Bronchoconstriction induced by inhaled adenosine 5'-monophosphate in subjects with allergic rhinitis.

Adenosine and its related nucleotide, adenosine 5'-monophosphate (AMP) induce bronchoconstriction in asthmatics, probably caused by histamine release from airway mast cells. The objective of this study was to determine the effect of inhaled AMP on lung function in subjects with allergic rhinitis. A total of 52 adults (28 subjects with allergic rhinitis, 14 asthmatics and 10 healthy subjects) were challenged with increasing concentrations of AMP and methacholine. Airflow was assessed after each concentration and the response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall (PC20) in forced expired volume in one second (FEV1). All 14 asthmatics, 10 subjects with allergic rhinitis and none of the healthy controls were hyperresponsive to AMP. Subjects with allergic rhinitis had higher prevalence of hyperresponsiveness to AMP than healthy controls (p=0.038). Although the prevalence of hyperresponsiveness for methacholine and for AMP in subjects with allergic rhinitis was similar (39% and 36%, respectively), four subjects had hyperresponsiveness to methacholine but not to AMP, whereas three subjects had hyperresponsiveness to AMP but not to methacholine. To conclude, inhaled adenosine 5'-monophosphate causes airway narrowing in a significantly higher proportion of subjects with allergic rhinitis than healthy volunteers. Furthermore, methacholine and adenosine 5'-monophosphate hyperresponsiveness are not detected in the same individuals with allergic rhinitis, thus suggesting that responsiveness to the two bronchoconstrictor stimuli is not reflecting the same abnormalities of the airways.     

Airway obstruction induced by inhaled acetaldehyde in asthma: repeatability relationship to adenosine 5'-monophosphate responsiveness.

Inhaled acetaldehyde and adenosine 5'-monophosphate (AMP) cause bronchoconstriction in asthmatics by a mechanism believed to involve histamine release from airway mast cells. This study investigates the repeatability of the acetaldehyde challenge and the relationship between airway responsiveness to acetaldehyde and AMP. To this end, we examined the effect of inhaled acetaldehyde on airway tone in comparison with either methacholine or AMP in 16 asthmatics. Furthermore, the repeatability of the acetaldehyde challenge was assessed in 14 subjects with mild asthma. The response to each bronchoconstrictor agent was measured by the PC20 (provocative concentration required to produce a 20% fall in FEV1). The geometric mean (range) PC20 values were 3.1 mmol/l (0.5-46.0 mmol/l) for methacholine, 883.1 mmol/l (190.7-1816.1 mmol/l) for acetaldehyde, and 50.1 mmol/l (3.2-1152.1 mmol/l) for AMP. Thus, acetaldehyde was 18-fold less potent than AMP in causing bronchoconstriction. A similar correlation was observed between PC20 acetaldehyde and either PC20 AMP (r = 0.58, p = 0.02) or PC20 methacholine (r = 0.56, p = 0.02). The challenge procedure with acetaldehyde was moderately repeatable (coefficient of repeatability = +/- 1.4 doubling concentrations, intraclass correlation coefficient = 0.64). We conclude that inhaled acetaldehyde is less potent than AMP in causing bronchoconstriction in asthma, and that the response to inhaled acetaldehyde is repeatable. Furthermore, the present data lends indirect support to the suggestion that acetaldehyde responsiveness and AMP responsiveness are not identifying the same alterations in the airways.     

Exhaled nitric oxide and bronchial responsiveness to adenosine 5'-monophosphate in subjects with allergic rhinitis

STUDY OBJECTIVES: To determine differences in exhaled nitric oxide (ENO) between subjects with allergic rhinitis with and without increased responsiveness to direct and indirect bronchoconstrictor agents. STUDY DESIGN: Cross-sectional study with the order of challenge tests randomized. SETTING: Specialist allergy unit in a university hospital. PATIENTS: Thirty-eight subjects without asthma with allergic rhinitis and 10 healthy nonatopic control subjects. MEASUREMENTS AND RESULTS: Participants were challenged with increasing concentrations of adenosine 5'monophosphate (AMP) and methacholine. ENO was measured with the single-exhalation method. A positive response to both bronchoconstrictor agents was detected in nine subjects with allergic rhinitis, whereas four subjects showed increased responsiveness to AMP but not to methacholine. The geometric mean (range) ENO values were significantly higher in subjects with allergic rhinitis with increased responsiveness to either methacholine or AMP than in subjects with normal responsiveness to both agonists: 51.3 parts per billion (ppb) [22.0 to 108.5 ppb] vs 25.1 ppb (5.7 to 102.9 ppb, respectively; p = 0.007) and healthy control subjects (11.2 ppb [5.0 to 31.9 ppb], p < 0.001). Subjects with allergic rhinitis with normal responsiveness to both agonists also had higher concentrations of ENO than healthy control subjects (p = 0.007). No correlation was found between ENO and either of the provocative concentrations of methacholine or AMP causing a 20% fall in FEV(1). CONCLUSIONS: In subjects without asthma but with allergic rhinitis, the presence of bronchoconstriction in response to methacholine or AMP is associated with increased ENO concentrations. However, elevated concentrations of ENO are detected even in subjects with allergic rhinitis without airway hyperresponsiveness. These results suggest that the presence of airway hyperresponsiveness is not the only factor that determines the increased NO levels detected in subjects with allergic rhinitis.     

Differences in airway responsiveness to acetaldehyde and methacholine in asthma and chronic bronchitis.

Inhaled acetaldehyde may induce bronchoconstriction in asthmatic subjects and provides a new method to investigate airway responsiveness. The objective of the study was to determine whether acetaldehyde was a more specific stimulus than methacholine in differentiating asthma from chronic bronchitis with or without airflow limitation. Bronchial provocation challenges with methacholine and acetaldehyde were performed in 62 asthmatics and in 59 smokers with chronic bronchitis (32 with chronic bronchitis alone and 27 with chronic bronchitis and coexisting chronic obstructive pulmonary disease (COPD)). The response to both bronchoconstrictor agents was measured by the provocative concentration required to produce a 20% fall in forced expiratory volume in one second (FEV1; PC20). The two types of challenge yielded a similarly high level of sensitivity (100% for methacholine and 92% for acetaldehyde) in revealing airway hyperresponsiveness in asthma. However, bronchoprovocation with acetaldehyde yielded considerably greater specificity (95%) than bronchoprovocation with methacholine (24%) in separating asthma from chronic bronchitis. In subjects with asthma, methacholine and acetaldehyde responsiveness were weakly but significantly correlated (r=0.42, p=0.001) but no correlation was found between airway responsiveness to acetaldehyde and baseline FEV1 (r=0.13, p=0.33). These findings suggest that the demonstration of bronchoconstriction in response to acetaldehyde may be a more specific test than methacholine in the differentiation of asthma from chronic bronchitis. Furthermore, methacholine and acetaldehyde hyperresponsiveness are not reflecting the same pathophysiological process in the airways.     

Effect of cigarette smoking on airway responsiveness to adenosine 5'-monophosphate in subjects with allergic rhinitis

STUDY OBJECTIVES: The objective of this study was to determine differences in airway responsiveness to adenosine 5'-monophosphate (AMP) between smokers and nonsmokers with allergic rhinitis. METHODS: A total of 41 adults with allergic rhinitis (16 smokers and 25 nonsmokers) were challenged with increasing concentrations of methacholine and AMP. Airflow was assessed after each concentration, and the response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV(1) (PC(20)). RESULTS: The geometric mean PC(20) AMP values were significantly lower in smokers than in nonsmokers: 72.4 mg/mL (95% confidence interval [CI], 33.9 to 154.9) vs 204.2 mg/mL (95% CI, 120.2 to 346.7) [p = 0.021]. The proportion of subjects with bronchoconstriction in response to AMP was higher in smokers (12 of 16 subjects) than in nonsmokers (7 of 25 subjects) [p = 0.005]. CONCLUSIONS: We conclude that smokers with allergic rhinitis have a greater AMP sensitivity than nonsmokers.     

Modifications of airway responsiveness to adenosine 5'-monophosphate and exhaled nitric oxide concentrations after the pollen season in subjects with pollen-induced rhinitis

STUDY OBJECTIVE:s: To determine the effect of cessation of exposure to pollen on airway responsiveness to adenosine 5'-monophosphate (AMP) in subjects with pollen-induced rhinitis, and to explore the relationship between changes in airway responsiveness and changes in exhaled nitric oxide (ENO) levels. STUDY DESIGN: Subjects were studied during the pollen season and out of season. SETTING: Specialist allergy unit in a university hospital. PATIENTS: Fourteen subjects without asthma with pollen-induced rhinitis who showed bronchoconstriction in response to methacholine and AMP during the pollen season and 10 healthy nonatopic control subjects. MEASUREMENTS AND RESULTS: In subjects with pollen-induced rhinitis, ENO concentrations, provocative concentration of agonist causing a 20% fall in FEV(1) (PC(20)) methacholine, and PC(20) AMP were determined during the pollen season and out of season. Healthy control subjects were studied during the pollen season. In subjects with allergic rhinitis, PC(20) AMP increased from a geometric mean of 79.4 mg/mL (95% confidence interval [CI], 31.6 to 199.5 mg/mL) during the pollen season to 316.2 mg/mL (95% CI, 158.5 to 400.0 mg/mL) out of season (p = 0.004). The ENO concentrations decreased from 63.1 parts per billion (ppb) [95% CI, 50.1 to 79.4 ppb] during the pollen season to 30.2 ppb (95% CI, 23.4 to 38.0 ppb) out of season (p < 0.001). The ENO concentrations out of pollen season were still significantly increased in subjects with pollen-induced rhinitis when compared with healthy control subjects. There was no relationship between individual changes in ENO levels and changes in either PC(20) methacholine or PC(20) AMP. CONCLUSIONS: In pollen-sensitive subjects with allergic rhinitis, the cessation of exposure to pollen is associated with a significant reduction of airway responsiveness to inhaled AMP. However, no association was found between allergen-induced changes in ENO values and in airway responsiveness to either direct or indirect bronchoconstrictors. These findings suggest that modifications in ENO and in airway responsiveness are the consequence of different alterations induced by allergen exposure on the lower airways.     

Relationship between airway sensitivity to adenosine 5' monophosphate and the shape of the concentration-response curve to methacholine in subjects with allergic rhinitis.

The objective of this study was to determine differences in airway sensitivity to adenosine 5'-monophosphate (AMP) between allergic rhinitis subjects with plateau and those without evidence of plateau on the concentration response curves to methacholine. A total of 51 adults (38 subjects with allergic rhinitis and 13 healthy controls) were challenged with increasing concentrations of methacholine and AMP. The methacholine challenge was terminated when there was a 40% or more decrease in forced expiratory volume in 1 sec (FEV1), whereas the AMP challenge was stopped when FEV1 had fallen by more than 20%. A plateau for methacholine was detected in all 13 healthy controls and in 27 patients with allergic rhinitis (AR-plateau group), whereas 11 subjects with allergic rhinitis did not exhibit a plateau (AR-non-plateau group). The median (range) PC20 AMP (provocative concentration required to produce a 20% fall in FEV1) value for the AR-non-plateau group was 44.0 mg ml(-1) (3.3-400.0), compared with 400.0 mgml(-1) (12.1-400.0) in the AR-plateau group (P=0.03) and 400.0 mgml(-1) in the healthy control group (P=0.007). The proportion of subjects who showed bronchoconstriction in response to AMP was higher in the AR-non-plateau group (73%) than in the AR-plateau group (30%) (P=0.03). However, three subjects with allergic rhinitis who had normal sensitivity to methacholine and plateau showed bronchoconstriction in response to AMP. We conclude that, in subjects with allergic rhinitis, the absence of plateau on the concentration response curves to methacholine is associated with a higher prevalence and degree of bronchoconstriction in response to AMP. However, the two bronchoconstrictor stimuli were not identifying the same abnormalities of the airways.     

Increased airway responsiveness to acetaldehyde in asthmatic subjects with alcohol-induced bronchoconstriction.

Bronchial responsiveness to acetaldehyde, a main factor in alcohol-induced bronchoconstriction, and methacholine were compared between 10 subjects with alcohol-induced bronchoconstriction and 16 asthmatic subjects without alcohol sensitivity. In the alcohol-sensitive group, the geometric mean (geometric SEM (GSEM)) of the provocative concentration of methacholine (PC20,meth) and acetaldehyde (PC20,acet) causing a 20% fall in forced expiratory volume in one second were 0.947 mg x mL(-1) (GSEM 0.139) and 21.0 mg x mL(-1) (GSEM 0.112), respectively, which were not significantly different from those in the nonalcohol-sensitive group, which were 0.634 mg x mL(-1) (GSEM 0.115) and 31.7 mg x mL(-1) (GSEM 0.077), respectively. The ratio of airway responsiveness to acetaldehyde relative to methacholine (log PC20,acet/PC20,meth) was 1.345+/-0.093 (mean+/-SEM) in the alcohol-sensitive group, which was significantly different from the value of 1.699+/-0.059 in the nonalcohol-sensitive group (p=0.0025). A significant correlation was observed between PC20,meth and PC20,acet in both the alcohol-sensitive group (r=-0.742, p=0.0115) and nonsensitive group (r=0.882, p<0.0001). In conclusion, the airways of asthmatic subjects with alcohol-induced bronchoconstriction have a selective hyperresponsiveness to acetaldehyde.     

Bronchoalveolar lavage does not alter airway responsiveness in asthmatic subjects

Bronchoalveolar lavage (BAL) during fiberoptic bronchoscopy is being used increasingly for the investigation of asthma. Airway responsiveness to methacholine is a sensitive indicator of the presence and severity of asthma. Therefore, we studied the effect of BAL on methacholine airway responsiveness in stable asthmatics. Geometric mean methacholine PC20 was 1.34 mg/ml before and 1.80 mg/ml after BAL (p = 0.26) in asthmatics. Immediate symptoms of airway narrowing after BAL occurred only in the 3 asthmatics with moderate to severe hyperresponsiveness. These symptoms were rapidly relieved by inhaled bronchodilator. There was no relationship between the occurrence of symptoms and the amount of topical lidocaine used for local anaesthesia or the volume of lavage fluid returned. The absence of an effect of BAL on airway responsiveness supports the safety of this procedure in the controlled asthmatic patient with near normal FEV1, irrespective of the level of baseline airway responsiveness.     

New Considerations About Measuring Airway Hyperresponsiveness

Measuring airway responsiveness to inhaled bronchoconstrictor stimuli, such as methacholine or histamine, has become an important tool in the diagnosis of asthma. This is measured by patients inhaling increasing closes or concentrations of the bronchoconstrictor stimulus until a given level of bronchoconstriction is achieved. Inhaled allergens initiate processes that increase airway inflammation and enhance airway hyperresponsiveness in asthmatic subjects. Studies using inhaled allergen challenges have provided insight into how changes in airway hyperresponsiveness are regulated by induced inflammatory processes. These changes in airway hyperresponsiveness (1-2 doubling doses) have been shown to be of much smaller magnitude than those demonstrated when asthmatics with stable airway hyperresponsiveness are compared to normals (4-8 doubling doses). These allergen-induced changes would be of little relevance in subjects with normal airway responsiveness, because they would not increase the degree of airway responsiveness into the asthmatic range. They are, however, important in asthmatics who already have airway hyperrespon-siveness because they are similar to changes associated with worsening asthma control. It is likely that the mechanisms responsible for the changes in airway hyperresponsiveness following experimental allergen exposure are similar to those producing transient worsening of control in asthmatics. Nevertheless, it is unlikely that the mechanisms of the transient allergen-induced airway hyperresponsiveness will explain the underlying mechanisms of the persistent airway hyperresponsiveness in asthmatic patients when compared with normal individuals.     

Histamine bronchoconstriction reduces airway responsiveness in asthmatic subjects

Tachyphylaxis occurs to repeated challenges with inhaled histamine but not with inhaled acetylcholine in asthmatic subjects. This study was undertaken to determine whether prior histamine bronchoconstriction reduces airway responsiveness to inhaled acetylcholine in mild asthmatic subjects demonstrating histamine tachyphylaxis. All subjects developed histamine tachyphylaxis with repeated histamine challenge. The mean histamine PC20 increased from 3.74 to 5.92 mg/ml (p less than 0.005) when the histamine challenges were separated by 1 h. Prior acetylcholine bronchoconstriction did not reduce airway responsiveness to subsequent inhalation of either acetylcholine or histamine in these subjects. However, histamine inhalation did reduce airway responsiveness to acetylcholine in all subjects. The mean acetylcholine PC20 following acetylcholine inhalation was 3.37 mg/ml (%SD 2.17) and this increased to 7.76 mg/ml (%SD 1.80) after histamine inhalation (p less than 0.0005). Thus, this study demonstrates that prior histamine, but not acetylcholine, bronchoconstriction can partially protect against bronchoconstriction caused by both histamine and acetylcholine. Therefore, reduced airway responsiveness caused by histamine bronchoconstriction is specific for histamine and is not due to bronchoconstriction per se. However, the reduced airway responsiveness following histamine bronchoconstriction, is nonspecific.     

Regular inhaled salbutamol : effect on airway responsiveness to methacholine and adenosine 5'-monophosphate and tolerance to bronchoprotection

OBJECTIVE: Regular treatment with inhaled beta(2)-agonists increases airway responsiveness consistently to indirect bronchoconstrictors (allergen, exercise, hypertonic saline solution, etc) and inconsistently to direct bronchoconstrictors (histamine, methacholine). Studies demonstrating tolerance to beta(2)-agonist bronchoprotection against the indirect bronchoconstrictor adenosine 5'-monophosphate (AMP) have not examined changes in baseline AMP responsiveness. This study assessed the effect of regular salbutamol on AMP and methacholine responsiveness and on tolerance to bronchoprotection. DESIGN: Double-blind, randomized, crossover study. SETTING: University hospital bronchoprovocation laboratory. PATIENTS: Fourteen atopic asthmatic subjects with FEV(1) > 65% predicted, and methacholine provocative concentration causing a 20% fall in FEV(1) (PC(20)) < 8 mg/mL. INTERVENTIONS: Salbutamol, 100 microg, and placebo inhalers, two puffs qid, each for 10 days. MEASUREMENTS: Methacholine PC(20) and AMP PC(20) measured 12 h after blinded inhaler after each treatment period. Methacholine PC(20) and AMP PC(20) repeated 10 min after salbutamol, 200 microg (eight subjects). RESULTS: There was no difference between placebo and salbutamol treatment in geometric mean methacholine PC(20) (0.85 mg/mL vs 0.82 mg/mL, p = 0.86) or AMP PC(20) (22 mg/mL vs 17.4 mg/mL, p = 0.21; n = 14). The acute bronchoprotective effect of salbutamol was greater vs. AMP than vs methacholine (5.1 doubling concentrations vs. 3.5 doubling concentrations, p = 0.06) and loss of protective effect of salbutamol (mean +/- SD) was greater vs AMP than vs. methacholine (2.4 +/- 0.33 doubling concentration loss vs 0.8 +/- 0.21 doubling concentration loss, p = 0.008; n = 8). CONCLUSION: Regular salbutamol (mean +/- SD) treatment did not enhance airway responsiveness to either the indirect bronchoconstrictor AMP or the direct bronchoconstrictor methacholine. Compared to its effect on methacholine, salbutamol had a greater acute protective effect vs AMP and produced greater loss of protection vs AMP when used regularly.     

Methacholine airway responsiveness decreases during exercise in asthmatic subjects

In many asthmatic subjects, bronchoconstriction develops 2 to 5 min after exercise, reaches a maximum at approximately 10 min, and declines over the next 60 min. However, bronchodilation is typically observed during and immediately after exercise. We measured the bronchoconstrictor responses to increasing concentrations of inhaled methacholine at rest and during two levels of exercise in seven asthmatic subjects to determine the protection against bronchoconstriction afforded by exercise. On the first day, an incremental Stage 1 exercise test was performed to determine the work capacity (Wcap) of each subject. On the second, third, and fourth days, methacholine was inhaled at rest or during steady-state exercise at one-third or two-thirds of Wcap. The bronchoconstrictor response to methacholine was significantly reduced during exercise (p less than 0.0001). The concentration of methacholine required to produce a 20% reduction in FEV1 (PC20) increased from 2.80 mg/ml (%SEM, 1.62) at rest to 7.29 mg/ml (%SEM, 1.43) during exercise at one-third Wcap, and to 31.03 mg/ml (%SEM, 1.74) during exercise at two-thirds Wcap (p less than 0.001). This study has demonstrated that there is greater than tenfold protection against bronchoconstriction by methacholine during exercise, and the magnitude of the protection depends on the intensity of exercise performed. The mechanism of this protection is not known, but may have clinical utility.     

Effect of an inhaled thromboxane mimetic (U46619) on airway function in human subjects.

Thromboxane A2(TxA2) has been implicated in the pathogenesis of airway hyperresponsiveness. The effects of inhaled TxA2 on human airway function have not been studied because of its short half-life. U46619 is a chemical that mimics the effects of TxA2. The purpose of this study was to evaluate the effects of inhaled U46619 on human airway function and methacholine airway responsiveness. Airway responsiveness to methacholine and U46619 was measured in 19 subjects (13 asthmatic and six normal) and expressed as the provocative concentration causing a 20% fall in FEV1 (PC20). On one day, methacholine alone was inhaled. On a second day, U46619 was inhaled, then 1 h later methacholine was inhaled. On a third day, U46619 was inhaled, then repeated 1 h later. In six subjects, the effects of isotonic saline or a subthreshold concentration of histamine or U46619 were examined on methacholine airway responsiveness. U46619 was 178 times more potent as a bronchoconstrictor than was methacholine. Airway responsiveness to methacholine was correlated to airway responsiveness to U46619 (r = 0.87, p = 0.001). Subthreshold concentrations of U46619, but not of histamine, increased methacholine airway responsiveness. The mean maximal fall in FEV1 after inhaled methacholine was 13.2% (SEM, 3.4%) after saline, 12.4% (SEM, 2.4%) after histamine, and 25.7% (SEM, 2.0%) after U46619 (p = 0.0004). This effect lasted less than 1 h. There was no tachyphylaxis to repeated inhalations of U46619. These results indicate that in human subjects inhaled U46619 is a potent bronchoconstrictor that, when present in the airways, can cause airway hyperresponsiveness to inhaled methacholine in asthmatic subjects.     

Airway responsiveness as a direct factor contributing to the dyspnoea perception in asthma.

It is not clear whether airway responsiveness is directly related to the perception of bronchoconstriction in asthma. The purpose of this study is to directly compare the perception of induced bronchoconstriction among the groups classified according to the degree of airway responsiveness. Two hundred and twenty-seven patients with the definitive or suspected asthma underwent a methacholine provocation test. During the test, the degree of dyspnoea was assessed by a modified Borg scale. The perception of induced bronchoconstriction was indicated by the slope in the linear regression analysis between changes in Borg score and the reduction in forced expiratory volume in 1 sec (FEV1) as a percentage of baseline value. The provocative concentration of methacholine resulting in 20% fall in FEV1 (PC20) was calculated. The degree of airway responsiveness to methacholine was categorized as moderate to severe airway hyper-responsiveness (AHR) if PC20 was < 1 mgml(-1), mild AHR if PC20 was > or =1 but < or =4 mgml(-1), borderline AHR if PC20 was >4 but < or =16 mgml(-1), and normal airway responsiveness (negative AHR) if PC20 was > 16 mgml(-1). Positive AHR was defined as PC20< or =4 mgml(-1). Another index of bronchial responsiveness (BR index) was calculated as the log [(% decline in FEV1/log final methacholine concentration as mg dl(-1)+10]. We found that the geometric mean of the slope was lower in subjects with positive AHR (0.12, n=115) than in subjects with negative AHR (0.17, n=72; P<0.01). The geometric mean of the slope in subjects with borderline AHR (0.14, n=40) was between the two groups. Furthermore, the slope was decreased in asthmatics with moderate to severe AHR compared with mild AHR (P <0.05), although the baseline FEV1 did not differ between the two groups. In multiple regression analysis, airway responsiveness expressed as BR index had a significant effect on the perception of bronchoconstriction. We conclude that the perception of bronchoconstriction is diminished in patients with AHR and the degree of airway responsiveness may be directly related to the perception of bronchoconstriction in asthmatic subjects.     

Adenosine-induced bronchoconstriction in asthma. Role of parasympathetic stimulation and adrenergic inhibition

Adenosine by inhalation causes bronchoconstriction in asthmatic but not in normal subjects by an undefined mechanism. This study investigated the roles of cholinergic reflex stimulation and decreased beta 2-adrenoceptor responsiveness to explain adenosine's bronchoconstrictor action. The protection afforded by the inhaled muscarinic cholinergic antagonist, ipratropium bromide (IB) 1 mg, from bronchoconstriction induced by inhaled adenosine was compared with that of methacholine in 8 allergic asthmatic subjects. After saline placebo, the geometric mean concentrations of adenosine required to produce a 20% fall in FEV1 (PCf20) was 2.20 mg/ml and a 35% fall in SGaw (PCs35) was 1.97 mg/ml, which compared to 0.13 and 0.11 mg/ml, respectively, for methacholine. The IB increased FEV1 by 11 to 15% and SGaw by 69 to 73% and provided a large degree of protection against methacholine, with a geometric mean concentration ratio (CR) of 196 when airway caliber was measured as SGaw (p less than 0.001). In contrast, IB provided little protection against adenosine-induced bronchoconstriction (CR 1.3 for SGaw and 1.51 for FEV1). Beta 2-adrenoceptor responsiveness of the airways after inhaled adenosine and histamine was further studied in 12 asthmatic subjects by observing the antibronchoconstrictor effect of inhaled isoproterenol. After equivalent degrees of bronchoconstriction, 35 to 36% fall in FEV1 and 60 to 62% fall in SGaw cumulative doses of inhaled isoproterenol produced almost identical maximal increases in FEV1 and SGaw after adenosine as achieved after histamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo.

Neuropeptides such as neurokinin A (NKA) have been proposed as important mediators of bronchoconstriction and airway hyperresponsiveness in asthma. Inhaled NKA causes bronchoconstriction in patients with asthma, but not in normal subjects. This is possibly due to the activity of an endogenous neuropeptide-degrading enzyme: neutral endopeptidase (NEP). We investigated whether a NEP-inhibitor, thiorphan, reveals bronchoconstriction to NKA or NKA-induced changes in airway responsiveness to methacholine in normal humans in vivo. Eight normal male subjects participated in a double-blind crossover study, using thiorphan as pretreatment to NKA challenge. Dose-response curves to inhaled NKA (8 to 1,000 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, and methacholine tests were performed 48 h before and 24 h after the NKA challenge. Ten minutes prior to NKA challenge the subjects inhaled either thiorphan (2.5 mg/ml, 0.5 ml) or placebo. To detect a possible nonspecific effect of thiorphan, we investigated the effect of the same pretreatment with thiorphan or placebo on the dose-response curve to methacholine in a separate set of experiments. The response was measured by the flow from standardized partial expiratory flow-volume curves (V40p), expressed in percent fall from baseline. NKA log dose-response curves were analyzed using the area under the curve (AUC) and the response to the highest dose of 1,000 micrograms/ml (V40p,1000). The methacholine dose-response curves were characterized by their position (PC40V40p) and the maximal-response plateau (MV40p). Baseline V40p was not affected by either pretreatment (p greater than 0.15).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise provocation test in the diagnosis of bronchial asthma and detection of airway responsiveness]

Exercise provocation test was performed on a bicycle ergometer in 110 asthmatics, 15 allergic rhinitis patients, 10 patients with moderate chronic bronchitis and 22 healthy subjects. 87.5% (21/24) of atypical asthmatics revealed positive exercise induced asthma (EIA), with the overall positive rate of asthmatics being 90% (99/110). There was a close negative linear correlation between the maximal reduction rate in FEV1 induced by exercise (delta FEV1%) and the inhaled histamine dose needed to reduce FEV1 by 20% (PD20FEV1) (r = -0.59, P less than 0.01). None of the healthy subjects, one of 15 allergic rhinitis patients and one of 10 patients with moderate chronic bronchitis showed positive response to exercise test. In contrast, seven of 18 allergic rhinitis patients and all nine patients with moderate chronic bronchitis had positive response to histamine bronchial provocation test. Therefore, exercise provocation test is a reliable method for diagnosing EIA and detecting airway responsiveness and it may possess higher specificity than histamine provocation test in diagnosing bronchial asthma, particularly in atypical bronchial asthma.     

Effect of inhaled furosemide on metabisulfite- and methacholine-induced bronchoconstriction and nasal potential difference in asthmatic subjects

To evaluate the hypothesis that furosemide inhibits indirect bronchoconstrictor challenges by altering airway epithelial ion transport, we studied its effects on indirect bronchoconstriction induced by inhaled metabisulfite (MBS) and nasal potential difference (PD) in seven subjects with mild asthma. Its effect on direct bronchoconstriction by the inhaled muscarinic agonist methacholine (MC) was studied in six of these subjects. Each subject inhaled furosemide, 30 mg, in a randomized, double-blind, placebo-controlled fashion immediately before challenge with MBS (0.3 to 160 mg/ml in increasing doubling concentrations) and, in another study, MC (0.125 to 32 mg/ml) aerosols from a nebulizer attached to a dosimeter. PC20MBS and PC20MC, the concentration of each agent needed to lower FEV1 by 20%, were calculated by linear interpolation of the log dose-response curves. Furosemide had no effect on resting lung function, but it caused a significant threefold reduction in sensitivity to MBS (PC20MBS: GM +/- GSEM, 15.1 +/- 1.6 mg/ml after placebo and 40.7 +/- 1.7 mg/ml after furosemide; p less than 0.001) with a protective index of 64.8 +/- 10.7%. Furosemide caused no change in sensitivity to MC (PC20 MC:GM +/- GSEM, 2.37 +/- 1.61 mg/ml after placebo and 2.19 +/- 1.751 mg/ml after furosemide; NS). In a third study, furosemide, 30 mg, and placebo were inhaled through the nose in a randomized double-blind fashion immediately prior to inhalation of a PC20 concentration of MBS through the nose. Nasal PD was measured before and after placebo or furosemide, and again after MBS inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of infused angiotensin II on the bronchoconstrictor activity of inhaled endothelin-1 in asthma

STUDY OBJECTIVES: Endothelin (ET)-1 is a potent bronchoconstrictor, and asthmatics demonstrate bronchial hyperresponsiveness to ET-1 given by inhalation. Angiotensin II (Ang II) is increased in plasma in acute severe asthma, causes bronchoconstriction in asthmatics, and potentiates contractions induced by ET-1 in bovine bronchial smooth muscle in vitro, and contractions induced by methacholine both in vitro and in vivo. We wished to examine any potentiation of the bronchoconstrictor activity of inhaled ET-1 by infused Ang II at subbronchoconstrictor doses. DESIGN: Double-blind randomized placebo-controlled study. SETTING: Asthma research unit in university hospital. PATIENTS: Eight asthmatic subjects with baseline FEV1 88% predicted, bronchial hyperreactivity (geometric mean, concentration of methacholine producing 20% fall, methacholine PC20 2.5 mg/mL), and mean age 37.1 years. INTERVENTIONS: We examined the effect of subbronchoconstrictor doses of infused Ang II (1 ng/kg/min and 2 ng/kg/min) or placebo on bronchoconstrictor responses to inhaled ET-1 (dose range, 0.96 to 15.36 nmol). MEASUREMENTS: Oxygen saturation, noninvasive BP, and spirometric measurements were made throughout the study visits. Blood was sampled for plasma Ang II levels at baseline and before and after ET-1 inhalation. RESULTS: Ang II infusion did not produce bronchoconstriction per se at either dose prior to ET-1 challenge. Bronchial challenge with inhaled ET-1 produced dose-dependent bronchoconstriction, but there was no difference in bronchial responsiveness to ET-1 comparing infusion of placebo with Ang II at 1 ng/kg/min or 2 ng/kg/min (geometric mean, concentration of ET-1 producing 15% fall, 5.34 nmol, 4.95 nmol, and 4.96 nmol, respectively) (analysis of variance, p > 0.05). There was an increase in systolic and diastolic BP at the higher dose of Ang II compared to placebo (mean 136/86 vs 117/75 mm Hg, respectively). Plasma Ang II was elevated following infusion of both doses of Ang II compared to placebo. CONCLUSIONS: In contrast to the potentiating effect on methacholine-induced bronchoconstriction, Ang II at subbronchoconstrictor doses does not potentiate ET-1-induced bronchoconstriction in asthma.