 (- 0.829, 1.079), 0.717 (0.249, 0.787), and 1.318 (0.121, 1.699), respectively (p = 0.516). Respiratory symptoms were less frequently observed in CholU-Anhd than in conventional SAT-CholU or CholU-PA. FeNO of patients with conventional SAT-CholU, CholU-PA, and CholU-Anhd was 23 (18.5, 65.0), 39 (32.0, 59.5), and 25 (19.0, 33.0) ppb, respectively (p = 0.237). Nine% of conventional SAT-CholU patients and more than half of CholU-PA patients required treatment for asthma. Log D tended to be lower in patients with SAT-CholU than in those with CholU-Anhd. CholU-PA might be associated with asthma.
Topics: Humans; Cross-Sectional Studies; Bronchial Hyperreactivity; Methacholine Chloride; Urticaria; Asthma; Nitric Oxide; Cholinergic Agents
PubMed: 36302805
DOI: 10.1038/s41598-022-22655-6 -
Scientific Reports Feb 2020Mechanisms mediating the protective effects of molecular hydrogen (H) are not well understood. This study explored the possibility that H exerts its anti-inflammatory... (Observational Study)
Observational Study
Mechanisms mediating the protective effects of molecular hydrogen (H) are not well understood. This study explored the possibility that H exerts its anti-inflammatory effect by modulating energy metabolic pathway switch. Activities of glycolytic and mitochondrial oxidative phosphorylation systems were assessed in asthmatic patients and in mouse model of allergic airway inflammation. The effects of hydrogen treatment on airway inflammation and on changes in activities of these two pathways were evaluated. Monocytes from asthmatic patients and lungs from ovalbumin-sensitized and challenged mice had increased lactate production and glycolytic enzyme activities (enhanced glycolysis), accompanied by decreased ATP production and mitochondrial respiratory chain complex I and III activities (suppressed mitochondrial oxidative phosphorylation), indicating an energy metabolic pathway switch. Treatment of ovalbumin-sensitized and challenged mice with hydrogen reversed the energy metabolic pathway switch, and mitigated airway inflammation. Hydrogen abrogated ovalbumin sensitization and challenge-induced upregulation of glycolytic enzymes and hypoxia-inducible factor-1α, and downregulation of mitochondrial respiratory chain complexes and peroxisome proliferator activated receptor-γ coactivator-1α. Hydrogen abrogated ovalbumin sensitization and challenge-induced sirtuins 1, 3, 5 and 6 downregulation. Our data demonstrates that allergic airway inflammation is associated with an energy metabolic pathway switch from oxidative phosphorylation to aerobic glycolysis. Hydrogen inhibits airway inflammation by reversing this switch. Hydrogen regulates energy metabolic reprogramming by acting at multiple levels in the energy metabolism regulation pathways.
Topics: Animals; Asthma; Bronchoconstrictor Agents; Cells, Cultured; Disease Models, Animal; Female; Glycolysis; Humans; Hydrogen; Lactic Acid; Leukocytes, Mononuclear; Lung; Male; Methacholine Chloride; Mice; Middle Aged; Ovalbumin; Oxidative Phosphorylation; Primary Cell Culture
PubMed: 32029879
DOI: 10.1038/s41598-020-58999-0