Bronchial responsiveness to exercise in a random sample of 494 children and adolescents from Copenhagen

To investigate the bronchial response to exercise, we studied a random sample of 494 children and adolescents, aged 7-16 years, from Copenhagen. Exercise challenge consisted of steady running on a 10% sloping treadmill for 6 min in a climate chamber. Furthermore, in 464 subjects a histamine challenge test was also performed. Of the 494 subjects studied, 81 (16%) had at least 10% and 30 (6%) at least 15% reduction in FEV1 within 15 min after exercise. Twenty-nine (6%) subjects had bronchial hyperresponsiveness to both histamine and exercise, 48 (10%) subjects had bronchial hyperresponsiveness to exercise, but histamine responsiveness within the normal range, whereas 340 (73%) subjects had neither bronchial hyperresponsiveness to exercise nor inhaled histamine. With regard to the presence of asthma defined as substantial exercise induced bronchoconstriction (delta-FEV1 greater than or equal to 10%), exercise testing may not be appropriate for identifying clinical asthma in a random sample, because the highest predictive value of a positive test was 25%. On the other hand, a history of clinical asthma was frequently associated with increased bronchial responsiveness to exercise (77%). In conclusion, 16% of a random sample of children and adolescents had abnormal bronchial responsiveness to exercise (delta FEV1 greater than or equal to 10%), 6% of the subjects had a delta FEV1 greater than or equal to 15%. Furthermore, because of a low predictive value of a positive test, the exercise challenge test has only a supplementary role in the detection of clinical asthma in population samples.     

Bronchial responsiveness to inhaled histamine and exercise.

Bronchial responsiveness to inhaled histamine and exercise was measured in 19 asthmatics. Histamine aerosol was inhaled to determine the provocative concentration producing a 20% fall in forced expired volume in one second (FEV1) (PC20). Exercise was performed on a treadmill and a cycle ergometer; following each procedure the percent fall in the FEV1 (delta FEV1) and the exercise lability (percent rise in FEV1 plus percent fall in FEV1) were calculated. Delta FEV1 and exercise lability after both forms of exercise were similar. PC20 correlated with delta FEV1 and exercise lability in both forms of exercise; however, the correlation with exercise lability was better. PC20 was more sensitive in demonstrating bronchial hyperresponsiveness. The close correlation between the level of bronchial responsiveness to histamine and exercise supports the view that release of endogenous chemical mediators is an important determinant of exercise-induced asthma. The treadmill exercise and cycle ergometry protocols were equally effective in producing exercise-induced asthma.     

Comparison of airway conductance and FEV(1) as measures of airway responsiveness to methacholine. Discrimination of small differences in bronchial responsiveness with Gaw and FEV(1).

When defining bronchial responsiveness in healthy, non-asthmatic, subjects exposed in different working situations, it is not clear whether different outcome measures yield similar results. Therefore, the concentration and dose of methacholine that caused a 20% decrease in forced expiratory volume in 1 s (FEV(1)) (PC20(FEV(1)) and PD20(FEV(1))), the corresponding change in Gaw and the relationship between the dose-response slope (DRS) for FEV(1) and Gaw was studied in different working populations and healthy control subjects (n=1038). The two outcome measures were compared in groups of subjects in whom differences in bronchial responsiveness could be anticipated [atopics (n=72) and non-atopics (n= 207) and subjects exposed (n=54) and not exposed (n=32) to saw dust]. A bronchial challenge was also made before and after exposure in a swine confinement building, an exposure known to increase bronchial responsiveness (n=37). PD20(FEV(1)) was 1.7 mg in atopics and 4.9 mg in non-atopics, 7.1 mg in saw dust exposed and >20 mg in non-exposed subjects and 5.3 mg before and 0.79 mg after exposure to organic dust. There was a correlation between DRS(FEV(1)) and DRS(Gaw), r=0.87 (P<0.001). In subjects who were highly sensitive to methacholine a 20% change in FEV(1) corresponded to <40% change in Gaw, while a 20% decrease in FEV1 corresponded to none or a minor decrease in Gaw in subjects with less methacholine-sensitive airways. The ability to detect differences in bronchial responsiveness between groups, or to detect changes in bronchial responsiveness following exposure was approximately the same for FEV(1) and Gaw. The reproducibility was similar for both variables and a second measurement was within one doubling of the methacholine concentration of the first provocation in approximately 95% of all measurements (n=41). In conclusion, with our methacholine provocation method, FEV(1) and Gaw had similar sensitivity in detecting small differences in bronchial responsiveness in healthy subjects.     

Influence of asthmatic and rhinitic symptomatology duration on bronchial responsiveness to histamine

Our Study aimed to investigate the influence of the time in years elapsed from the onset of symptoms on bronchial nonspecific responsiveness in rhinitic and asthmatic patients. The study was performed on 83 asthmatic patients and on 46 patients with allergic rhinopathy. The beginning of the symptoms and years of asthmatic or rhinitic history were particularly investigated. A histamine challenge was performed. The dose of histamine producing at 20% change in FEV1 (forced expiratory volume in one second) was calculated from the individual semilogarithmic dose-response curve (PD20). Bronchial responsiveness to histamine showed wide variability in subjects of two groups, and an overlap of the distribution curves was observed between asthmatic and rhinitic patients. A significant relationship (p less than 0.01) between the years elapsed from the onset of symptoms and bronchial responsiveness to histamine was observed in each group of patients. We noticed that the number of the years passed heightened the bronchial responsiveness to histamine in both groups of patients.     

A detailed genetic map of the chromosome 7 bronchial hyper-responsiveness locus

Non-specific bronchial hyper-responsiveness to various inhaled stimuli is a characteristic of asthma. We have previously shown linkage of bronchial responsiveness to methacholine (measured as dose-response slope (DRS)) and the peripheral blood eosinophil count (EOS) to chromosome 7. We have now further investigated these linkages by genotyping 49 microsatellite markers across the DRS locus on chromosome 7. The markers were spaced on average 2.6 cM apart and spanned a sex averaged cumulative genetic distance of 129 cM. Multipoint linkage to DRS was bimodal and dipped at the centromere. The two peaks of linkage were close to markers D7S484 (P=0.0003) and D7S669 (P=0.006) respectively. Separate testing for linkage to paternally and maternally derived alleles showed that the linkage near D7S484 was paternally derived (P<0.00001): maternally derived alleles did not exhibit significant linkage. The results indicate that two disparate loci may be influencing asthma from chromosome 7.     

Distribution of serum IgE in children and adolescents aged 7 to 16 years in Copenhagen, in relation to factors of importance

The distribution of total serum-IgE and factors of importance for the level of IgE was studied in a random sample of 508 children and adolescents, aged 7-16 years, from Copenhagen. A detailed history about asthma, rhinitis, dermatitis and urticaria was obtained, and a physical examination, skin prick test with 9 common allergens, lung function test, bronchial challenge with inhaled histamine and exercise, and measurement of IgE (kU/l) were performed. The distribution of IgE among children and adolescents was found to exhibit a log normal distribution and a positive skin prick test, allergic symptoms, a family history of allergic diseases, age and smoking were found to be significantly related to an increased level of IgE. No relationship was found between increased bronchial responsiveness and IgE. The geometric mean of "normal" values of IgE (*1 SD and *2 SD) of the Danish children and adolescents was 18 kU/l (*4.7, *18.2), suggesting that normal IgE values were within 330 kU/l. Measurement of IgE as the only screening for allergic disease is unreliable, as the predictive value of an elevated IgE in population samples was found to be 50%, whereas misclassification (1-specificity) of asymptomatic subjects as allergic because of an increased IgE was low (4%). In conclusion, total IgE is highly influenced by allergen skin reactivity. Further, this study suggests that normal IgE values were within 330 kU/l, although the range was wide.     

Distribution of radioactive aerosol in the airways of children and adolescents with bronchial hyper-responsiveness.

The purpose of this study was to examine the relationship between the pulmonary distribution of inhaled radioaerosol, bronchial responsiveness, and lung function in children and adolescents. The participating subjects (n = 39) were divided into three groups: (1) 14 asthmatics with bronchial hyper-responsiveness (BHR), (2) five non-asthmatic subjects with BHR, and (3) 20 controls without BHR. Pulmonary distribution of [99Tcm) albumin radioaerosol, maximal expiratory flow when 25% of forced vital capacity remain to be exhaled (MEF25), and bronchial responsiveness to inhaled histamine were measured. Twenty subjects (52%) had irregular central distribution and 19 subjects (48%) had regular distribution of radioaerosol in their lungs. No difference in distribution of radioaerosol was found between the three groups of children. The median MEF25 among non-asthmatic subjects (80% predicted) was lower than that found in controls (92% predicted) but higher than that found in asthmatic subjects (55% predicted). A relationship was found between reduced flow at the peripheral airways, as indicated by MEF25 and the degree of central distribution of radioaerosol. Furthermore, subjects with irregular central distribution of radioaerosol had an increased degree of bronchial responsiveness. In conclusion, children and adolescents who have flow rates in the peripheral airways or increased degree of bronchial responsiveness tend to have abnormal distribution of radioaerosols.     

Prevalence and characteristics of late asthmatic responses to exercise

The prevalence and characteristics of late asthmatic responses to exercise were studied in an adult asthmatic population. Twenty-four subjects (eight male and 16 female), aged 17 to 39 years (mean, 23.7 years), performed a 6-minute exercise on a bicycle ergometer at 75% of their maximum oxygen intake. FEV1 was measured at regular time intervals up to 8 hours after exercise. Seven subjects demonstrated a late asthmatic reaction defined as a fall in FEV1 greater than 10% between 2 to 8 hours. Bronchial reactivity to histamine was unchanged 24 hours after the exercise, compared to baseline. On a control day, a fall in FEV1 similar to the one observed after exercise was induced by methacholine inhalation. Measurements of FEV1 were done at the same time intervals as on exercise day. Neutrophil chemotactic activity was measured in the serum of 15 subjects, on exercise day for early responders, and on the 3 test days for subjects with a dual response. There was no difference between subjects with an isolated early or late response for age, sex, or atopic status. Baseline expiratory flows and nonspecific bronchial reactivity to histamine were similar in both groups. These results demonstrate the occurrence of a late asthmatic response in 30.4% of the population studied. There was no significant change of nonspecific bronchial responsiveness after the late asthmatic response to exercise. No significant increase in neutrophil chemotactic activity could be observed.     

Effects of SK&F 104353, a leukotriene receptor antagonist, on the bronchial responses to histamine in subjects with asthma: a comparative study with terfenadine

We compared the effects of pretreatment of 800 micrograms of inhaled Smith Kline & French (SK&F) 104353, a leukotriene receptor antagonist, and 120 mg of oral terfenadine on the bronchial responses to inhaled histamine in 12 subjects with asthma. The study took place on 3 different days and was conducted according to a double-blind, crossover, double-dummy, randomized, and placebo-controlled design. There was no difference in baseline and prechallenge FEV1 after placebo, SK&F 104353, and terfenadine administration. The median ratio of the provocative dose causing a 20% fall in FEV1 from baseline (PD20) with terfenadine over PD20 with placebo was 12.36 (range, 3.2 to 30.3; p less than 0.01) and that of PD20 with SK&F 104353 over PD20 with placebo was 1.51 (range, 0.8 to 5.9; not significant). Analysis of individual results demonstrated a shift toward the right of the dose-response curves to histamine with SK&F 104353 compared to that with placebo in three subjects, whereas the active compound did not exhibit any protective effect against histamine in the remaining nine subjects. We conclude that there is a leukotriene component to the bronchial responses to histamine in some, but not all, subjects. This component remains, however, small and does not appear to be clinically important in the population of subjects with asthma that was studied.     

Release of histamine from leucocytes and its determinants in vitro in rotation to bronchial responsiveness to inhaled histamine and exercise in vivo

The hypothesis studied is that increased responsiveness in asthma is not limited to the airways. Forty asthmatic children were analysed for their bronchial responsiveness (BR) to exercise. Twenty patients revealed bronchial obstruction after exercise while the remainder did not. These observations were compared with the responsiveness of leucocytes, which was determined by their histamine ‘releasability’. Twenty healthy children served as controls. Release of histamine induced by calcium ionophore-aided calcium influx was significantly higher in both groups of asthmatics than in the healthy children (P < 0.005). Similar findings were obtained by induction of microtubule aggregation due to deuterium oxide (D₂O). The S-shaped dose-response relationship with D₂O was shifted to the left in the patients with BR to exercise compared to patients without (P < 0.025). The slope was increased in both patient groups compared with the healthy children (P < 0.01). It is concluded that the mean ‘releasability’ of histamine release due to both stimulants correlated well (P < 0.01). This suggests that the ‘releasability’ is determined by the responsiveness of the microtubules. This may also apply to allergen-induced histamine release, as was revealed from studies with anti-IgE. The differences in histamine release found in relation to BR due to exercise were also present if the patients were divided according to BR due to histamine. A significant relationship existed between the degree of BR to histamine and the responsiveness of the microtubules (P < 0.02).     

Relationship between atopy and bronchial responsiveness to histamine in a random population

Although there are theoretical reasons to suggest that atopy might predispose to non-allergic bronchial hyperresponsiveness, previous studies have yielded conflicting results. We assessed this by determining the atopic status and bronchial responsiveness to inhaled histamine in 400 randomly selected college students. An atopy score was determined as the number of "+"s from a standard battery of seven allergy prick skin tests each graded from + to +, and the atopic status was graded as non-atopic (no +'s) mildly atopic (1 to 4 +'s), moderately atopic (5 to 8 +'s), or markedly atopic (greater than 8 +'s). Non-allergic bronchial responsiveness to inhaled histamine was measured with a standardized histamine inhalation test from which the histamine provocation concentration producing a 20% FEV1 fall (PC20) was calculated. The prevalence of bronchial hyperresponsiveness to histamine (PC20 less than or equal to 8 mg/ml) was 10.3% in the entire population. There was a progressive increase from 6.1% in the non-atopic group to 33% in the markedly atopic group (p less than 0.001). In 43 subjects with both measurable atopy score (greater than or equal to 1) and PC20 (less than or equal to 16 mg/ml), a regression of atopy score vs. log PC20 produced a small (r = -0.36) but significant (p less than 0.02) correlation. These data indicate a significant relationship exists between atopic status and increased non-allergic bronchial responsiveness to histamine. Although cause and effect cannot be inferred from this study, it is hypothesized that atopy is one factor, among others, which predisposes to non-allergic bronchial hyperresponsiveness.     

Oropharyngeal angioedema induced by inhaled histamine

Inhaled histamine used to measure airway responsiveness produces some side effects more frequently than does methacholine. It is possible that the inhaled histamine induces the side effects in asthmatics with increased end organ responsiveness to histamine. A 56-yr-old woman with chronic idiopathic angioedema presented with asthma-like symptoms. Methacholine challenge test was performed, with a negative result. Five days later, histamine inhalation test was done. FEV1 fell by 37% after inhalation of histamine concentration of 8 mg/mL. Immediately thereafter, severe angioedema on face, lips, and oropharyngeal area, foreign body sensation at throat, and hoarseness occurred. To assess end organ responsiveness to histamine, skin prick tests with doubling concentrations of histamine (0.03-16 mg/mL) were carried out on the forearm of the patient and six age- and sex-matched asthmatic controls. The wheal areas were measured. The patient showed greater skin responses than the controls. Regression analysis showed that the intercept and slope were greater than cut-off levels determined from six controls. The patient showed an increased skin wheal response to histamine, indicating the enhanced end organ responsiveness to histamine, which is likely to contribute to the development of the oropharyngeal angioedema by inhaled histamine.     

Effect of vitamin C on histamine bronchial responsiveness of patients with allergic rhinitis

The effect of acute oral administration of 2 g vitamin C on bronchial responsiveness to inhaled histamine in 16 patients with allergic rhinitis was compared with placebo on two consecutive days in a double-blind, crossover design. The PC15FEV1 was significantly increased one hour after treatment with vitamin C but not after placebo.     

Comparison of bronchial reactivity to histamine and methacholine in asthmatics

Eight subjects with asthma underwent bronchial challenge with histamine and methacholine. Dose-response curves were drawn on a scale which made the dosages equivalent in molecular weight. The results were analysed in terms of both the slope of the dose-response curve and the dose required to elicit a 20% fall in FEV1. No significant difference between methacholine and histamine was found in either measurement. Because of the similarity of the responses we conclude that the two agents are similar in action and may be used with equal effectiveness in bronchial challenges.     

Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms

Functional abnormalities of the extrathoracic airway (EA) may produce symptoms mimicking bronchial asthma. We assessed the bronchial (B) and EA responsiveness to inhaled histamine in 40 patients with asthmatic symptoms and in nine asymptomatic controls. FEV1 and maximal mid-inspiratory flow (MIF50) were used as index of bronchial and EA narrowing. Hyperresponsiveness of the intra-(BHR) or extra-(EA-HR) thoracic airway was diagnosed when the provocative concentrations of histamine (PC20FEV1 or PC25MIF50) were less than 8 mg/ml. Fiberoptic laryngoscopy was performed in nine patients and three controls. The glottal region was measured at mid-volume of maximal inspiration (AgMI) and expiration (AgME) before and after histamine. Predominant EA-HR was found in 13 patients, predominant BHR in 12, equivalent BHR and EA-HR in another 12; no significant airway narrowing was observed in three patients and in the nine controls. EA-HR was significantly associated with female sex, sinusitis, post-nasal drip, dysphonia; BHR with atopy, wheezing and lower MEF50. The percent change in AgMI after histamine was closely related to the PC25MIF50 (r = 0.87, P less than 0.001), that of AgME to the PC20FEV1 (r = 0.78, P less than 0.01). These findings suggest that the assessment of EA responsiveness may be useful in the evaluation of asthmatic symptoms, especially in patients with no BHR.     

Selective subsensitization of beta-adrenergic receptors in central airways of asthmatics and normal subjects during long-term therapy with inhaled salbutamol

In five subjects with mild asthma and in five normal subjects, we determined the effect of a 4 wk course of inhaled salbutamol (albuterol), 200 μg q.i.d., on (I) acute bronchodilator responsiveness, (2) bronchial sensitivity to inhaled histamine, (3) beta-adrenergic protection against histamine-induced bronchospasm, and (4) beta-receptor density of peripheral blood lymphocytes. We observed a diminution in central airway bronchodilator responsiveness (as measured by airway conductance responses) to acutely inhaled salbutamol and to subcutaneous terbutaline in both groups of subjects, although only the response to subcutaneous terbutaline was statistically significant (p < 0.02). On the other hand, no impairment of small airway bronchodilator responsiveness was noted in either group of subjects when responses were measured as partial expiratory flow rates at 60% below total lung capacity. These findings suggest the development of selective subsensitization of beta-receptors in the larger central airways, where a proportionately greater amount of the inhaled beta-agonist aerosol would necessarily be deposited. A greater loss of protection against histamine-induced bronchospasm was seen in asthmatics than in normals (approximately twofold), although the difference was not significant. A modest but not significant reduction in peripheral blood lymphocyte beta-receptor density was observed by the end of the 4 wk treatment period. The possibility that the observed changes in bronchodilator responsiveness might influence the morbidity and mortality associated with bronchial asthma is discussed.     

Atopy and bronchial responsiveness in random population sample of 527 children and adolescents.

The relationship between bronchial responsiveness, lung function, and results of skin prick testing was studied in 527 children and adolescents from Copenhagen. All participants completed a questionnaire concerning allergic symptoms (asthma, rhinitis, atopic dermatitis, and urticaria). Furthermore, skin prick test reactivity to nine common aeroallergens, lung function, serum IgE and bronchial responsiveness to histamine and exercise were measured. A total of 53 subjects were atopic, (skin prick 3+), 105 subjects had moderate skin reactivity (1-2+), and 366 subjects had no signs of atopic disease (prick test negative); 58% of the subjects with skin test reactivity (1-3+) were asymptomatic. Increasing degree of atopy was correlated significantly with symptoms such as asthma, rhinitis, dermatitis, and urticaria (P less than .001); increasing level of IgE (P less than .001); month of birth (P = .001); and family history of allergic diseases (P less than .05). The most important markers for the degree of bronchial responsiveness to inhaled histamine were the presence of respiratory symptoms (P less than .001), the degree of atopy (P = .001), a history of asthma in at least two first degree relatives (P less than .01), and the skin reactivity to house dust mites (P = .001), horse epithelium (P = .01), Alternaria iridis, and dog epithelium (P less than .05). In contrast, the degree of bronchial responsiveness to exercise was significantly correlated with asthma (P less than .001), the level of IgE (P less than .05), month of birth (P less than .001), and birth weight (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchial hyperreactivity to histamine and methacholine in asthmatic children after inhalation of SCH 1000 and chlorpheniramine maleate.

Nine asthmatic patients with a mean age of 14 yr received bronchial challenges with histamine and methacholine. The challenges were repeated after inhalation of 80 microgram of SCH 1000 (ipratropium bromide) and 5 mg of chlorpheniramine maleate. The provocation doses which produced a 20% fall in forced expiratory volume in 1 sec (FEV1) and the slopes of the dose-response curves were analyzed. SCH 1000 prevented methacholine-induced bronchoconstriction and chlorpheniramine prevented methacholine-induced bronchoconstriction. There was no significant change in the dose-response curve of histamine after SCH 1000 or in the dose-response curve of methacholine after chlorpheniramine. The findings indicate that the mechanisms and receptor sites involved in bronchial provocation by histamine and methacholine are distinctly different. The histamine response is unlikely to be vagally mediated because histamine-induced bronchoconstriction was not prevented by SCH 1000. Both SCH 1000 and chlorpheniramine caused significant bronchodilatation, suggesting the presence of both histamine- and vagal-dependent bronchomotor tone.     

Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma

Background: Recently it has been suggested that the bronchospasm and hyperresponsiveness phenomena observed in asthma are secondary to the actions of the eosinophils; the purpose of this study was to evaluate the relationship between the peripheral number of eosinophils and various markers of disease activity in a group of asthmatics examined in childhood (mean age 10 years) and early adulthood (mean age 21 years). Methods: The relationship between eosinophil count and pulmonary function (FEV₁), respiratory symptoms, bronchial responsiveness to histamine and diurnal variation in peak expiratory flow rate (PEF) was studied in 70 subjects with bronchial asthma, of whom 24 had intrinsic and 46 extrinsic asthma. Self-reported symptoms of asthma were graded on a scale from 0 to 5, where 0 = no symptoms within the preceding 12 months and 5 = daily including nocturnal symptoms, and histamine responsiveness was analysed by means of the dose-response slope (DRS). Results: In both childhood and adulthood, a direct correlation was found between blood eosinophil count and symptom score (r= 0.69, P< 0.001 and r= 0.58, P < 0.001, respectively), whereas inverse correlations were observed between number of eosinophils and FEV, % predicted (r= .0.75, P < 0.001 and r= 0.80, P < 0.001. respectively). Furthermore, in adulthood, eosinophil count was found to be significantly correlated to hisiamine responsiveness (log DRS) (r= 0.65, P < 0.001) and diurnal PEF variation (r= 0.81, P < 0.001); these correlations were also noted after dividing the subjects into intrinsic and extrinic asthmatics. In both groups of subjects a significant inverse correlation was also found between histamine responsiveness and pre challenge FEV₁% predicted. The eosinophil count in childhood was weakly correlated to the symptom score in adulthood (r= 0.29, P < 0.02). Conlusions: This study showed a relationship between eosinophil count and seventy of asthmatic symptoms, level of pulmonary function, histamine responsiveness and diurnal variation in PEF in both intrinsic and extrinsic asthma; suggesting that the peripheral eosinophil count reflects asthmatic activity, and possibly the degree of inflammation in the airways, in both children and adults. Furthermore, a low number of eosinophils in childhood might be related to a relatively favourable prognosis with regard to symptoms of asthma in early adulthood.     

Effects of beta adrenergic blockade on histamine and prostaglandin-F2 alpha responsiveness in the dog

To examine whether either the degree of existing beta adrenergic tone or the magnitude of beta adrenergic response during bronchoconstriction might account for the differences that exist between dogs in their pulmonary responsiveness to aerosol challenge with bronchoconstrictor agents, dose-response curves were performed in a group of dogs to either histamine or prostaglandin-F2 alpha, both before beta blockade with propranolol. Beta blocked had no significant effect on control values of dynamic compliance (Cdyn) or resistance of the lung (RL) or on pulmonary responsiveness to prostaglandin f2 alpha. Although propranolol did not have a significant effect on aerosol responsiveness to histamine for the group of dogs taken together, those dogs initially least responsive to aerosol histamine did become more responsive after beta blockade. This effect of beta blockade was statistically significant only for Cdyn and not for RL, suggesting enhancement of peripheral airway effects. We conclude that a beta adrenergic mechanism may contribute to the range of responsiveness found among dogs in their pulmonary responsiveness to histamine but that other as yet undefined factors must also contribute to the differences that exist among dogs in their pulmonary responsiveness to bronchoconstrictor agents.