The effect of oral zindotrine (MDL-257), a bronchial smooth muscle relaxant, on histamine airways responsiveness in asymptomatic asthmatics

We evaluated the efficacy of an oral dosage form of the investigational smooth muscle relaxant, zindotrine, a novel pyridazine derivative, in counteracting histamine-induced bronchospasm in a group of 12 non-medicated asymptomatic asthmatics. Histamine inhalation challenges were performed before (control) and 45, 150, and 300 minutes after zindotrine (200 and 300 mg), or the corresponding dose of placebo was administered orally in a randomized, double-blind crossover fashion. When compared to the control state, the 300-mg zindotrine dose markedly lowered histamine airway responsiveness as indicated by a significant (P less than .01) increase in the inhaled histamine dose necessary to provoke a 20% decrease in the forced expired volume in one second (PD20FEV1) 45 minutes after drug administration. The PD20FEV1 then decreased linearly over time but remained higher than the control PD20FEV1 value (P less than .05) during the entire observation period. The 200-mg zindotrine dose failed to affect the PD20FEV1. Our data indicate that orally administered zindotrine lowers airways responsiveness to inhaled histamine in asymptomatic asthmatics in a dose-dependent and time-dependent fashion.     

Effect of cromolyn on carbachol-induced bronchoconstriction

The effect of premedication with cromolyn 40 mg on the bronchial response to inhaled carbachol was investigated in four atopic and four non-atopic subjects with mild asthma. Paired carbachol inhalation tests were carried out on consecutive days in a double-blind fashion following randomized premedication with cromolyn or placebo. Bronchial sensitivity was expressed as the log dose of carbachol provoking a 15% decrease in FEV1 (log PD15 FEV1) or a 30% decrease in FEF25-75 (log PD30 FEF25-75). The mean log PD15 FEV1 was significantly greater following cromolyn compared to placebo (2.34 +/- .22 vs 1.87 +/- .10; mean +/- SE; p less than 0.05) as was log PD30 FEF25-75 (2.30 +/- .16 vs 1.72 +/- .08; p less than 0.005). These results indicate that cromolyn interferes with cholinergic induced bronchoconstriction and support the suggestion that it has an effect at a more fundamental level than the inhibition of antigen induced mediator release from mast cells.     

The effect of atropine and albuterol aerosols on the human bronchial response to histamine.

This study was designed to determine whether histamine-induced bronchoconstriction in human asthmatics is mediated by the parasympathetic nervous system and involves cholinergic pathways. Inhalation challenges were performed on 14 adult asthmatic patients using the standardized procedure for inhalation challenge recently recommended by the Asthma and Allergic Disease Centers panel. The effect of pretreatment with either aerosolized atropine sulfate or aerosolized albuterol, a specific beta-2 adrenergic agonist, was studied. The comulative units of histamine required for induction of a positive bronchial response (20% or greater drop in FEV1 from baseline) was used as the basis of comparison of the effects of these drugs. This value was expressed as the PD20-FEV1 to histamine. Analysis of the data showed that aerosolization of sufficient atropie to effect a cholinergic blockade, as shown by inhibition of the bronchial response to inhaled methacholine, only minimally affected the bronchial response to histamine (p less than 0.05). However, the administration of albuterol markedly shifted the response to histamine (p less than 0.005). Although there was a statistically significant change in the mean PD20-FEV1 to histamine following atropine blockade, this effect was small in comparison to that which could be demonstrated with a beta agonist. It would thus appear that the major influence of histamine is not through cholinergic pathways.     

Influence of antihistamine (astemizole) and anticholinergic drugs (ipratropium bromide) on bronchoconstriction induced by substance P.

Several studies have demonstrated that neuropeptides are present in bronchial tissue. The aim of this study was to evaluate in vivo the influence of antihistamine in comparison to an anticholinergic drug on bronchospasm induced by inhalation of substance P (SP). Seven moderate asthmatic patients (mean age = 34.4 +/- 8.9), five being female, were studied. The acetate salt of SP was prepared in 0.9% saline to produce a dose range of 23 to 184 x 10(-6) mol. Patients were studied on three separate days with an interval of 3 weeks between challenges. On the first day the dose of SP producing a 20% change in FEV1 was calculated from the individual semilogarithmic dose-response curve. On subsequent days, in a randomized double-blind manner, the patients were treated either with astemizole (20 mg BID for three days) and placebo ipratropium bromide or with placebo of astemizole (twice a day for three days) and with pressurized aerosol of ipratropium bromide (IB) (40 micrograms 20 minutes before the challenge). Two way analysis of variance was used for statistical analysis. Our results demonstrated that inhaled SP is able to produce a dose-response curve of bronchoconstriction with a geometric mean of PD20 of 50.51 x 10(-6) moles (37.38 to 68.19 x 10(-6) mol). Treatment with astemizole induced a geometric mean PD20 of 65.51 x 10(-6) mol (33.02 to 130.21 x 10(-6) mol) and the premedication with the IB induced a significant (P less than .05) shift of dose-response curve to SP (geometric mean PD20 = 109.1 x 10(-6) mol; 58.67 to 204.05 x 10(-6) mol). Our results demonstrated that bronchoconstriction induced by SP could be attributed to a weak cholinergic activation and not to histamine release.     

The inhibitory effect of azelastine hydrochloride on histamine- and allergen-induced bronchoconstriction in atopic asthma

We have examined the effect of azelastine, a new H1 histamine receptor antagonist, against bronchoconstriction induced by histamine and allergen. Twelve mild, atopic asthmatics each underwent two histamine and two allergen concentration-response inhalation challenges 4 hr after treatment with either 8.8 mg of azelastine or a matched placebo. Following azelastine the dose of histamine required to provoke a 20% fall in FEV1 (PD20 histamine) rose, from a geometric mean of 0.31 mg/ml to greater than 13.2 mg/ml. Azelastine also significantly inhibited allergen-induced bronchoconstriction, the PD20 allergen rising from 9.3 cumulative breath units (c.b.u.) to greater than 47.9 c.b.u., a greater than 5-fold increase. We conclude that azelastine effectively inhibits both histamine and allergen-induced bronchoconstriction, with considerably greater potency against histamine.     

The effect of inhaled allergen on circulating basophils in atopic asthma.

There is increasing evidence for the role of basophils in the allergen-induced late asthmatic response (LAR). To study the effect of inhaled allergen on basophil function in subjects with asthma, ex vivo basophil spontaneous histamine release (SHR) in peripheral blood and plasma histamine was measured before and 2, 5, 10, and 15 minutes, and 2, 4, 6, and 8 hours after allergen bronchial challenge (allergen study day) in six subjects with atopic asthma. Allergen inhalation induced an early response and LAR consisting of a mean (+/- SD) 32.5% (+/- 7.9%) and 28.8% (+/- 7.7%) fall in FEV1, respectively. As a control for the effects of bronchoconstriction, on another occasion, methacholine challenge was performed to produce a mean 33.4% (+/- 3.4%) fall in FEV1 during the early response and no LAR, and blood was obtained to measure basophil histamine release (HR) and plasma histamine. There was a small, but significant (p less than 0.05), rise in median SHR from 4.6% to 6.1% of total basophil histamine after allergen but not after methacholine inhalation. HR remained high after allergen inhalation during the 8 hours of study, whereas it demonstrated a steady, significant, decrease between 4 to 8 hours after methacholine inhalation. No significant changes in plasma histamine were recorded on either allergen or methacholine study days. On a third occasion, SHR was measured after challenge with physiologic saline to control for any effects of methacholine on SHR, and a decrease in HR was recorded during the day similar to HR observed after methacholine challenge. These studies suggest an enhancing effect of inhaled allergen on SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of inhaled leukotriene E4 on the airway responsiveness to histamine in subjects with asthma and normal subjects

Eight subjects with asthma inhaled on separate occasions leukotriene E4 (LTE4) (6.1 nmol, geometric mean), methacholine, and diluent, which produced an average 41.0%, 37.0%, and 3.3% decrease in specific airway conductance (SGaw), respectively. When the SGaw had recovered to baseline levels at 60 minutes after challenge, the provocative dose of inhaled histamine that produced a 35% decrease in SGaw (PD35) was determined. The histamine PD35 observed after inhalation of LTE4 was 0.46 mumol, and this was significantly less than the histamine PD35 observed after inhalation of methacholine (0.88 mumol; p less than 10(-4) and diluent (0.97 mumol; p less than 10(-5). Histamine responsiveness was also enhanced by a fiftyfold lower dose of LTE4 (p = 0.005), and the enhancement was less than that elicited by the higher dose of LTE4 in the same individuals (p = 0.02). The changes in histamine PD35 during a 1-week period after LTE4 and methacholine challenges were compared in four subjects with asthma. There was a time-dependent enhancement in histamine responsiveness that reached a maximal of 3.5-fold at 7 hours after LTE4. The enhancement had disappeared by 1 week. Similar changes were not observed after methacholine challenge, which elicited the same degree of bronchoconstriction as LTE4. Inhalation of LTE4 in five normal subjects that produced a mean 37.6% decrease in SGaw did not change histamine responsiveness for up to 7 hours. These findings suggest that LTE4 may play a role in the perpetuation of nonspecific airway hyperresponsiveness in bronchial asthma.     

Protection of nedocromil sodium on bronchoconstriction induced by inhaled neurokinin A (NKA) in asthmatic patients

Neurokinin A (NKA) has been shown to exert a potent contractile action on bronchial smooth muscles both in vitro and in vivo. Although this effect seems to be due either to a direct action of this peptide on specific muscular receptors or to an indirect effect on mast cells and/or nerves, its mechanism of action in bronchial asthma is still unknown. In the present study we have investigated the airway response to inhaled NKA in 10 asthmatic subjects and the activity of the novel pyranoquinoline dicarboxylic acid drug, nedocromil sodium, on this response. Ten asthmatic patients with stable asthma took part in the study consisting of four separate visits. On the first two occasions we derived histamine and NKA PD15 values in absence of any drug treatment. On the following two visits the inhalation challenge with NKA was performed after administration of either nedocromil sodium or matched placebo administered as pressurized aerosols via metered dose inhalers in a randomized double-blind order. Inhaled NKA produced a dose-related fall in FEV1 in all the subjects studied. Inhaled nedocromil sodium had a significant effect on the FEV1 response to NKA inhalation, the geometric mean PD15 value increasing from 16.6 to 32.2 x 10(-9) mol. We conclude that nedocromil sodium attenuates subsequent responsiveness to inhaled NKA in asthmatic subjects.     

Bronchoconstriction due to isocapnic cold air inhalation minimally influences bronchial hyperresponsiveness to methacholine in asthmatic subjects

The aim of this study was to investigate if bronchial hyperresponsiveness to methacholine could be influenced by a previous bronchoconstriction due to isocapnic inhalation of cold air. Twelve adult asthmatic subjects in a clinical steady state were seen on four different days in a randomized way according to three different sequences. After assessment of spirometry, bronchial responsiveness to inhaled methacholine was determined on each occasion by the provocative concentration causing a fall of 20% in FEV1 (PC20). On two occasions, the methacholine test was preceded by the inhalation of dry cold air which caused significant (greater than 20% change in FEV1) bronchoconstriction. The methacholine test was performed after functional recovery. There was a significant (t = 2.53; p less than 0.05) but minimal (mean changes of 0.65 single two-fold concentration difference) reduction in PC20 after cold air inhalation. It is concluded that cold air-induced bronchoconstriction causes significant but minimal changes in bronchial responsiveness to methacholine in asthmatic subjects.     

Methacholine responsiveness increases after ultrasonically nebulized water but not after ultrasonically nebulized hypertonic saline in patients with asthma

Airway obstruction can be induced in patients with asthma by the inhalation of ultrasonically nebulized aerosols of nonisotonic solutions. It is the change in osmolarity of the periciliary fluid that is believed to be the stimulus for bronchoconstriction. However, it is not known whether hyperosmolar and hypo-osmolar aerosols induce asthma via the same mechanism. We have previously reported that patients with asthma have a reduction in the dose of provoking agent that induces a 20% fall in FEV1 (PD20) for methacholine after challenge with nebulized water. To determine whether hyperosmolar aerosols also increase sensitivity to methacholine, we studied 13 subjects with asthma on 3 days. On day 1, the PD20 to methacholine was determined. On day 2, a challenge with nebulized 4.5% saline was followed by a challenge with methacholine 40 to 60 minutes later. On day 3, a challenge with nebulized water was followed by a methacholine challenge. Sensitivity to methacholine was significantly increased after water (p less than 0.02) but not after 4.5% saline. Furthermore, there was no relationship between the PD20 to water and to 4.5% saline. When the Spearman's correlation coefficient was used to compare sensitivity to the challenges, there was a significant relationship between the PD20 to 4.5% saline and methacholine (p less than 0.01) but not between the PD20 to water and methacholine. These results suggest that the mechanism of asthma induced by hyperosmolar and hypo-osmolar solutions is different.     

Protective activity of inhaled nonsteroidal antiinflammatory drugs on bronchial responsiveness to ultrasonically nebulized water.

Relatively high doses of oral aspirin are needed to afford a significant protective effect against the bronchial obstructive reaction to ultrasonically nebulized distilled water (UNDW) in asthmatic patients. Sodium salicylate at similar doses and indomethacin at normal dose afford no protection. The present study was undertaken to assess the protective activity of these drugs taken by inhalation. Thirteen asthmatic patients performed two UNDW challenges 20 minutes and 24 hours after inhalation of 900 mg lysine acetylsalicylate (L-ASA) or placebo. The volume of UNDW causing a 20% fall in FEV1 (UNDW PD20) was calculated by linear interpolation on the dose-response curve. UNDW response after placebo was not significantly different from the preliminary test (PD20 4.3 +/- 0.7 and 4.1 +/- 04 ml, respectively, mean +/- SE), whereas after L-ASA, UNDW PD20 increased to 17 +/- 2.7 ml (p < 0.01 vs placebo) and remained significantly increased after 24 hours. In another group of 12 patients under the same experimental conditions, an equivalent dose of inhaled sodium salicylate caused no effect. Finally, in a third group of asthmatic patients pretreatment with inhaled indomethacin at two dose levels (6 patients, 25 mg; 10 patients, 50 mg) resulted in a significant dose-related protective effect. These findings indicate that inhaled indomethacin and especially L-ASA exert against UNDW-induced bronchoconstriction a potent protective effect, which appears to be mediated by inhibition of local prostaglandin synthesis in the airways. This fact could have therapeutic implications.     

The inhibitory effects of anti-asthmatic agents on ethanol-induced bronchoconstriction in Japanese asthmatic patients]

Asthmatic symptoms are worsened after drinking small amounts of alcoholic beverages in Japanese asthmatic patients. Our previous results showed that the ingestion of pure ethanol caused a fall in FEV1.0 in about half of the Japanese asthmatics we studied. We studied the inhibitory effects of pretreatment with three kinds of anti-asthmatic agents on ethanol-induced bronchoconstriction in six Japanese asthmatic patients. We tested oral cyproheptadine hydrochloride (8 mg), which is an anti histamine agent, inhaled disodium cromoglycate (2 mg), which has an inhibitory effect on the release of chemical mediators from mast cells, and inhaled atropine sulfate (3 mg), which is an anti-cholinergic agent. Pretreatment with cyproheptadine significantly inhibited the fall in FEV1.0 120 minutes after ethanol challenge (p less than 0.05). Inhaled DSCG had significant inhibitory effects on the fall in FEV1.0 15 and 30 minutes after ethanol challenge (p less than 0.05). Inhaled atropine had no inhibitory effect. These results suggest that histamine, released from mast cells, plays an important role in ethanol induced bronchoconstriction in Japanese asthmatic patients.     

Reduction of histamine-induced bronchoconstriction by magnesium in asthmatic subjects

The effects of inhaled MgSO4 on histamine bronchoprovocation test (BPT) were studied in nine asthmatics in clinical remission (FEV1 greater than 80% of predicted). Patients performed histamine BPT on 2 separate days, one day after saline and the other after MgSO4 inhalation, in a randomized double-blind design. Spirometry and flow/volume curve were recorded on each test day before and 5 min after NaCl or MgSO4. No significant difference was observed in lung function measurements 2 days before and after either NaCl or MgSO4. The dose of histamine which produced a 20% decrease in control FEV1 (PD20FEV1) was significantly increased by aerosolized MgSO4 (from 0.177 +/- 0.036 mg after NaCl to 0.350 +/- 0.085 after MgSO4, P less than 0.05. After MgSO4 the dose-steps of histamine concentration increased two-fold in two subjects and one-fold in five.     

Enhancing effect of dipyridamole inhalation on adenosine-induced bronchospasm in asthmatic patients

The study was performed on 13 asthmatic patients to determine whether inhaled dipyridamole would act directly by inducing bronchoconstriction or indirectly by potentiating the adenosine-induced bronchoconstriction. The study was performed in 3 consecutive days. On the first day adenosine challenge was performed and the PD20 value calculated. On the other days the adenosine challenge was done 5 min after randomized inhalations of dipyridamole or a control solution. The mean percent change in FEV1 after dipyridamole (delta % = 2.0) and control solution (delta % = 1.0) was not significant. Inhaled adenosine caused bronchoconstriction with a geometric mean PD20 of 1.09 mg. After control solution inhalation, a mean PD20 value of 1.31 mg was observed. Dipyridamole inhalation increased adenosine hyperresponsiveness and in all subjects shifted the dose-response curves of adenosine challenge to the left with a mean PD20 value of 0.40 mg. This enhancing effect of dipyridamole was significant when compared with the baseline value (P less than 0.01) and control solution (P less than 0.01). The study demonstrated that dipyridamole inhalation increased airway responsiveness to adenosine in all subjects. This effect is due to indirect activity of dipyridamole on airways without changes in baseline airway caliber.     

Inhalation provocation test with house dust allergen using tidal breathing

Using the modified 3-Hz oscillation method, the inhalation challenge test was performed with house dust allergen upon subjects while tidal breathing throughout the test. Their total respiratory resistance (Rrs) was continuously monitored with the inhalation of saline as a control, and 250-, 50-, and 10-fold diluted allergen solution to the inhalation of aerosolized metaproterenol. The starting point of the induced bronchoconstriction was checked and as soon as Rrs increased up to twice the base-line value, the subjects inhaled the aerosolized metaproterenol. From the dose-response curve of Rrs, the dose of inhaled allergen (minimum dose) as bronchial sensitivity was determined; also the decreasing rate of respiratory conductance, which was calculated from the slope of elevation of Rrs, as bronchial reactivity. It was found that the more diluted allergen required for a positive skin reaction, the more likely the patients were to have a subsequent positive bronchial inhalation challenge to house dust allergen. There was a relationship between the increased bronchial reactivity and the increased RAST score. These results indicate that this inhalation challenge test is specific, safe, and time-saving.     

Effect of inhalation aspirin challenge on exhaled nitric oxide in patients with aspirin-inducible asthma

BACKGROUND: A complex relationship between arachidonic acid metabolites and nitric oxide (NO) synthesis has been reported in asthma. The effects of inhaled aspirin on fractional exhaled NO (FENO) in patients with aspirin-tolerant (ATA) and aspirin-inducible (AIA) asthma compared with normal controls have been investigated. METHODS: The FENO was measured baseline, after saline and lysine-aspirin (L-ASA) bronchial challenge in 10 patients with ATA and in 10 patients with AIA [mean (PD(20)FEV(1) L-ASA): 14.7 +/- 12.7 mg], who had comparable age and baseline FEV(1). Ten healthy subjects served as controls. Sputum eosinophils were counted after saline and after L-ASA challenge in the two groups of asthmatics. RESULTS: Asthmatic patients had baseline FENO significantly higher than controls (29.7 +/- 6.8 vs 9.8 +/- 2.05 p.p.b. respectively, P < 0.0001). No difference was observed in methacholine PD(20)FEV(1) and baseline FENO between ATA and AIA patients. After L-ASA inhalation, FENO increased significantly only in patients with AIA, reaching the peak value 4 h after bronchoconstriction (from 31.1 +/- 6 to 43 +/- 4.8 p.p.b., P < 0.001), while no change was observed in patients with ATA and in controls. Sputum eosinophils increased significantly after L-ASA inhalation only in patients with AIA (from 8.1 +/- 2.7 to 11.1 +/- 2.8%, P < 0.005) and there was a significant relationship between the increase in sputum eosinophils and the increase in FENO after ASA challenge. CONCLUSION: Exhaled NO may indicate eosinophilic airway inflammation during ASA exposure in patients with ASA inducible asthma.     

Maximal forced expiratory maneuver to measure airway obstruction in allergen challenged mice

Our purpose was to develop a method of using a maximal forced expiratory maneuver (MFEM) for the study of bronchoconstriction and bronchial hyperreactivity (BHR) induced in mice by ovalbumin (OA) inhalation challenge. Eight mice (group I) were sensitized and then provocated with OA. Pulmonary function testing (PFT) at baseline and after varying doses of acetylcholine challenge was performed. Eight weight-matched normal mice served as controls (group II). Pulmonary functions include MFEM, dynamic respiratory system compliance (Crs) and respiratory system resistance (Rrs). The results showed that mice treated with OA had worse PFTs than normal controls, characterized by lower MFEF 50%, FEV0.1 and Crs but higher Rrs. The OA-sensitized mice also had more severe bronchoconstriction in response to acetylcholine, characterized by greater decreases in MFEF 50%, FEV0.1 and Crs but a higher Rrs than the controls. There was a good correlation between PD20MFEF50%Ach and PD20FEV0.1Ach with PD20CrsAch and PD20RrsAch. In conclusion, the MFEM can be used to evaluate airway obstruction and BHR induced in mice by allergen challenge.     

Inhaled lignocaine does not alter bronchial hyperresponsiveness to hyperventilation of dry cold air in asthmatic subjects

It has been hypothesized that bronchoconstriction due to exercise and hyperventilation is caused by the stimulation of irritant receptors in the upper airways. However, controversial results have been reported on the effect of lignocaine, which can inhibit the stimulation of these receptors. The aim of this study was to investigate the effect of inhaled lignocaine on bronchial responsiveness to hyperventilation of cold dry air in asthmatic subjects. Eight adult asthmatic subjects in a clinical steady state came on four different days (two placebo and two active days in random order) with a maximum interval of 3 weeks. After assessment of forced expiratory flow rates, inhalation of either phosphate-buffered saline (placebo) or lignocaine solution (40 mg) was carried out in a single-blind fashion. The technician was not aware which medication was being inhaled, but the asthmatic subject knew which drug it was by the sensation in his or her throat. Forced expiratory flow rates were reassessed 15 min after the nebulization; then, the subjects were asked to inhale cold dry air (-20 degrees C) in progressively increasing levels of ventilation (7.5, 15, 30 and 60 l/min and maximum voluntary ventilation). PD20 was interpolated from the dose-response curve, relating the dose of cold air on a non-cumulative logarithmic scale on the abscissa and the percentage change in FEV1 on the ordinate. There were no significant changes in FEV1 and PD20 after inhalation of lignocaine as compared to the placebo. We conclude that inhaled lignocaine does not significantly alter bronchial hyperresponsiveness to hyperventilation of cold air in asthmatic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors influencing the occurrence of a late reaction to allergen challenge in atopic asthmatics

Thirty extrinsic asthmatics were challenged by inhalation with Dermatophagoides pteronyssinus extract. In twenty-four an immediate reaction was observed and in sixteen this was followed by a late reaction. Those with late reactions tended to have more severe asthma but did not report greater sensitivity to housedust mite. The occurrence of a late reaction was not related to the degree of airways obstruction before challenge or to the intensity of the immediate reaction. Patients in whom the early reaction was induced by a low dose of inhaled antigen were those most likely to develop a late response. Results of histamine challenge testing suggested that this greater sensitivity of the airway might in part be due to greater non-specific bronchial reactivity.     

Effect of indomethacin on adenosine-induced bronchoconstriction

The exact mechanism of adenosine-induced bronchoconstriction in patients with asthma is unknown. Adenosine contraction of guinea pig trachea was antagonized by inhibitors of cyclooxygenase. The aim of this study was to investigate the effect of indomethacin (100 mg/day) on adenosine-induced bronchoconstriction in 14 asymptomatic patients with asthma. Airway response was evaluated as FEV1, and adenosine was administered as an aerosol diluted in 0.9% saline to produce a concentration range of 0.125 to 4 mg/ml. The dose of adenosine producing a 20% change in FEV1 (PD20) was calculated from the individual semilogarithmic dose-response curve; the results of PD20 were converted to log values for statistical analysis (Student's paired t test). The study was performed on 3 separate days. On the first day, the adenosine challenge was performed, and on subsequent days patients were pretreated with either placebo or indomethacin in a randomized, double-blind manner. Inhaled adenosine caused bronchoconstriction with a geometric mean PD20 of 0.71 mg (95% confidence limits, 0.44 to 1.16). After placebo, a geometric mean PD20 of 0.91 mg (95% confidence limits, 0.53 to 1.58) was obtained. Indomethacin pretreatment decreased adenosine hyperresponsiveness and shifted the dose-response curves of adenosine challenge to the right with a geometric mean PD20 of 1.28 mg (95% confidence limits, 0.64 to 2.56). The effect of indomethacin on adenosine bronchoconstriction (p less than 0.01 versus baseline; p less than 0.05 versus placebo) suggests an indirect mechanism of adenosine on inducing release of arachidonic acid derivatives. Inflammatory mediators inhibited by indomethacin may be involved in adenosine bronchoconstriction, even if this mechanism is not relevant.(ABSTRACT TRUNCATED AT 250 WORDS)