Diurnal variation in serum cortisol concentrations in asthmatic subjects after allergen inhalation.

To assess whether differences in the adrenal response to allergen are important in determining the magnitude of the allergen induced late responses in asthmatic subjects, we measured serum cortisol concentrations after inhalation challenge with allergen or control solution (phosphate buffered saline). The two challenges were performed in random order with an interval of 14 days. A normal diurnal decrease in serum cortisol concentrations was observed on both days. Mean blood cortisol concentrations three hours after inhalation of allergen (before the late response), nine hours afterwards (at the time of the late response), and 24 hours afterwards were virtually identical to those observed after inhalation of phosphate buffered saline. Serum cortisol concentrations before challenge and three, nine, and 24 hours after challenge were not related to the diurnal increase in blood eosinophils on the control day, or to the size of the late asthmatic response or accompanying changes in blood eosinophils after allergen challenge. It is concluded that serum cortisol concentrations show normal diurnal variation after allergen challenge and are unrelated to the size of the late response or associated changes in blood eosinophil counts.     

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.     

Airway response to inhaled salbutamol in hyperthyroid and hypothyroid patients before and after treatment.

For many years the development of thyrotoxicosis has been known to cause a deterioration in asthma but the mechanism is unknown. We have studied the effect of thyroid function on airway beta adrenergic responsiveness in 10 hyperthyroid and six hypothyroid subjects before and after treatment of their thyroid disease. Airway adrenergic responsiveness was assessed by measuring specific airway conductance (sGaw) after increasing doses of inhaled salbutamol (10-410 micrograms). After treatment there was no difference in resting FEV1, sGaw, or thoracic gas volume. FVC increased in the hyperthyroid subjects but did not change in the hypothyroid subjects. In the hyperthyroid subjects there was a significant increase in delta sGaw after 35, 60, 110, and 41 micrograms salbutamol; in sGaw after 60, 110, and 410 micrograms salbutamol; and in the area under the salbutamol dose response curve (AUC) after treatment of the thyroid disorder. In the hypothyroid subjects there was a significant reduction in sGaw after 10 and 60 micrograms salbutamol and in the AUC after treatment. When all subjects were considered, there was a negative correlation between the AUC and serum thyroxine values. These findings suggest that an inverse relationship exists between the level of thyroid function and airway beta adrenergic responsiveness.     

Airway response to salbutamol: effect of regular salbutamol inhalations in normal, atopic, and asthmatic subjects.

This study was designed to determine whether resistance to the airway effects of the beta-agonist, salbutamol, would develop in three groups of subjects while taking large doses of inhaled salbutamol. Six normal non-atopic, six atopic non-asthmatic, and eight atopic asthmatic subjects were studied by an identical technique. The development of resistance was assessed from salbutamol dose-response studies in which the airway response was measured as specific airway conductance (sGaw). Further evidence was sought in the atopic and asthmatic subjects by measuring the airway response to a standard histamine inhalation challenge and the protective effect of 100 micrograms salbutamol on this challenge, and by six-hourly peak flow recordings. Subjects were assessed before and during four weeks in which they took inhaled salbutamol regularly in doses increasing to 500 microgram quid in week 4. Normal subjects showed a progressive reduction in the bronchodilator (sGaw) response to salbutamol during the four weeks, indicating the progressive development of resistance. The atopic subjects, both asthmatic and non-asthmatic, showed no reduction in the response to salbutamol during the four weeks, nor any change in the response to histamine challenge or in regular peak flow readings. These results demonstrate that asthmatic patients do not develop bronchial beta-adrenoceptor resistance easily and suggests that they and atopic non-asthmatic subjects are less susceptible to its development than normal subjects.     

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.     

The effect of inhaled frusemide on airway sensitivity to inhaled 4.5% sodium chloride aerosol in asthmatic subjects.

BACKGROUND: Frusemide inhaled by asthmatic subjects before a variety of indirect bronchial challenges inhibits the airway response to these challenges. Since inhalation of hyperosmolar saline is an indirect bronchial challenge, the effect of inhaled frusemide and its vehicle on airway sensitivity to a 4.5% sodium chloride (NaCl) aerosol challenge was investigated. METHODS: Eleven asthmatic subjects (five females, six males) who had a 20% fall in forced expiratory volume in one second after 4.5% NaCl challenge were enrolled in this double blind controlled crossover trial. Sensitivity was measured as the dose of aerosol required to provoke a 20% fall in FEV1. Frusemide (33.2 mg) or its vehicle was delivered through a Fisoneb ultrasonic nebuliser and inhaled 10 minutes before challenge with 4.5% NaCl. A Mistogen ultrasonic nebuliser was used to generate the 4.5% NaCl aerosol and FEV1 was measured before and one minute after each challenge period of 0.5, one, two, four, eight, eight and eight minutes. The doubling dose difference for PD20 was calculated. RESULTS: Frusemide or vehicle had no effect on baseline lung function. The geometric mean PD20 after vehicle was 1.3 ml with a 95% confidence interval of 0.7-2.3 and after frusemide was 8.2 ml with a 95% confidence interval of 4.7-14.1. This represented a 2.6 doubling dose increase in PD20 after frusemide inhalation. In five of the 11 subjects an increase from baseline FEV1 occurred after exposure to 4.5% NaCl challenge in the presence of frusemide. This transient bronchodilatation may be caused by the release of prostaglandin E2. CONCLUSION: Inhalation of frusemide is very effective in delaying airway narrowing induced by an aerosol of 4.5% NaCl in asthmatic subjects.     

Effect of inhaled frusemide and oral indomethacin on the airway response to hypertonic saline challenge in asthmatic subjects

BACKGROUND: Inhaled frusemide inhibits airway narrowing and causes a transient increase in forced expiratory volume in one second (FEV1) during hypertonic saline challenge. This inhibitory effect could be secondary to prostaglandin release during challenge. The involvement of prostaglandins in the inhibitory action of frusemide during challenge with 4.5% NaCl was investigated by premedicating with indomethacin, a prostaglandin synthetase inhibitor. METHODS: Fourteen asthmatic subjects (eight women) aged 26.6 (range 18-56) years participated in a double blind, placebo controlled, crossover study. The subjects attended five times and inhaled 4.5% NaCl for 0.5, 0.75, 1, 1.5, 2, 4, 8, 8, and 8 minutes, or part thereof, or until a provocative dose causing a 20% fall in FEV1 (PD20 FEV1) was recorded. Indomethacin (100 mg/day) or placebo were taken three days before all visits, except control day. The FEV1 was measured and frusemide (38.0 (6.4) mg, pH = 9) or vehicle (0.9% NaCl, pH = 9) were inhaled 10 minutes before the challenge. Bronchodilation was calculated as the percentage rise in FEV1 from the prechallenge FEV1 to the highest FEV1 recorded during the challenge. RESULTS: Frusemide caused a fold increase in PD20 FEV1 compared with the vehicle which was similar in the presence of both indomethacin and placebo (3.7 (95% CI 2.0 to 7.3) versus 3.3 (2.0 to 5.4)). Frusemide, but not vehicle, also caused a transient percentage rise in FEV1 during challenge with 4.5% NaCl which was not blocked by indomethacin (3.6% (1.2 to 6.0)) or placebo (3.1% (1.0 to 5.2)). CONCLUSIONS: Inhaled frusemide inhibited airway narrowing and caused a transient increase in FEV1 during challenge with 4.5% NaCl. These effects were not blocked by indomethacin, which suggests that the inhibitory action of frusemide is not secondary to prostaglandin release.


     

Time course of bronchoconstrictive response in asthmatic subjects to reduced temperature.

Thirteen young adults with bronchial asthma and a like number of controls were subjected for 45 minutes to a temperature of 2 degrees C after leaving a temperature of 24 degrees C to which they subsequently returned. Pre-exposure examination included VC, FEV1, MMEF, FEV1/VC%, and urinary catecholamines. The pulmonary measurements were repeated at 15, 80, and 200 minutes after exposure. Catecholamines were measured from a second urine sample, the collection of which corresponded to the period during and after the stress. Controls showed no significant pulmonary changes throughout the time of study, but 15 minutes after exposure the asthmatic subjects showed a significant mean decrease of all pulmonary measurements from pre-exposure values. The controls showed a significant mean increase in urinary catecholamines after the stress, whereas those with asthma showed no significant increase.     

Laryngeal resistance immediately after panting in asthmatic subjects.

The panting manoeuvre may be used during the assessment of airway resistance and in asthmatic patients during bronchial provocation testing or spontaneous asthma. To study whether panting opens the larynx in patients with asthma, laryngeal resistance was examined in six patients with stable asthma before and after methacholine induced bronchoconstriction and in another six patients with spontaneous asthma. Subjects were asked to pant and then to hold their breath immediately afterwards. Laryngeal resistance after panting was compared to that during quiet tidal breathing. Change in laryngeal resistance was estimated by a method using low frequency sound and respiratory resistance by forced oscillation at 10 Hz. Mean baseline respiratory resistance during inspiration was 0.245 and 0.470 kPa/l.s before and after methacholine in the patients with stable asthma and 0.480 kPa/l.s in the patients with spontaneous asthma. In the patients with stable asthma mean laryngeal resistance was lower after panting than during the preceding quiet tidal breathing, both before and after methacholine induced bronchoconstriction (by 0.08 before and by 0.065 kPa/l.s after). In contrast, the patients with spontaneous asthma showed an increase in laryngeal resistance after panting of 0.089 kPa/l.s. The magnitude of change in laryngeal resistance after panting was similar to the change in respiratory resistance in the patients with spontaneous asthma and in the patients with stable asthma after methacholine, but was greater than the change in respiratory resistance in the patients with stable asthma before methacholine. These results suggest that panting may cause different effects on the laryngeal aperture in patients with stable and spontaneous asthma.     

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.     

Effect of inhaled L-arginine on exhaled nitric oxide in normal and asthmatic subjects

BACKGROUND—Nitric oxide (NO) plays an importantpart in the regulation of many physiological functions and may also beinvolved in several pulmonary diseases. Endogenous NO is synthesised bydifferent isoforms of NO synthase (NOS) from L-arginine.
METHODS—The effect of inhaledL-arginine 0.75 g (six normal and six asthmatic subjects),1.5 g (six normal and six asthmatic subjects), and 3 g (seven normaland six asthmatic subjects) has been studied in a double blind placebocontrolled, randomised, parallel group design study. In addition, theeffect of a single dose (3 g) of inhaled L-alanine hasbeen assessed in five normal and five asthmatic subjects.
RESULTS—L-arginine increased exhaledNO in a dose-dependent fashion with a maximum at 60 minutes. Thecumulative effect of L-arginine (3 g) on NO in asthmaticsubjects, expressed as the area under the curve in arbitrary units (au)and compared with the effect of placebo (0.9% NaCl), was significantlyhigher (mean 0.11 au; 95% confidence interval (CI) 0.03 to 0.19) thanin normal subjects (0.012 au; 95% CI 0.002 to 0.022). There was anegative correlation (r = -0.72) between the increase inexhaled NO and the fall in forced expiratory volume in one second(FEV₁) (0.034 au, 95% CI 0.030 to 0.038) after 3 gL-arginine in asthmatic subjects. Inhalation of 3 g ofL-alanine produced a similar reduction in FEV₁(0.033au, 95% CI 0.007 to 0.059) but no significantly differentchanges in exhaled NO (0.017 au, 95% CI 0.001 to 0.039) compared with placebo (0.020 au, 95% CI 0.001 to 0.042).
CONCLUSIONS— An increase in the amount ofsubstrate for NOS increases the formation of endogenous NO.L-arginine may have therapeutic potential in diseases inwhich there is defective production of NO, but in asthma it may amplifythe inflammatory response in the airways.

     

Effect of inhaled substance P and neurokinin A on the airways of normal and asthmatic subjects.

The neuropeptides substance P and neurokinin A are present in sensory airway nerves. Their effect on airway calibre was compared in six healthy non-smoking subjects and six asthmatic subjects. On separate days increasing concentrations (from 10(-9) to 10(-6) mol/ml) of each neuropeptide were administered by nebuliser and the airway response measured as change in specific airway conductance (sGaw). Substance P and neurokinin A caused no change in sGaw in the healthy subjects. Inhalation of substance P up to the highest concentration of 10(-6) mol/ml caused no change in sGaw in the asthmatic subjects. Neurokinin A, however, caused bronchoconstriction with a mean fall in sGaw of 48% (SEM 12%) after 5 x 10(-7) mol/ml. The onset of bronchoconstriction was rapid, but sGaw had returned to baseline values within one hour in all but one patient.     

The nasal response to exercise and exercise induced bronchoconstriction in normal and asthmatic subjects.

Two studies were carried out to test the hypothesis that the fall and recovery of nasal resistance after exercise in asthmatic and non-asthmatic subjects are related to the development of bronchoconstriction after exercise. In study 1 nasal resistance (posterior rhinomanometry) and specific airway resistance (sRaw) were measured before challenge and one, five, 10 and 30 minutes after four minutes of exhausting legwork exercise in nine asthmatic subjects and nine age matched healthy subjects. One minute after exercise there was a reduction in nasal resistance of 49% (SD 15%) from baseline in the healthy subjects and of 66% (17%) in the asthmatic subjects. This response and the subsequent return of nasal resistance to baseline values did not differ significantly between the two groups despite a substantial difference in the change in sRaw, an increase of 74% (45%) in the asthmatic subjects 10 minutes after exercise, and no change in the non-asthmatic subjects. In study 2, nasal and specific airway resistances were monitored according to the same measurement protocol in six subjects with increased airway reactivity. Subjects exercised on two occasions, wearing a noseclip, once while breathing cold, dry air and once while breathing warm, humid air. The fall in nasal resistance was similar under both conditions (to 47% and 39% of baseline), through sRaw rose only after cold air inhalation (to 172% of baseline). The results indicate that the nasal response to exercise is not related to bronchial obstruction in asthmatic subjects after exercise or to the temperature or humidity of the air inspired through the mouth during exercise.     

Hypoxic and hypercapnic response in asthmatic subjects with previous respiratory failure.

Three children and two young adults with severe asthma who had frequent episodes of respiratory failure were studied. Isocapnic hypoxia and hyperoxic hypercapnia were produced separately using a rebreathing apparatus. Alveolar carbon dioxide tension and oxygen tension were estimated by continuously sampling expired gases. The three young children had a diminished response to hypoxia but a normal response to hypercapnia when compared to control asthmatic children (p less than 0.05) or healthy children (p less than 0.05). The two young adult patients had a normal response to hypoxia but one had a low response to hypercapnia. Studies of parents of these patients suggested that the chance combination of a possibly familial, inappropriate response to hypoxia with severe asthma would lead to a risk of respiratory failure.     

Modulation of histamine-induced bronchoconstriction with inhaled, oral, and intravenous clemastine in normal and asthmatic subjects.

Although histamine plays an important role in the pathophysiology of asthma through stimulation of H1 receptors, H1 antagonists are of only limited use in this disease when given orally. In order to investigate the pharmacological response to a specific H1 antagonist administered by different routes, we measured the effect of inhaled clemastine on airway responsiveness to histamine aerosol and compared the results with those after oral and intravenous administration in normal and asthmatic subjects. Inhalation of 0.6 mg clemastine provided significant protection without side effects and was comparable to intravenous administration of 1.0 mg in both groups. In normal subjects 2.0 mg clemastine orally was significantly less effective than the two other routes of administration whereas in asthmatics an enhanced reaction to histamine was observed.     

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.     

Relationship between exposure to domestic allergens and bronchial hyperresponsiveness in non-sensitised, atopic asthmatic subjects

BACKGROUND: The effect of exposure to allergens not causing sensitisation in atopic asthmatic subjects has not previously been studied. A study was undertaken to assess the degree of asthma severity (measured by spirometry, airway reactivity and exhaled nitric oxide) in atopic asthmatic patients not sensitised to the domestic allergen to which they were exposed. METHODS: Dust samples were collected from the living room carpet and mattress in the homes of 248 subjects and dust mite, cat and dog allergen concentrations were measured. Spirometry, non-specific bronchial reactivity (BR), and exhaled nitric oxide (eNO) were ascertained. Patients' sensitisation status was assessed by skin prick testing. RESULTS: Adult atopic asthmatics not sensitised to mite but exposed to high levels of mite allergen had significantly more severe BR than subjects not exposed to high levels of mite (PD(20), geometric mean (GM) 0.21 mg (95% CI 0.09 to 0.47) v 0.86 mg (95% CI 0.44 to 1.67), mean ratio difference 4.1 (95% CI 1.5 to 11.4), p=0.008). Subjects not sensitised but exposed to high levels of dog allergen also had significantly more severe BR than subjects not exposed (PD20 GM 0.16 v 0.52 mg, mean ratio difference 3.3 (95% CI 1.2 to 9.2), p=0.01). The differences in BR between these groups were still significant after adjusting for confounding factors. This effect of greater airway reactivity was not seen in subjects exposed but not sensitised to cat allergens. CONCLUSION: Atopic asthmatic subjects who are exposed to high levels of dust mite or dog allergens but not sensitised to these allergens have evidence of increased airway reactivity.