Effect of inhaled procaterol on cough receptor sensitivity to capsaicin in patients with asthma or chronic bronchitis and in normal subjects.

BACKGROUND--To evaluate the effect of inhaled beta 2 adrenergic agonists on the sensitivity of airway cough receptors, the effect of inhaled procaterol on cough induced by aerosolised capsaicin, a stimulant of C fibres, was studied in patients with asthma or chronic bronchitis and in normal subjects. METHOD--Eleven patients with asthma and 10 with chronic bronchitis and 14 normal subjects participated. Increasing concentrations of capsaicin solution were inhaled for 15 seconds by tidal breathing through the mouth at one minute intervals until five or more coughs were elicited, before and 30 minutes after inhalation of 20 micrograms procaterol or placebo (freon gas alone) through a metered dose inhaler. Cough threshold was defined as the lowest concentration of capsaicin that elicited five or more coughs. To evaluate the bronchodilator effect of procaterol and the bronchoconstrictor effect of inhaled capsaicin, forced expiratory volume in one second (FEV1) was measured before and one minute after a capsaicin provocation test. This test was carried out both before and 30 minutes after treatment with procaterol or placebo. RESULTS--The geometric mean value of cough threshold to capsaicin was significantly increased by procaterol and placebo in both groups of patients but not in the control subjects. The increment in the cough threshold was not significantly different between the treatments with procaterol and placebo in each group. FEV1 was significantly increased by procaterol but not by placebo in all three groups. CONCLUSIONS--Inhaled procaterol has no effect on airway cough receptor sensitivity to capsaicin. The attenuation of the cough sensitivity seen after inhalation of procaterol in patients with asthma and bronchitis may result from tachyphylaxis to capsaicin.     

Effect of oral mexiletine on the cough response to capsaicin and tartaric acid

BACKGROUND: The effect of the orally active local anaesthetic mexiletine on the cough response to two different tussive agents, a C-fibre ending stimulator capsaicin and a chemostimulant tartaric acid, was examined in normal subjects. METHODS: The cough threshold, defined as the lowest concentration of capsaicin (C(5)-CP) or tartaric acid (C(5)-TA) causing five or more coughs, and histamine induced bronchoconstriction were measured three hours after a single oral dose of 300 mg mexiletine or placebo in 14 normal subjects. RESULTS: Mexiletene in a mean (SE) serum concentration of 0.99 (0. 04) microg/ml significantly increased C(5)-TA from a geometric mean (SE) of 32.0 (1.27) mg/ml with placebo to 49.9 (1.34) mg/ml, but C(5)-CP did not differ significantly between treatment with mexiletine (12.2 (1.33) microM) and placebo (14.9 (1.23) microM). CONCLUSIONS: These results suggest that the cough response to capsaicin and tartaric acid may be mediated in part via different neural pathways.     

Sex difference in the inhaled tartaric acid cough threshold in non-atopic healthy subjects.

The threshold for cough induced by inhaled tartaric acid was measured in 71 non-atopic healthy volunteers. The cough threshold was lower in women than in men, which may be relevant to previous reports that angiotensin converting enzyme inhibitors induce cough more frequently in women than in men.     

Effects of inhaled histamine, methacholine and capsaicin on sputum levels of alpha 2-macroglobulin

BACKGROUND: Plasma exudation-derived proteins and peptides contribute significantly to inflammation in the airway mucosa in vivo. In the guinea pig trachea both histamine and the neurogenic stimulant capsaicin produce acute mucosal tissue distribution and luminal entry of bulk plasma, whereas cholinergic agonists fail to produce this effect. Of these agents, only histamine induces mucosal exudation of plasma in human nasal airways. The exudative effect of the above agents on human bronchi remains unknown. METHODS: The bronchial exudative responses to inhalation of histamine, methacholine, and capsaicin were examined in two groups of healthy volunteers. Sputum was induced on three occasions in each study group by inhalation of hypertonic saline (4.5%) given as an aerosol for 40 minutes using an ultrasonic nebuliser. The second and third occasions were preceded by histamine and capsaicin challenges in the first study group, and by histamine and methacholine challenges in the second study group. Histamine and methacholine were given in cumulative doses (total doses 3160 micrograms, respectively) or until a 20% reduction in forced expiratory volume in one second (FEV1) was achieved. Cumulative doses of capsaicin were inhaled until coughing prevented the subjects from drawing a full breath. Sputum levels of alpha 2-macroglobulin (729 kDa) were measured as an index of mucosal exudation of bulk plasma. RESULTS: Histamine increased mean (SE) sputum levels of alpha 2-macroglobulin from 2.72 (1.01) micrograms/ml (95% confidence interval (CI) 0.49 to 4.94) to 18.38 (8.03) micrograms/ml (95% CI 0.49 to 36.27) in the first group, and from 1.66 (0.84) micrograms/ml (95% CI -0.18 to 3.49) to 9.43 (3.63) micrograms/ml (95% CI 1.59 to 17.27) in the second group. In contrast, capsaicin evoked no exudation (sputum levels of alpha 2- macroglobulin 1.21 (0.28) micrograms/ml (95% CI 0.59 to 1.83)) and methacholine produced a minor increase in sputum levels of alpha 2- macroglobulin (2.90 (0.92) micrograms/ml (95% CI 0.90 to 4.89)). CONCLUSIONS: These results indicate that histamine is a useful agent for studying bronchial exudative responsiveness in man and that exudative effects are only of marginal importance in the cough and bronchoconstriction produced by capsaicin and methacholine.


     

Association of genetic variations in neurokinin-2 receptor with enhanced cough sensitivity to capsaicin in chronic cough

BACKGROUND: Chronic cough is associated with increased sensitivity to inhaled capsaicin, and both tachykinins and their receptors play important roles in the cough reflex. However, associations between polymorphisms of the tachykinin receptor genes and cough sensitivity in patients with non-productive chronic cough have not been reported. METHODS: Direct sequencing was used to identify single nucleotide polymorphisms (SNPs) in the genes for the neurokinin-1 and neurokinin-2 receptors (NK-1R and NK-2R, respectively). Informative non-synonymous SNPs were scored using the single base extension method for 312 patients with chronic cough and for 100 age matched healthy controls. The cough response to capsaicin was recorded for 312 patients with chronic cough, and the potential genetic association between cough sensitivity to capsaicin and the NK-1R and NK-2R genotypes was evaluated. RESULTS: Two informative SNPs were identified in NK-2R (Gly231Glu and Arg375His), whereas no informative SNP was found in NK-1R. After adjusting for atopy, sex, age, and smoking, the prevalence of enhanced cough sensitivity to capsaicin was higher in the chronic cough patients with the 231Glu allele (p = 0.004; OR 1.69 (95% CI 1.18 to 2.42)) and the 231Glu_375Arg haplotype (p = 0.003; OR 1.71 (95% CI 1.20 to 2.24)). Moreover, the lowest capsaicin concentration to cause five consecutive coughs (C5) was significantly lower in patients with 231Glu (mean (SD) 44.1 (53.2) v 60.9 (55.8) microM/l, p = 0.04) and those with 231Glu_375Arg (43.2 (52.7) v 69.6 (52.0) microM/l, p = 0.03). CONCLUSIONS: The results of this study suggest that NK-2R gene polymorphisms are involved in the enhanced cough sensitivity to capsaicin of patients with chronic cough.     

Effect of inhaled menthol on citric acid induced cough in normal subjects.

BACKGROUND--Menthol is a commonly used ingredient in many over the counter cough remedies, but there is little objective evidence as to its efficacy. METHODS--Twenty healthy subjects received a cough challenge consisting of five inhalations of 33 mumol citric acid from an air driven dosimeter. The challenge was repeated at hourly intervals for five hours. Five minutes before each challenge subjects inhaled, in a randomised design, either menthol 75% in eucalyptus oil or one of two placebos (pine oil or air). RESULTS--Menthol inhalation caused a reduction in evoked cough when compared with either placebo. CONCLUSIONS--Menthol is an effective antitussive agent in an evoked cough model.     

Effect of methacholine induced bronchoconstriction on the pulmonary distribution and plasma pharmacokinetics of inhaled sodium cromoglycate in subjects with normal and hyperreactive airways.

Inhalation treatment may be less effective in the presence of bronchoconstriction because of the reduced penetration of drugs into the airways. The effect of bronchoconstriction on the lung deposition and plasma pharmacokinetics of inhaled sodium cromoglycate was examined. Ten subjects attended the laboratory on three occasions. On the first occasion a bronchial provocation test was performed to determine the concentration of methacholine required to reduce the forced expiratory volume in one second (FEV1) by 20% (PC20). On the two subsequent occasions subjects inhaled either saline or their PC20 methacholine, followed five minutes later by an aerosol containing sodium cromoglycate and stannous phytate labelled with technetium-99m. Twenty minutes later a gamma emission lung scan was performed to determine the intrathoracic deposition of the nebulised aerosol. The central:peripheral (C:P) ratio of lung deposition was then calculated. Measurements of FEV1 were made and blood samples taken for analysis of plasma sodium cromoglycate concentration at intervals for four hours. Methacholine led to a 23.4% (SEM 0.6%) lower FEV1 and a 2.8 times higher C:P ratio than those observed after saline. There was a direct correlation between log PC20 methacholine and the increase in the C:P ratio (r = 0.81). Despite these changes with methacholine, the plasma pharmacokinetics of inhaled sodium cromoglycate were not significantly different after methacholine and after saline, except that the maximum concentration achieved (Cmax) was increased. These observations suggest that the area of cromoglycate deposition and the anatomical site are less important in determining the plasma pharmacokinetics of cromoglycate than is the total dose delivered to the lung.     

Abolition of methacholine induced bronchoconstriction by the hyperventilation of exercise or volition.

Total pulmonary resistance was measured from continuous records of flow and oesophageal pressure in five normal subjects on three separate days before and after inhalation of methacholine. The dose of methacholine produced, on average, a fivefold increase in airway resistance. Immediately after methacholine inhalation the subjects underwent a progressive exercise test on a cycle ergometer (day 1) or voluntary hyperventilation (day 2) or remained resting (day 3). On the first day during exercise pulmonary resistance fell rapidly to baseline levels within two to three minutes and remained there for the 10 minute duration of the exercise. On day 2 voluntary reproduction of the same level and pattern of ventilation as during exercise resulted in a similar fall of resistance. On the third day, when the subjects remained at rest, pulmonary resistance remained raised for 10 minutes. It is concluded that the bronchodilator effects of exercise can be explained by the increased ventilation rather than the exercise itself, but with much smaller tidal volumes than have previously been thought necessary to reduce drug induced bronchoconstriction.     

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 inhaled lignocaine and adrenaline on capsaicin-induced cough in humans.

BACKGROUND--The hypothesis that adrenaline can augment and/or prolong the antitussive effect of nebulised lignocaine was examined. METHODS--The effect of inhaled lignocaine alone (20 mg) and in combination with adrenaline (400 micrograms) was studied on capsaicin-induced cough in 10 healthy subjects. RESULTS--Cough was significantly reduced between five and 25 minutes by lignocaine. Adrenaline alone had no inhibitory effect and it neither augmented nor prolonged the antitussive effect of lignocaine. The subjective anaesthesia by lignocaine was short lasting (less than 15 minutes) and not altered by adrenaline, suggesting different sensory mechanisms for anaesthesia and cough suppression. Plasma concentrations of lignocaine were low (< 30 ng/ml), not altered by adrenaline, and did not correlate with the local anaesthetic or the antitussive effect. CONCLUSIONS--Lignocaine acts locally in the oropharynx and airways and adrenaline does not alter the effect or absorption of nebulised lignocaine on the human respiratory mucosa.     

Reproducibility and comparison of responses to inhaled histamine and methacholine.

The efficiency of a standardised inhalation test procedure was studied by examining the reproducibility of responses to histamine and methacholine. In addition, the responses to the two agents were compared. Each set of duplicate tests was carried out on a separate day within one week, and all factors known or presumed to influence responses were carefully controlled. The results were expressed as the provocative concentration of the agent causing a 20% fall in forced expired volume in one second (PC20). Responses to histamine and methacholine were highly reproducible (coefficients of determination [r2] = 0.994 and 0.990 respectively). Responsiveness to histamine correlated closely with responsiveness to methacholine (r2 = 0.85). There was a small but significant cumulative dose effect with methacholine (P less than 0.01) but not with histamine. Side effects of throat irritation, flushing, and headache were more frequent with histamine than methacholine, and were dose-related. The high level of reproducibility indicates the efficiency of the test procedure. The similar severity of effects by agents with different mechanisms of action suggests that the primary cause of non-specific bronchial hyperreactivity lies at the level of bronchial smooth muscle.     

Effect of bronchodilators on the cough response to inhaled citric acid in normal and asthmatic subjects.

Coughing was induced in seven normal and eight asthmatic subjects by giving successive inhalations of citric acid aerosols of progressively higher concentration (range 0.5-32%). A baseline cough response was obtained on each of four experimental days, and there was no significant difference between days in this respect. Then the subjects received by inhalation either a bronchodilator (salbutamol 5 mg or ipratropium 1 mg) or placebo, in a paired double blind crossover design. A second citric acid run followed and was used for paired drug-placebo comparisons. In the asthmatic subjects the cough response was diminished by both bronchodilators (p less than 0.05), and the cough threshold was significantly higher after ipratropium but not salbutamol. In normal subjects no significant effects were found. Airways calibre was assessed, by an oscillatory technique that measures the resistance of the respiratory system (Siemens Siregnost FD 5), in four of the seven normal and all eight asthmatic subjects. The mean respiratory resistance was higher in asthmatic than in normal subjects, and fell significantly after both bronchodilators. In normal subjects smaller decreases in respiratory resistance occurred, significant only with salbutamol. The simplest hypothesis which explains the results relates change in cough response to altered neuroreceptor sensitivity associated with rapid changes in bronchial calibre.     

Modification of concentration-response curves to inhaled methacholine after the pollen season in subjects with pollen induced rhinitis.

BACKGROUND--The effect of cessation of exposure to pollen on the concentration-response curves to inhaled methacholine was investigated. METHODS--Methacholine inhalation challenges (up to 200 mg/ml) were performed in 13 non-asthmatic patients with grass and/or Parietaria pollen-induced rhinitis during the pollen season, and one and four months after it. Concentration-response curves were characterised by their PC20, position, and plateau. RESULTS--Geometric mean methacholine PC20 increased from 6.4 mg/ml during the pollen season to 28.2 mg/ml and 54.9 mg/ml one and four months after the end of season, respectively. The mean (SE) level of the plateau decreased from 30.5 (4.3%) in the pollen season to 23.3 (3.7)% and 20.1 (3.3)% one and four months after the end of pollen season, respectively. Although the methacholine concentration that produced 50% of the maximal response increased from 2.9 mg/ml to 4.3 mg/ml and 6.0 mg/ml, the differences were not significant. CONCLUSIONS--In non-asthmatic patients with pollen-induced rhinitis cessation of exposure to pollen is associated with significant modifications in the methacholine threshold value and level of plateau, and with a small shift in the concentration-response curves to the right.     

Potentiating effect of inhaled acetaldehyde on bronchial responsiveness to methacholine in asthmatic subjects.

BACKGROUND--It has recently been reported that acetaldehyde induces bronchoconstriction indirectly via histamine release. However, no study has been performed to assess whether acetaldehyde worsens bronchial responsiveness in asthmatic subjects so this hypothesis was tested. METHODS--Methacholine provocation was performed on three occasions: (1) after pretreatment with oral placebo and inhaled saline (P-S day), (2) after placebo and inhaled acetaldehyde (P-A day), and (3) after a potent histamine H1 receptor antagonist terfenadine and acetaldehyde (T-A day) in a double blind, randomised, crossover fashion. Nine asthmatic subjects inhaled 0.8 mg/ml acetaldehyde or saline for four minutes. After each inhalation a methacholine provocation test was performed. RESULTS--Methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) on the P-A day (0.48 mg/ml, 95% CI 0.21 to 1.08) and T-A day (0.41 mg/ml, 95% CI 0.22 to 0.77) were lower than those on the P-S day (0.85 mg/ml, 95% CI 0.47 to 1.54). There was no change in the PC20-MCh between the P-A and T-A days. A correlation was observed between the logarithmic values of PC20-MCh (log PC20-MCh) on the P-S day and the potentiating effect of acetaldehyde on the methacholine responsiveness [(log PC20-MCh on P-A day)-(log PC20-MCh on P-S day)] (rho = 0.82). CONCLUSIONS--Acetaldehyde induces bronchial hyperresponsiveness in patients with asthma by mechanisms other than histamine release.     

Changes in methacholine induced bronchoconstriction with the long acting beta 2 agonist salmeterol in mild to moderate asthmatic patients.

BACKGROUND--Beta-2 agonists protect against non-specific bronchoconstricting agents such as methacholine, but it has been suggested that the protection afforded by long acting beta 2 agonists wanes rapidly with regular treatment. METHODS--The changes in airway responsiveness were investigated during and after eight weeks of regular treatment with salmeterol 50 micrograms twice daily in 26 adult asthmatic patients, 19 of whom were receiving maintenance inhaled corticosteroids. The study was of a randomised, placebo controlled, double blind design. Airway responsiveness to methacholine was measured as PD20 by a standardised dosimeter technique 12 hours after the first dose, at four weeks and eight weeks during treatment (12 hours after the last dose of test medication), and at 60 hours, one week and two weeks after stopping treatment. RESULTS--There were no significant differences between the baseline characteristics of the two groups. A significant improvement in PD20 was seen at all points during treatment with salmeterol compared with the placebo group, with no significant fall off with time. PD20 measurements returned to baseline values after cessation of treatment with no significant difference from the placebo group. CONCLUSIONS--Salmeterol gave significant protection against methacholine induced bronchoconstriction 12 hours after administration. This protection was of small magnitude, but there was no significant attenuation with eight weeks of regular use and no rebound increase in airway responsiveness on stopping treatment in a group of moderate asthmatic patients, the majority of whom were receiving inhaled corticosteroids.     

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.




     

Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children.

The prevalence of bronchial hyperreactivity to inhaled methacholine and of a clinical history of symptoms of asthma was determined in a birth cohort of 9 year old New Zealand children. A history of current or previous recurrent wheezing was obtained in 220 of 815 children. Of 800 who had spirometric tests, 27 (3.4%) had resting airflow obstruction (FEV1/FVC less than 75%). Methacholine challenge was undertaken without problem in 766 children, the abbreviated protocol being based on five breaths and four concentrations. A fall in FEV1 of more than 20% was observed in 176 children (23% of challenges, 22% of the full cohort) after inhalation of methacholine in concentrations of up to 25 mg/ml. The prevalence of bronchial reactivity in children with symptoms was related to the frequency of wheezing episodes in the last year, and the degree of reactivity to the interval since the last episode. Sixty four children (8.0%) with no history of wheeze or recurrent dry cough were, however, also responsive to methacholine 25 mg/ml or less, while 35% of children with current or previous wheezing did not respond to any dose of methacholine. Bronchial challenge by methacholine inhalation was not sufficiently sensitive or specific to be useful as a major criterion for the diagnosis of asthma in epidemiological studies. The occurrence of airway reactivity in children without symptoms of asthma, however, raises the possibility that adult onset asthma and the development of airways obstruction in some subjects with chronic bronchitis could have origins in childhood.     

Effects of calcium channel blockade on histamine induced bronchoconstriction in mild asthma.

Inhalation histamine dose-response curves were constructed 15 minutes after inhalation of saline placebo or verapamil (4 mg) for eight patients with mild atopic asthma in a double blind, random manner. No significant change in baseline specific airways conductance occurred after inhalation of verapamil, though there was a significant decrease in sensitivity to histamine (increase in threshold of response) (p less than 0.01). There was, however, an associated significant increase (p less than 0.01) in the slopes of the subsequent histamine dose-response curves.     

Effect of nedocromil sodium on the airway response to inhaled capsaicin in normal subjects.

In six normal subjects treatment with 4 mg nedocromil sodium failed to alter the cough and bronchoconstriction induced by inhaled capsaicin. Because nedocromil has previously been shown to inhibit reflex bronchoconstriction provoked by inhaled sulphur dioxide and inhaled bradykinin, the results suggest that inhaled capsaicin acts on different nerve fibres.