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(Chest. 2002;122:940-947.)
© 2002 American College of Chest Physicians

Modifications of Airway Responsiveness to Adenosine 5'-Monophosphate and Exhaled Nitric Oxide Concentrations After the Pollen Season in Subjects With Pollen-Induced Rhinitis*

Luis Prieto, PhD; Sonia Uixera, MD; Valentina Gutiérrez, PhD and Laura Bruno, MD

* From the Sección de Alergología (The NAOMI Project), Hospital Universitario Dr. Peset and Universidad de Valencia, Valencia, Spain.

Correspondence to: Luis Prieto, PhD, Sección de Alergología, Hospital Universitario Dr. Peset, C/Gaspar Aguilar 90, 46017 Valencia, Spain; e-mail: prieto_jes{at}gva.es


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: 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 FEV1 (PC20) methacholine, and PC20 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, PC20 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 PC20 methacholine or PC20 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.

Key Words: adenosine 5'-monophosphate • airway responsiveness • allergen exposure • allergic rhinitis • methacholine • nitric oxide


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Airway hyperresponsiveness, an abnormal increase in airflow limitation after exposure to a number of nonsensitizing bronchoconstrictive stimuli, is present in almost all patients with clinically current asthma. Clinically and for research purposes, airway responsiveness is measured by bronchial challenge, usually with methacholine or histamine.1 Both agonists act on the relevant receptors on airway smooth muscle, stimulating airway muscle contraction directly. In contrast, adenosine 5'-monophosphate (AMP) acts indirectly, causing primed mast cell degranulation and the release of proinflammatory mediators (histamine and leukotrienes) with subsequent smooth-muscle contraction.2 3 4

Nitric oxide (NO) is raised in exhaled air from subjects with asthma compared with healthy control subjects, and several studies5 6 strongly suggest that exhaled NO (ENO) measurements reflect airway inflammation. Different technical factors can have significant effects on absolute values of ENO, but efforts have been made to standardize measurement procedures.7

Some authors suggest that allergic rhinitis and asthma are manifestations of the same disease in two parts of the respiratory tract.8 In support of this hypothesis are the observations that both airway diseases share the same trends of increasing incidence,9 predisposing factors,10 and pathophysiologic mechanisms.11 12 Furthermore, multiple investigations1 13 have shown that some patients with allergic rhinitis but no history of asthma exhibit airway hyperresponsiveness to direct bronchoconstrictor agents (histamine or methacholine). In addition, some reports have indicated that, in subjects without asthma and with allergic rhinitis, the presence of airway hyperresponsiveness to inhaled methacholine is associated with increased ENO levels.14 Besides methacholine, an important proportion of subjects with allergic rhinitis also have increased sensitivity to inhaled AMP.15 16 Because bronchoconstriction induced by AMP depends, at least in part, on the state of activation of airway mast cells,2 3 4 the bronchial response to AMP may be a more direct marker of allergic airway inflammation than direct bronchoconstrictors such as histamine or methacholine.

There is convincing evidence that, in sensitized subjects with pollen-induced rhinitis, natural exposure to pollen during the season provokes an increase in methacholine responsiveness17 18 and also induces inflammatory changes in the lower airways.19 In addition, airway responsiveness to inhaled AMP increases during periods of natural allergen exposure in subjects with asthma,20 but no information is available for subjects with allergic rhinitis.

Therefore, this study was designed with two objectives: (1) to determine the effect of cessation of exposure to pollen on airway responsiveness to AMP in subjects without asthma with seasonal allergic rhinitis; and (2) to explore the relationship between changes in airway responsiveness to either direct or indirect bronchoconstrictor agents and changes in ENO levels.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
A total of 24 subjects volunteered for this study. A group of subjects with seasonal allergic rhinitis (n = 14) who showed bronchoconstriction (FEV1 fall >= 20%) in response to inhaled methacholine and AMP when tested during the pollen season were recruited from a cohort of 18 subjects with allergic rhinitis with increased responsiveness, identified during two recent studies15 16 on the prevalence of airway hyperresponsiveness to methacholine and AMP in subjects with allergic rhinitis. Patients with seasonal allergic rhinitis were defined as individuals with a characteristic history (rhinorrhea, sneezing, obstruction, and pruritus) and who also had a positive skin-prick test result (>= 3 mm wheal diameter) to pollen allergens (grass pollen, Parietaria judaica, and/or Olea europaea) and no skin sensitization for other perennial allergens tested, namely house dust mites, Alternaria alternata, Aspergillus, Penicillium, Cladosporium, and cat and dog dander (allergens available from ALK-Abello; Madrid, Spain). No subject had a history of asthma (wheezing, dyspnea, chest tightness, chronic cough, or exercise wheeze).

A control group of 10 subjects was also studied. They were recruited from volunteers in the laboratory and among students. Selection criteria for this group included no history of asthma, allergic rhinitis, atopic eczema, or other relevant disease, and no medication and negative skin-prick test result for six common airborne allergens (Dermatophagoides pteronyssinus, mixed grass pollen, olive, Parietaria judaica, and cat and dog dander).

All 24 subjects were life-long nonsmokers, and no subjects had a history of chronic bronchitis, emphysema, or respiratory tract infections during the 4 weeks before the study. Current smokers or ex-smokers, pregnant women, and patients with significant renal, hepatic, or cardiovascular disease were specifically excluded. The study protocol was approved by the medical ethics committee of Hospital Universitario Dr. Peset. Written informed consent was obtained from each subject before participation.

Study Design
Subjects with seasonal rhinitis and healthy control subjects were first evaluated in May through June, during the pollen season. Subjects attended the laboratory on two visits, at the same time of day (± 2 h). On each of the two visits (at least 7 days but not > 9 days apart), spirometry and concentration-response studies with either methacholine or AMP were performed. Methacholine and AMP challenges were conducted on separate days with the order of challenge randomized and baseline FEV1 varied by < 10%. At the second visit, ENO was measured before the spirometry and challenge test. Subjects with allergic rhinitis were instructed to withhold their treatments for at least 2 weeks (nasal topical corticosteroids and nasal topical cromoglycate) and 3 days (antihistamines) before each challenge.

All subjects with pollen-induced rhinitis were also studied in October, out of pollen season, at a time when they were free of symptoms. Subjects attended the laboratory on two visits. On each of the two visits (at least 7 days but not > 9 days apart), spirometry and concentration-response studies with either methacholine or AMP were performed. At the second visit, ENO was measured before the spirometry and challenge test.

Pulmonary Function
Spirometry was performed with a calibrated dry rolling seal spirometer (model 2130; SensorMedics; Yorba Linda, CA) according to standardized guidelines.21 Baseline FEV1 and FVC were measured until three reproducible recordings differing < 5% were obtained. Maneuvers were accepted as technically satisfactory if the back-extrapolated volume was < 100 mL or 5% of FVC, and if the expiratory time was at least 6 s. Highest values were used for analyses. Reference values were those of the European Community for Coal and Steel.22

Inhalation Challenge Tests
Inhalation provocation tests were performed using the method described by Chai et al23 with some modifications.24 Methacholine and AMP (Sigma Chemical; St. Louis, MO) were dissolved freshly in 0.9% saline solution to produce doubling concentration ranges of 0.39 to 25 mg/mL for methacholine and 1.56 to 400 mg/mL for AMP. Each solution was administered from a jet nebulizer attached to a breath-activated dosimeter (Mefar MB3; Mefar; Brescia, Italy) at a nebulization time of 1 s and a pause time of 6 s. The nebulizer delivers particles with an aerodynamic mass median diameter of 3.5 to 4.0 µm at an output of 10 µL per breath. Subjects inhaled the aerosolized methacholine and AMP solutions in five inhalations from functional residual capacity to total lung capacity through a mouthpiece with the subject’s nose clipped. Normal saline solution was inhaled initially, followed by five breaths of doubling concentrations of methacholine or AMP at 2-min to 3-minute intervals. Because of the effect of a deep inspiration on subsequent airway tone,25 single measurements of FEV1 were made 60 to 90 s after inhalation of each concentration, unless the forced expiratory maneuver was judged to be technically unsatisfactory. The test was interrupted when a 20% decrease in FEV1 from the post-saline solution value was recorded or when the highest concentration was reached. Two inhalations of albuterol (200 µg) from a metered-dose inhaler were then administered to each subject, and the FEV1 was measured 15 min later. The provocative concentration of agonist required to produce a 20% fall in FEV1 (PC20) was calculated using a formula given by Cockcroft et al.26

ENO Measurement Technique
On the basis of the recommendation of the American Thoracic Society,7 the ENO concentration was measured using a rapid-response chemiluminescent NO analyzer (NIOX; Aerocrine; Solna, Sweden) with a sensitivity of 1.5 parts per billion (ppb) and a detection range of 0 to 200 ppb. The sampling flow was 300 mL/min, and the response time was < 0.8 s. The analyzer was calibrated regularly according to the manufacturer guidelines, using certified calibration gases containing 200 ppb (AGA; Lidingo, Sweden). Zero point determination used instrument-filtered zero-air. We used a restricted breath technique, which used exhalation via a high resistance, and positive mouth pressure to close the velum, thus excluding nasal NO. Subjects inhaled ambient air that was passed through a filter to reduce inhaled NO concentrations to < 5 ppb. Subjects inhaled without a nose clamp to total lung capacity, and immediately exhaled while targeting a constant pressure of 20 cm H2O with the aid of a visual feedback display. This produced an expiratory flow rate of 45 mL/s. Water vapor was absorbed by means of an NO-inert filter in the tube. An end-expiratory plateau of at least 3 s, where flow varied ± 10% of the target flow, was the end point of the measurement. Participants repeated the maneuver until three acceptable tests were performed. The average of the three plateau values was recorded.

Data Analysis
A PC20 methacholine value of 25 mg/mL was assigned to nine patients with allergic rhinitis out of pollen season and to eight healthy control subjects in whom FEV1 dropped < 20% even when the highest concentration of methacholine was used. Further, PC20 AMP could not be calculated in 11 subjects with allergic rhinitis out of pollen season and 10 healthy control subjects. On these occasions, the PC20 value was censored to the highest concentration of AMP given (400 mg/mL).

All PC20 and ENO values were log-transformed before analysis and presented as geometric means with 95% confidence intervals (CIs). All other numerical variables are reported as arithmetic means with 95% CIs. Changes in PC20 were expressed in terms of doubling concentrations of methacholine or AMP calculated as {Delta}log PC20'/log 2.

Comparisons of the baseline characteristics of the two groups were performed by unpaired Student t tests for continuous data and the Fisher exact test for categorical data. Changes in FEV1, ENO, and PC20 were assessed by paired t tests. Correlations between variables were calculated with Pearson correlation test. p values are two sided, and values < 0.05 were considered statistically significant. Data were analyzed with a statistical software package (InStat for Windows version 3.00; GraphPad Software; San Diego, CA).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The clinical and pulmonary function data for subjects with seasonal rhinitis and healthy volunteers are presented in Table 1 . The two groups were similar with regard to age, sex, and pulmonary function. In subjects with allergic rhinitis, the FEV1 decreased from a mean value of 3.09 L (95% CI, 2.59 to 3.59 L) during the pollen season to 3.07 L (95% CI, 2.57 to 3.58 CI) out of season, although the differences were not significant (p = 0.58).


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  		Table 1. Subject Characteristics*

 
Methacholine and AMP Responsiveness In and Out of Pollen Season
As determined by the inclusion criteria, PC20 methacholine and PC20 AMP values were significantly lower (p < 0.001) in subjects with seasonal rhinitis during the pollen season than that in control subjects (Table 2 ). However, PC20 methacholine and PC20 AMP values out of season in patients with pollen-induced rhinitis did not differ significantly from those in control subjects (Table 2) .


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  		Table 2. Airway Responsiveness and ENO Concentrations*

 
PC20 methacholine values during the pollen season and out of season in subjects with seasonal rhinitis are shown in Figure 1 . Methacholine PC20 increased from a geometric mean of 7.4 mg/mL (95% CI, 4.7 to 11.7 mg/mL) during the pollen season to 18.2 mg/mL (95% CI, 11.5 to 25.0 mg/mL) out of season (p = 0.001). The average change was 1.3 doubling concentrations (95% CI, 0.6 to 1.9 doubling concentrations).



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  		Figure 1. Individual values for PC20 methacholine during the pollen season and out of season in subjects with pollen-induced rhinitis. Geometric means are represented by horizontal lines; shaded area indicates censored values (> 25 mg/mL).

 
Figure 2 shows the individual changes in PC20 AMP values in subjects with seasonal rhinitis. AMP PC20 increased from a geometric mean of 79.4 mg/mL (95% 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 average change was 1.8 doubling concentrations (95% CI, 0.6 to 2.8 doubling concentrations).



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  		Figure 2. Individual values for PC20 AMP during the pollen season and out of season in subjects with pollen-induced rhinitis. Geometric means are represented by horizontal lines; shaded area indicates censored values (> 400 mg/mL).

 
ENO In and Out of Pollen Season
The ENO concentrations in patients with allergic rhinitis were fivefold greater than in healthy control subjects (p < 0.001; Table 2 ) when measured during the pollen season. When measured out of season, the ENO concentrations in these patients with seasonal rhinitis showed statistically significant lower values (geometric mean, 30.2 ppb; 95% CI, 23.4 to 38.0 ppb), compared with the concentrations found during the pollen season (geometric mean, 63.1 ppb; 95% CI, 50.1 to 79.4 ppb; p < 0.001) [Fig 3 ]. However, the ENO concentrations out of season were still significantly increased (p < 0.001) when compared with the ENO values in healthy control subjects.



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  		Figure 3. Individual values for ENO concentrations during the pollen season and out of season in subjects with seasonal allergic rhinitis. Geometric means are represented by horizontal lines.

 
Correlations
There was no relationship between individual changes in ENO levels and individual changes in PC20 methacholine or PC20 AMP (Fig 4 ). Furthermore, changes in PC20 methacholine and PC20 AMP were not significantly related.



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  		Figure 4. Correlation between allergen-induced changes in ENO and in airway responsiveness to methacholine (top, a) and AMP (bottom, b). Modifications of PC20 are expressed in terms of doubling concentrations ([log PC20 out of season - log PC20 in season]/log 2), whereas changes in ENO are expressed as NO out of season/NO in season (r = - 0.15, p = 0.65 for methacholine; r = - 0.25, p = 0.38 for AMP).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of the present study have confirmed that in subjects who are pollen sensitive and have allergic rhinitis, the cessation of exposure to pollen is associated with decreased responsiveness to methacholine and ENO concentrations. The new findings are that in subjects without asthma and with seasonal allergic rhinitis, there is a reduction in airway responsiveness to inhaled AMP out of pollen season to values that are similar to those in nonatopic control subjects. Furthermore, no significant correlation was found between changes in airway responsiveness to either direct or indirect bronchoconstrictor agents and changes in ENO levels.

Several studies have demonstrated that in subjects without asthma and with pollen-induced rhinitis, natural pollen exposure significantly increases airway responsiveness to direct bronchoconstrictor agents17 18 and ENO concentrations.14 27 Our results are in agreement with these observations. Furthermore, in keeping with previous reports,14 27 28 29 we have observed that patients with allergic rhinitis have higher levels of ENO than nonatopic volunteers when measurements were performed during the pollen season. In addition, when ENO determinations were repeated out of pollen season, we found significantly elevated levels of ENO in those patients with pollen-induced rhinitis as was reported in previous reports.14 27

To the best of our knowledge, there are no studies that have investigated the effects of natural allergen exposure on airway responsiveness to inhaled AMP in subjects without asthma and with pollen-induced rhinitis. The results of our study demonstrate that, in this group of subjects, there is a reduction in AMP responsiveness out of the pollen season to values that are similar to those in nonatopic control subjects. Our results also demonstrate that PC20 AMP improved to a greater extent out of pollen season than did PC20 methacholine (1.8 doubling concentrations vs 1.3 doubling concentrations, respectively). Furthermore, our results suggest that in subjects with allergic rhinitis, changes in airway responsiveness to methacholine and AMP after the cessation of natural allergen exposure are not correlated. This lack of correlation could be caused by the fact that the two bronchoconstrictors are identifying different alterations in the lower airways induced by the allergen. Although the critical features that determine the presence of increased responsiveness to direct and indirect bronchoconstrictors in subjects with allergic rhinitis are not yet identified, some studies2 3 have demonstrated that AMP caused mast cell degranulation in the lower airways. Because mast cells are believed to play a predominant role in asthmatic airway inflammation, the response to AMP may reflect acute inflammatory changes in the bronchial mucosa, whereas methacholine responsiveness might be predominantly dependent on structural changes of the airways.30 The results of our study demonstrate that subjects with seasonal rhinitis and increased responsiveness to direct and indirect stimuli during the pollen season have increased concentrations of ENO. However, increased concentrations of ENO were also detected in this group of subjects out of the pollen season, when airway responsiveness to both methacholine and AMP have reached normal values in most individuals. If ENO levels reflect the presence of airway inflammation, the findings of this study suggest that airway inflammation is present even in subjects with allergic rhinitis who had normal responsiveness. This is consistent with previous studies31 32 33 that showed that patients with allergic rhinitis and without bronchial hyperresponsiveness to direct bronchoconstrictor agents have bronchial inflammation in induced sputum, BAL fluid, and bronchial biopsy specimens. Furthermore, inflammatory cells assessed by sputum induction are present in the airways of patients with seasonal allergic rhinitis, even outside natural allergen exposure.31

There are, however, several possible reasons for the elevated concentrations of ENO in subjects with seasonal allergic rhinitis. One possibility is that it reflects the presence of subclinical inflammation within the lower airways. This explanation is supported by data from histopathologic studies12 19 33 34 that demonstrate the presence of bronchial inflammation in subjects without asthma and with allergic rhinitis. However, the relationship between ENO levels and histologic markers of bronchial inflammation has not been studied in subjects with allergic rhinitis. Therefore, the precise mechanism that links NO with airway inflammation and whether it reflects airway inflammation remain to be elucidated. A second explanation could be an independent effect of atopy on NO production. NO is produced in the airways by NO synthase, and it has been demonstrated that ENO concentrations are significantly higher in subjects with allergic rhinitis compared with nonallergic rhinitis.29 In addition, ENO is elevated in subjects who are asymptomatic and sensitized to inhaled allergens.35 This indicates that atopic status might be the most important determinant of enhanced NO production. Thus, inhalation of allergens in sensitized individuals may have a direct effect on NO production, regardless of the presence of inflammation in the airways, and the presence of atopy per se may be sufficient to increase ENO. In our subjects with seasonal rhinitis, even though the number of subjects is small, no association was found between allergen-induced changes in ENO values and either changes in PC20 methacholine or PC20 AMP. These findings suggest that changes in ENO concentrations and in airway responsiveness to direct and indirect bronchoconstrictors are the consequence of different alterations induced by allergen exposure on the lower airways. This, however, does not eliminate the possibility that airway inflammation is a significant determinant of airway hyperresponsiveness.

We do not believe that our findings can be explained by measurement errors, because the results were obtained after carefully addressing such aspects of methodology as study design and challenge methods. First, the baseline FEV1 values in each period were not significantly different. Thus, effects caused by differing baseline airway caliber on the subsequent determination of PC20 could be eliminated. In addition, challenges were carried out at the same time of the day, thus ruling out a possible influence of circadian variations on airway responsiveness. Second, none of the subjects were being treated with medications that could have affected ENO levels or the response to bronchoconstrictor agents. Third, the increased concentration of ENO in allergic rhinitis cannot be explained by technical factors. Contamination of the exhaled air by NO-rich air from the nasal cavity is unlikely, because the soft palate elevates when expiration is performed against a resistance.36 However, the ENO levels measured in this study tend to be somewhat higher than those measured in other reports.14 27 28 29 The reasons for such discrepancies might be related to important differences in methodology. It has been shown that there is a marked flow dependence of ENO values, with lower values measured at high flow rates and vice versa.36 We used an expiratory flow of 45 mL/s, which is lower than the flow used in other studies.14 27 28 29 Finally, other factors known to influence the concentration of ENO, such as a history of asthma, current smoking, and acute upper and chronic lower respiratory tract infections were absent in the subjects studied.

There were some methodologic limitations to our study, which are important to consider. We intentionally chose patients with seasonal rhinitis who showed bronchoconstriction in response to methacholine and AMP during the pollen season. However, estimation of the airway responsiveness was complicated because nine patients (64%) with allergic rhinitis out of pollen season and eight healthy control subjects (80%) had PC20 methacholine values above the upper limit of measurement. In addition, 11 subjects (78%) with allergic rhinitis out of pollen season and 10 healthy control subjects (100%) had PC20 AMP values above the upper limit of measurement. PC20 values of 25 mg/mL for methacholine and 400 mg/mL for AMP were assigned to these subjects, but this gives an underestimation of the true PC20 values. Given these restrictions, the significance of the differences in airway responsiveness of the various groups is almost certainly an underestimation.

The present observations are relevant to understanding the mechanisms of airway hyperresponsiveness in subjects with allergic rhinitis. Our observation that airway hyperresponsiveness to direct and indirect bronchoconstrictor agents may diminish to values that are similar to those in healthy nonatopic subjects and even disappear in most patients with allergic rhinitis when they are not exposed to natural allergen (outside the pollen season) supports the hypothesis that acquired, rather than inherited factors lie behind this phenomenon. It is not clear, however, why natural exposure to an allergen does not also cause symptoms of asthma in subjects with allergic rhinitis, but it is possible that there may be a threshold in the intensity of airway inflammation that is required before asthmatic symptoms become apparent. Therefore, it is tempting to speculate that subjects with seasonal rhinitis might develop asthma symptoms if they are exposed to a sufficiently strong allergenic stimulus during the pollen season. Obviously, this needs to be examined in careful prospective studies.

In summary, in this study we have shown that in subjects who are pollen sensitive and have allergic rhinitis, the cessation of exposure to pollen is associated with a significant reduction of airway responsiveness to both direct and indirect bronchoconstrictor agents, and with a reduction of ENO concentrations. However, no significant correlation was found between changes in airway responsiveness to either direct or indirect bronchoconstrictor agents and changes in ENO levels. These findings suggest that changes in ENO concentrations and in airway responsiveness are the consequence of different alterations induced by allergen exposure on the lower airways.


   Acknowledgements
 
The authors thank R. Rojas and B. Camps for technical assistance, and Laboratorios Bial-Arístegui (Bilbao, Spain) for help and collaboration.


   Footnotes
 
Abbreviations: AMP = adenosine 5'-monophosphate; CI = confidence interval; ENO = exhaled nitric oxide; NO = nitric oxide; PC20 = provocative concentration of agonist causing a 20% fall in FEV1; ppb = parts per billion

Received for publication November 21, 2001. Accepted for publication March 22, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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L. Prieto, C. Badiola, J. Cortijo, C. Perez-Frances, V. Gutierrez, and A. Lanuza
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