Peripheral mononuclear leucocyte beta adrenoceptors and non-specific bronchial responsiveness to methacholine in young and elderly normal subjects and asthmatic patients.

BACKGROUND--As beta adrenoceptor dysfunction occurs in both the normal elderly subject and in young asthmatic patients, the hypothesis was examined that age related beta adrenoceptor changes are important in the pathogenesis of late onset asthma in old age. METHODS--Subjects were non-smokers who comprised 17 young normal subjects of mean (SE) age 29.4 (1.3) years, 17 elderly normal subjects of 67.2 (1.3) years, seven young asthmatic patients of 31.0 (2.8) years, and 17 elderly asthmatic patients of 68.5 (1.4) years. All asthmatic patients withheld inhalers for 12 hours and oral treatment for 24 hours before each study day. Subjects underwent an inhaled methacholine challenge (Newcastle dosimeter method) on two nonconsecutive days. The slope of the flow at 50% of the vital capacity (FEF50) dose-response curve was derived from the percentage fall in FEE50 divided by methacholine dose (sFEF50). Beta-adrenoceptor density (Bmax) and affinity (%KH) were determined with (125I)iodocyanopindolol as the radioligand in membranes prepared from mononuclear leucocytes. RESULTS--Log sFEF50 was shown to be reproducible (repeatability coefficient 0.41) on the two study days and was inversely related to %KH but not to Bmax. Multiple regression analysis (all 58 subjects, overall R2 = 0.57) revealed an inverse relation between log sFEF50 and %KH, and between log sFEF50 and Bmax. The inverse relation between log sFEF50 and %KH was preserved whereas that between log sFEF50 and Bmax was lost when young asthmatic subjects or when all asthmatic subjects were excluded from multiple regression analysis. CONCLUSIONS--The beta adrenoceptor dysfunction observed in late onset asthma may be similar to that seen during ageing. Thus late onset asthma may represent the extreme of a spectrum of age associated beta adrenoceptor dysfunction.     

Use of induced sputum cell counts to investigate airway inflammation in asthma.

BACKGROUND: Airway inflammation is considered to be important in asthma but is relatively inaccessible to study. Less invasive methods of obtaining sputum from patients unable to produce it spontaneously should provide a useful investigational tool in asthma. METHODS: A method to induce sputum with inhaled hypertonic saline was modified for use in 17 asthmatic patients and 17 normal subjects who could not produce sputum spontaneously. The success rate and safety of the method, the reproducibility of cell counts, and differences in cell counts between the asthmatic and normal groups were examined. Hypertonic saline solution 3-5% was inhaled for up to 30 minutes after inhalation of salbutamol. Subjects were asked to expectorate sputum every five minutes. The quality of the sample was scored on the volume of plugs and the extent of salivary contamination. Plugs from the lower respiratory tract were selected for a total cell count and for differential cell counts of eosinophils and metachromatic cells (mast cells and basophils) in direct smears. RESULTS: Adequate samples from the lower respiratory tract were obtained in 76% of first attempts. The mean fall in the forced expiratory volume in one second (FEV1) during inhalation of saline was 5.3% and the maximum fall 20%. Eosinophil and metachromatic cell counts were reproducible (reliability coefficient 0.8 and 0.7 respectively). When compared with sputum from normal subjects sputum from asthmatic patients contained a significantly higher proportion of eosinophils (mean 18.5% (SE 3.8%) v 1.9% (0.6%)) and metachromatic cells (0.50% (0.18%) v 0.039% (0.014%)). In the asthmatic group the differential eosinophil count correlated with the baseline FEV1. CONCLUSION: Induced sputum is capable of detecting differences in cell counts between normal and asthmatic subjects and merits further development as a potential means of assessing airway inflammation in asthma.     

Dissociation between exhaled nitric oxide and hyperresponsiveness in children with mild intermittent asthma

BACKGROUND: Bronchial hyperresponsiveness and airway inflammation are distinctive features of asthma. Evaluation of nitric oxide (NO) levels in expired air have been proposed as a reliable method for assessing the airway inflammatory events in asthmatic subjects. A study was undertaken to evaluate whether airway hyperresponsiveness is related to levels of exhaled NO. METHODS: Thirty two steroid-naive atopic children with mild intermittent asthma of mean (SD) age 11.8 (2.3) years and 28 age matched healthy controls were studied to investigate whether baseline lung function or airway hyperresponsiveness is related to levels of exhaled NO. Airway responsiveness was assessed as the dose of methacholine causing a 20% decrease in forced expiratory volume in one second (FEV(1)) from control (PD(20) methacholine) and exhaled NO levels were measured by chemiluminescence analysis of exhaled air. RESULTS: At baseline asthmatic children had significantly higher NO levels than controls (mean difference 25.87 ppb (95% CI 18.91 to 32.83); p<0.0001) but there were no significant differences in lung function parameters (forced vital capacity (FVC), FEV(1) (% pred), and forced expiratory flows at 25-75% of vital capacity (FEF(25-75%))). In the asthmatic group exhaled NO levels were not significantly correlated with baseline lung function values or PD(20) methacholine. CONCLUSIONS: These results suggest that levels of exhaled NO are not accurate predictors of the degree of airway responsiveness to inhaled methacholine in children with mild intermittent asthma.     

Inhibition of allergen-induced airway obstruction and leukotriene generation in atopic asthmatic subjects by the leukotriene biosynthesis inhibitor BAYx 1005

BACKGROUND: Leukotriene receptor antagonists significantly blunt allergen-induced bronchoconstriction in asthmatic subjects. Inhibitors of leukotriene synthesis should theoretically provide similar protection, but conflicting results have been obtained when synthesis inhibitors have been tested in allergen challenge. BAYx 1005, a new inhibitor of leukotriene synthesis, was therefore evaluated in an allergen bronchoprovocation study. METHODS: Ten men with mild allergic asthma and bronchial hyperresponsiveness to histamine were recruited. On two different occasions each subject inhaled a single dose of allergen, previously determined to cause at least a 20% fall in forced expiratory volume in one second (FEV1) four hours after ingestion of 750 mg BAYx 1005 or placebo in a double blind crossover design. Urinary excretion of leukotriene E4 was measured before and during the challenges. RESULTS: The mean (SE) maximal fall in FEV1 was 7.1 (1.7)% after BAYx 1005 and 21.0 (3.0)% after placebo (p < 0.001). The mean difference between treatments was 13.9 (95% CI 7.0 to 20.8) for the maximal fall in FEV1. All subjects were protected by BAYx 1005, the mean inhibition of the fall in FEV1 being 70.0 (7.0)%. The mean area under the curve (AUC) for urinary excretion of leukotriene E4 in the first two hours after the challenge was 1.7 (0.9) after placebo and 0.4 (0.6) after BAYx 1005 (difference = 1.3 (95% CI-0.1 to 2.7); p < 0.05). CONCLUSIONS: These results indicate that BAYx 1005 is a potent inhibitor of allergen-provoked leukotriene synthesis in asthmatic subjects and lend further support to the suggestion that leukotrienes are important mediators of allergen-induced bronchoconstriction.


     

Perception of airflow obstruction and associated breathlessness in normal and asthmatic subjects: correlation with anxiety and bronchodilator needs.

BACKGROUND--Perception of bronchoconstriction varies between individuals and its determinants remain to be identified. The perception of airflow obstruction and breathlessness during induced bronchoconstriction was studied, and the effects of anxiety, repetition of the stimulus, and bronchodilator needs on these measurements were examined in normal and asthmatic subjects. METHODS--Fifteen normal (control) and 25 asthmatic subjects had two consecutive methacholine inhalation tests to induce a 20-50% fall in FEV1. Evaluation of the perceived magnitude of airflow obstruction, breathlessness, level of anxiety generated, and bronchodilator needs was obtained before each FEV1 measurement on a modified Borg scale from 0 to 10. RESULTS--Mean (SE) maximal fall in FEV1 in asthmatic and control subjects was of similar magnitude: test 1, 37.6 (1.4)% and 38.7 (3.1)%, and test 2, 36.0 (1.6)% and 27.7 (2.4)% respectively. There was a large interindividual variation in perception of airflow obstruction and breathlessness but, although they were well correlated in asthmatic subjects, they were perceived differently by the control subjects. Perception of airflow obstruction was greater in asthmatic subjects. The level of anxiety and the bronchodilator use were low and did not influence perception. CONCLUSIONS--During induced bronchoconstriction, the overall perception of airflow obstruction and breathlessness were similar among asthmatic subjects but controls showed a higher perception of airflow obstruction for any given level of breathlessness. Asthmatic subjects perceived airflow obstruction and breathlessness to a greater degree than did controls but anxiety and bronchodilator need were not correlated with respiratory sensation. The variability of bronchodilator use for similar degrees of bronchoconstriction suggests that it may be misleading to assess the severity of asthma control using only this indirect measure.     

Effect of nifedipine on arterial hypoxaemia occurring after methacholine challenge in asthma.

To investigate whether the effects of nifedipine on methacholine induced broncho-constriction could impair pulmonary gas exchange in bronchial asthma a randomised, double blind, crossover study in 13 symptom free asthmatic subjects was designed. Each patient underwent a methacholine bronchial challenge test on two separate days one week apart, after having either oral nifedipine (20 mg thrice daily) or placebo for three days. Arterial blood gases were measured before and after methacholine challenge in nine subjects. Prechallenge values of forced expiratory volume in one second (FEV1) and arterial oxygen tension (Pao2) were similar after nifedipine and after placebo. After challenge, the cumulative doses of methacholine required to produce a 20% fall in FEV1 (PD20 FEV1) were significantly larger after nifedipine (280 (SD 347)) cumulative breath units (CBU) than after placebo (120 (183) CBU; p less than 0.01). After challenge the fall in Pao2 values (17.1 (1.6) mm Hg; (2.28 (0.21) kPa)) was significantly greater than after placebo (11.7 (2.4) mm Hg; (1.56 (0.32) kPa) p less than 0.03). Our data show that although oral nifedipine significantly reduces airway reactivity in patients with mild bronchial asthma, it also adversely affects pulmonary gas exchange, resulting in a lowered postchallenge Pao2, probably because of worsening ventilation-perfusion relationships.     

Effect of nifedipine on bronchoconstriction induced by inhalation of cold air

The effect of nifedipine (20 mg sublingually) on the bronchial response to cold air was studied in eight asthmatic patients and eight normal subjects. Eucapnic hyperventilation with dry subfreezing air was performed for three minutes by each subject, with a minute volume of 30 X FEV1 for normal subjects and half that for the asthmatics. In the normal subjects there was no difference in the falls in the one-second forced expiratory volume (FEV1) and specific airways conductance (sGaw) produced by cold air inhalation on the days when they were pretreated with placebo and with nifedipine. In asthmatic patients, however, significant protection with nifedipine was demonstrated. The maximum recorded fall in FEV1 was reduced from 13% +/- 2% (SE) to 4% +/- 2% (p less than 0.005) and the maximum fall in sGaw from 35% +/- 5% to 17% +/- 4% (p less than 0.002). The possible causes of this difference are discussed. It is suggested that these results present further evidence for a different mechanism of response to cold air in asthmatic and normal subjects.     

Attenuation of early and late phase allergen-induced bronchoconstriction in asthmatic subjects by a 5-lipoxygenase activating protein antagonist, BAYx 1005

BACKGROUND: The cysteinyl leukotrienes (LTC4, LTD4 and LTE4) have been implicated in the pathogenesis of allergen-induced airway responses. The effects of pretreatment with BAYx 1005, an inhibitor of leukotriene biosynthesis via antagonism of 5-lipoxygenase activating protein, on allergen-induced early and late asthmatic responses has been evaluated. METHODS: Eight atopic subjects with mild asthma participated in a two period, double blind, placebo controlled, cross-over trial. Subjects were selected on the basis of a forced expiratory volume in one second (FEV1) of > 70% predicted, a methacholine provocative concentration causing a 20% fall in FEV1 (PC20) of < 32 mg/ ml, a documented allergen- induced early response (EAR, > 15% fall in FEV1 0-1 hour after allergen inhalation) and late response (LAR, > 15% fall in FEV1 3-7 hours after allergen inhalation), and allergen-induced airway hyperresponsiveness (at least a doubling dose reduction in the methacholine PC20 30 hours after allergen inhalation). During the treatment periods subjects received BAYx 1005 (500 mg twice daily) or placebo for 3.5 days; treatment periods were separated by at least two weeks. On the third day of treatment, two hours after administration of medication, subjects performed an allergen inhalation challenge and FEV1 was measured for seven hours. RESULTS: Treatment with BAYx 1005 attenuated the magnitude of both the allergen-induced early and late asthmatic responses. The mean (SE) maximal fall in FEV1 during the EAR was 26.6 (3.3)% during placebo treatment and 11.4 (3.3)% during treatment with BAYx 1005 (mean difference 15.2 (95% confidence interval (CI) 9.4 to 21.00) with a mean protection afforded by BAYx 1005 of 57.1%. The mean (SE) maximal fall in FEV1 during the LAR was 19.8 (5.7)% during placebo treatment and 10.7 (4.4)% during BAYx 1005 treatment (mean difference 9.2 (95% CI 1.4 to 17.0) with a mean protection afforded by BAYx 1005 of 46.0%. The area under the time response curve (AUC0-3) was also reduced after treatment with BAYx 1005 compared with placebo by 86.5%.h (mean difference 26.3 (95% CI 17.1 to 38.5)) and the AUC3-7 by 59.6%.h (mean difference 26.9 (95% CI-3.8 to 57.6)). CONCLUSIONS: These results show that antagonism of 5-lipoxygenase activating protein can attenuate allergen-induced bronchoconstrictor responses and support an important role for the cysteinyl leukotrienes in mediating these asthmatic responses.


     

Effect of inhaled H1 and H2 receptor antagonist in normal and asthmatic subjects

The effects on airflow resistance of an inhaled H1 receptor antagonist, clemastine, and an H2 receptor antagonist, cimetidine, have been investigated in normal and asthmatic subjects. No significant changes in specific conductance (sGaw) were seen in six normal subjects. In eight asthmatic subjects a significant increase in forced expiratory volume in one second (FEV1) occurred at 60 min (< 0.02), and 120 (< 0.05) after the inhalation of clemastine, whereas inhaled cimetidine had no effect on airflow resistance. Clemastine and cimetidine were tested on histamine-induced bronchoconstriction in eight normal and eight asthmatic subjects. Clemastine significantly reduced the fall in sGaw in normal subjects and the fall in FEV1 in asthmatic subjects, whereas cimetidine had no protective effect. Clemastine and ipratropium bromide were tested on methacholine-induced bronchoconstriction in eight normal subjects. Ipratropium bromide, but not clemastine, significantly reduced the fall in sGaw after methacholine. These results suggest that in normal and asthmatic subjects histamine-induced bronchoconstriction is mediated predominantly via H1 rather than H2 receptors in the airways.     

Effect of acute alterations in inspired oxygen tension on methacholine induced bronchoconstriction in patients with asthma

BACKGROUND: Recent in vitro and in vivo studies in animals have suggested that ambient oxygen tension may influence airway responsiveness to bronchoconstrictor stimuli. These observations may have relevance to the management of acute exacerbations of asthma. The present studies were designed to examine the influence of inspired oxygen tension (Fio2 1.0, 0.21, 0.15) on methacholine-induced broncho- constriction in patients with asthma. METHODS: In a dual study two groups of asthmatic patients performed methacholine inhalation challenges breathing either air (Fio2 0.21) or a hypoxic gas mixture (Fio2 0.15) in study 1 and air (Fio2 0.21) or hyperoxia (Fio2 1.0) in study 2. The gases were administered through a closed breathing circuit in a randomised double blind fashion. The PC20 values (dose of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) were calculated after each methacholine challenge by linear interpolation from the logarithmic dose response curve. Plasma catecholamine levels were measured before and after methacholine challenges as well as heart rate, oxygen saturation, and percentage end tidal carbon dioxide levels. RESULTS: The geometric mean PC20 value for methacholine was significantly lower on the hypoxic study day than on the normoxic day in study 1 (mean difference in PC20 values 2.88 mg/ml (95% CI 1.4 to 5.3); p < 0.05), but there was no significant difference in the geometric mean PC20 value for methacholine between the hyperoxic and normoxic study days in study 2 (mean difference in PC20 values 1.45 mg/ ml (95% CI 0.83 to 2.51)). CONCLUSIONS: Acute hypoxia potentiates methacholine induced bronchoconstriction and acute hyperoxia has no effect in mild to moderate patients with stable asthma.




     

Decreased peroxynitrite inhibitory activity in induced sputum in patients with bronchial asthma

BACKGROUND: The production of peroxynitrite, an extremely potent oxidant, is increased in inflammatory lung disease. It is therefore important to measure antioxidant activity against peroxynitrite in epithelial lining fluid to examine the physiological effects of peroxynitrite in the airways of patients with asthma. This study was designed to determine whether peroxynitrite inhibitory activity in induced sputum is correlated with clinical characteristics and airway inflammatory indices in asthmatic patients. METHODS: Inflammatory indices were measured in induced sputum from 25 patients with asthma and 12 normal control subjects. Peroxynitrite inhibitory activity was also measured by monitoring rhodamine formation in sputum samples. RESULTS: Peroxynitrite inhibitory activity in induced sputum was significantly lower in asthmatic patients (52.4 (24.5)%) than in normal control subjects (92.1 (3.9)%, p<0.0001). Its activity was significantly correlated with forced expiratory volume in 1 second (FEV(1)) % predicted (r=0.774, p<0.0001) and bronchial hyperreactivity to methacholine (r=0.464, p=0.023). There was a significant negative correlation between peroxynitrite inhibitory activity and the degree of eosinophilic airway inflammation (% eosinophils, r=-0.758, p<0.0001; eosinophil cationic protein, r=-0.780, p<0.0001). CONCLUSIONS: Decreased peroxynitrite inhibitory activity occurs in induced sputum of asthmatic patients. Since even in patients with stable asthma the airway lining fluid lacks peroxynitrite inhibitory activity, large amounts of peroxynitrite, which are further increased during an acute asthma attack, would not be completely inactivated and asthmatic airways might have markedly increased susceptibility to peroxynitrite induced airway injury.     

Comparison of circadian variations using FEV1 and peak expiratory flow rates among normal and asthmatic subjects.

BACKGROUND--Most studies that describe circadian variations in asthma have used maximum rate of peak expiratory flow (PEF) rather than forced expiratory volume in one second (FEV1) to assess airway calibre. This study was designed to assess circadian variations in PEF and FEV1 measured simultaneously and to compare variations in these measurements in normal and asthmatic subjects in a stable clinical state. METHODS--Twenty nine subjects (nine asthmatic subjects on bronchodilators, 10 on inhaled steroids, and 10 normal controls) were asked to record their PEF and FEV1 with a new portable instrument every two hours during the day and once on waking at night for two weeks. Circadian variations were examined in different ways using arithmetical indices and cosinor analysis. RESULTS--78% of PEF values and 75% of FEV1 values were considered to be reproducible and were included in the analysis. Variations obtained using PEF did not differ from those obtained using FEV1. Significant cosinor variations were found in at least 50% of recording days for most of the subjects and showed the same features as for arithmetical indices. Daily variations in PEF and FEV1 were significantly correlated with airway calibre and PC20 methacholine (r approximately 0.5 to approximately 0.6). CONCLUSIONS--PEF is as satisfactory as FEV1 for describing circadian variations among normal subjects and stable asthmatic subjects.     

Differences in responsiveness to hyperventilation and methacholine in asthma and chronic bronchitis.

In a previous study on 27 patients with chronic bronchitis we found that only three developed bronchoconstriction in response to hyperventilation of cold, dry air despite an increased responsiveness to methacholine inhalation. We therefore investigated bronchial responsiveness to hyperventilation with cold, dry air and methacholine in 27 patients with stable asthma who had a similar range of baseline FEV1 values but who developed bronchoconstriction that could be reversed to give an FEV1 more than 70% of the predicted value. Baseline FEV1 was 0.88-3.98 l (37-114% predicted). All but one subject developed bronchoconstriction in response to hyperventilation. There was a linear relationship between baseline FEV1 and response to methacholine (r2 = 0.37, p less than 0.001) and the relationship was significantly different from that found in the bronchitic subjects (F2.50 = 24.94, p less than 0.001). In general, the response to methacholine was greater in the asthmatic than in the bronchitic subjects for any baseline FEV1. The results suggest that there are different mechanisms underlying the increased responsiveness to methacholine in asthma and chronic bronchitis.     

Vitamin E supplements in asthma: a parallel group randomised placebo controlled trial

BACKGROUND: Increased dietary vitamin E intake is associated with a reduced incidence of asthma, and combinations of antioxidant supplements including vitamin E are effective in reducing ozone induced bronchoconstriction. A study was undertaken to investigate the effect of supplementation with vitamin E for 6 weeks on bronchial hyperresponsiveness in atopic adults with asthma. METHODS: 72 participants from a clinical trial register of adults with asthma were randomised to receive 500 mg natural vitamin E or matched placebo for 6 weeks in a placebo controlled, double blind parallel group clinical trial. Inclusion criteria included age 18-60 years, maintenance treatment of at least one dose of inhaled corticosteroid per day, a positive skin prick test to one of three common allergens, and bronchial hyperresponsiveness to methacholine (defined as a dose provoking a 20% fall in forced expiratory volume in 1 second (FEV(1)) (PD(20)) of 12.25 micromol). Secondary outcomes were FEV(1), forced vital capacity, mean morning and evening peak flow, symptom scores, bronchodilator use, and serum immunoglobulin E levels. RESULTS: In the primary intention to treat analysis the change in PD(20) was similar in the vitamin E and placebo groups with a mean difference of +0.25 doubling doses of methacholine (95% confidence interval -0.67 to +1.16 greater with vitamin E). There was no effect of vitamin E supplementation on any other measure of asthma control, either in the intention to treat or per protocol analysis. There was also no effect of vitamin E supplementation on serum immunoglobulin levels. CONCLUSION: Dietary supplementation with vitamin E adds no benefit to current standard treatment in adults with mild to moderate asthma.     

Involvement of vascular endothelial growth factor in exercise induced bronchoconstriction in asthmatic patients

BACKGROUND: There is evidence that the bronchial microcirculation has the potential to contribute to the pathophysiological mechanisms of exercise induced bronchoconstriction (EIB) in asthmatic subjects. Vascular endothelial growth factor (VEGF), which is highly expressed in asthmatic airways, increases vascular permeability. The relationship between VEGF levels in induced sputum and the severity of EIB in asthmatic subjects was studied. METHODS: The concentration of VEGF in induced sputum was examined in 23 asthmatic subjects and 11 normal controls. The asthmatic subjects performed an exercise test and the % maximal fall in forced expiratory volume in 1 second (FEV(1)) was measured. Beclomethasone dipropionate (BDP) 400 micro g twice daily was administered to the asthmatic subjects for 8 weeks and the exercise test and sputum induction were repeated. RESULTS: The concentration of VEGF in induced sputum was significantly higher in asthmatic subjects than in normal controls. There was a significant correlation between the concentration of VEGF and the % maximal fall in FEV(1) (r=0.826, p=0.0001) and between the concentration of VEGF and airway vascular permeability index (r=0.621, p=0.0037). After treatment with inhaled BDP there was a significant decrease in the concentration of VEGF in the asthmatic subjects (before treatment: 7051 (2361) pg/ml, after treatment: 4498 (2135) pg/ml, p<0.0001). The change in the concentration of VEGF was significantly correlated with the change in the % maximal fall in FEV(1) (r=0.463, p=0.031). CONCLUSIONS: Excessive production of VEGF in asthmatic airways may contribute to the pathogenesis of EIB via increased airway vascular permeability.     

Effect of oral L-arginine on airway hyperresponsiveness to histamine in asthma

BACKGROUND: Nitric oxide (NO) may exert protective properties within the airways of asthmatic patients. It was postulated that airways obstruction in asthma may be associated with endogenous NO deficiency caused by limited availability of NO synthase substrate. METHODS: In a double blind, crossover study 14 asthmatic patients received pretreatment with oral L-arginine (50 mg/kg body weight) or placebo prior to histamine challenge. Histamine challenge was performed until a 50% fall in forced expiratory volume in one second (FEV(1)) occurred and the response was expressed as the provocative concentration causing a 20% fall in FEV(1) (PC(20)) and as the dose-response slope (maximal % fall in FEV(1)/cumulative dose (micromol)). RESULTS: Pretreatment with L-arginine did not affect PC(20) histamine (mean change in doubling dose 0.18 (95% confidence interval (CI) -0.36 to 0.71), p = 0.5) but the dose-response slope to histamine was slightly reduced (mean change: 0.7 (95% CI 0.6 to 0. 9), p = 0.016). CONCLUSIONS: Oral L-arginine does not influence airway hyperresponsiveness to histamine as reflected by PC(20), although the dose-response slope is slightly reduced in patients with asthma. This indicates only marginal, clinically unimportant limitation of NO synthase substrate in asthma.     

Effect of methacholine induced bronchoconstriction on the spectral characteristics of breath sounds in asthma.

BACKGROUND: Analysis of breath sounds by digital techniques offers an attractive non-invasive method of monitoring changes in airway calibre. Asthmatic breath sounds have been analysed and related to changes in forced expiratory volume in one second (FEV1). METHODS: Bronchoconstriction was induced with methacholine in six asthmatic subjects on two occasions and changes in FEV1 and breath sound spectra were measured. RESULTS: Audible wheeze appeared after a mean (SE) fall in FEV1 of 35% (6.3%) but the level was not reproducible within patients. The mean and median frequency of the spectra of breath sounds correlated with the percentage of predicted FEV1 (r = -0.5 and -0.6 respectively; p < 0.001). Inclusion of the quartile frequencies in a stepwise multiple regression reduced the residual variance by a further 9%. CONCLUSION: Detecting changes in airway calibre by this method of sound analysis so far produces qualitative data only and will not yield quantitative data in individual patients.     

Effects of prior treatment with salmeterol and formoterol on airway and systemic beta 2 responses to fenoterol.

BACKGROUND: Previous studies have shown that both salmeterol and formoterol act as partial beta 2 receptor agonists in terms of antagonising the extrapulmonary responses to fenoterol in normal subjects. The aim of the present study was to extend previous observations in evaluating the effect of prior treatment with salmeterol and formoterol on bronchodilator responses to fenoterol, a full beta 2 receptor agonist, in patients with asthma. METHODS: Ten stable asthmatic patients of mean (SE) age 37 (3.7) years and forced expiratory volume in one second (FEV1) 59.5 (4.1)% of predicted completed the study. One hour after inhaling single doses of placebo, salmeterol 25 micrograms, or formoterol 12 micrograms, dose-response curves to repeated doses of inhaled fenoterol were constructed (cumulative doses of 100-3200 micrograms). Measurements of airway and systemic beta 2 receptor mediated responses were made at baseline, after inhalation of placebo, salmeterol, or formoterol, and after each dose of fenoterol. RESULTS: Salmeterol and formoterol produced significant bronchodilation compared with placebo (mean difference and 95% CI compared with placebo): FEV1, salmeterol 0.41 (95% CI 0.13 to 0.69) 1, formoterol 0.47 (95% CI 0.19 to 0.75) 1. Salmeterol and formoterol had no significant effect on systemic responses compared with placebo. There were no significant differences in peak airway responses to fenoterol after treatment with salmeterol or formoterol compared with placebo (mean (pooled SE)): FEV1, placebo 2.84 (0.03) 1, salmeterol 2.87 (0.03) 1, and formoterol 2.88 (0.03) 1. There were no significant differences in the area under the dose-response curve for any of the parameters during the dose-response curve following treatment with salmeterol or formoterol compared with placebo. There was no difference in the slope of the dose-response curves to fenoterol for FEV1 or forced expiratory flow (FEF25-75) after treatment with salmeterol or formoterol compared with placebo, although there was a significant (p < 0.05) attenuation of the slope in the dose-response curve for the peak expiratory flow rate (PEFR). CONCLUSIONS: Prior treatment with low doses of salmeterol or formoterol does not significantly alter bronchodilator dose-response curves to repeated doses of fenoterol in stable asthmatic patients.     

Reduction in exhaled nitric oxide immediately after methacholine challenge in asthmatic children

BACKGROUND: The measurement of exhaled nitric oxide (NO) has recently been proposed as a useful technique for the evaluation of airway inflammation in asthma. The purpose of this study was to determine the effect of methacholine bronchial provocation on the levels of exhaled NO in asthmatic children. METHOD: Exhaled NO was measurement immediately before and after methacholine provocation in 51 children with mild to moderate asthma. RESULTS: A significant decrease occurred in the level of exhaled NO (p<0.0001) after methacholine bronchial provocation which was not correlated with the percentage fall in forced expiratory volume in 1 second (FEV(1)). CONCLUSIONS: The methacholine test should not be used immediately before measurement of exhaled NO in children with asthma.     

Comparison of airway reactivity induced by histamine, methacholine, and isocapnic hyperventilation in normal and asthmatic subjects

In an investigation of a rapid screening test for airway reactivity using isocapnic hyperventilation with room air and cold air the results of this test were compared with the airway response to histamine and methacholine challenge. Twelve non-atopic, non-smoking normal subjects and 11 subjects with stable asthma who had an FEV1 above 74% of the predicted value were studied. In the normal subjects isocapnic hyperventilation with room air (75 l/min; 22 degrees C (SEM 0.2 degrees); 10 mg H2O/l air) and isocapnic hyperventilation with cold air (77 l/min; -10 degrees C (0.9 degrees); 2.4 mg H2O/l air) produced no significant change in FEV1. In the asthmatic subjects, hyperventilation with room air (71 l/min; 22 degrees C (0.8 degrees); 10 mg H2O/l air) caused a mean fall in FEV1 of 11.7%; cold air hyperventilation (70 l/min; -10 degrees C (0.9 degrees); 2.4 mg H2O/l air) caused a mean fall in FEV1 of 20.4%. Cold air hyperventilation produced greater separation between normal and asthmatic subjects than room air. The provocative concentration of histamine required to reduce the FEV1 by 20% (PC20) correlated closely with the PC20 for methacholine (r = 0.95; p less than 0.001). Both tests separated normal from asthmatic subjects. PC20 for both histamine and methacholine correlated with the fall in FEV1 after cold air hyperventilation (r = 0.93, p less than 0.001; r = 0.87, p less than 0.001 respectively). We conclude that the results of a rapid screening test based on hyperventilation with cold air correlate well with a standard pharmacological challenge.