Regular use of short-acting β-agonists may decrease control of asthma and increase airway responsiveness to bronchoconstrictor stimuli. The aim of this study was to determine the effects of regular treatment with the long-acting β-agonist, salmeterol, on the methacholine dose-response curve (DRC) in mild-tomoderate asthmatics.Changes in methacholine airway responsiveness were measured in 14 stable adult asthmatics, randomized in a double-blind, three-way cross-over design to receive salmeterol 50 µg, salbutamol 200 µg or placebo, each twice daily for 4 days. Two baseline methacholine DRC, were performed, one without premedication and one following a single dose of 200 µg salbutamol. Following 4 days of regular treatment, methacholine DRC to plateau were carried out commencing 15 min after the final dose of trial medication.There were no significant differences in mean baseline forced expiratory volume in one second (FEV1) between treatments. Four days treatment with salmeterol and salbutamol shifted the DRC to the right, but salmeterol provided less protection than salbutamol. The point of inflection of the curve from baseline moved 1.9 and 3.2 doubling doses, respectively, compared to placebo (p≤0.001), and the provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20) increased 1.6 and 3.1 doubling doses, respectively (p≤0.001). The slope of the DRC was increased slightly by both β-agonists compared to placebo (log slope 3.11, 3.06 and 2.77 for salmeterol, salbutamol and placebo, respectively). This effect of regular salmeterol on slope was more marked in subjects with lower baseline FEV1. Maximal response plateaus did not differ between the three treatments.These results suggest that regular use either of short-or long-acting β-agonists could increase the risk of a more precipitous asthma episode associated with "breakthrough" bronchoconstrictor responses, particularly in those with more severe initial airflow obstruction, if subjects are exposed to a sufficiently potent stimulus.

In the European Community Respiratory Health Study (ECRHS), airway responsiveness to methacholine was determined using the Mefar dosimeter protocol. Elsewhere, the 2-min tidal breathing method has become the preferred standardized method. The relationship between measurements of responsiveness by these two methods is not well established.This study measured airway responsiveness to methacholine by dosimeter and tidal breathing methods in 47 healthy asthmatic subjects aged 20±44 yrs. Tests were performed within 1 week and in random order.Baseline forced expiratory volume in one second (FEV1) varied by <10% between tests in 42/47 subjects. There was a close association between responsiveness determined by the two methods. A provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) value of #8.0 mg . mL -1 (tidal method) used to categorize airway hyperresponsiveness agreed most closely with a provocative dose of methacholine causing a 20% fall in FEV1 (PD20) value of #0.5 mg (dosimeter method) (kappa statistic 0.78). Each doubling or halving of PC20 to define a level of hyperresponsiveness agreed closely with a doubling or halving of PD20.Assessment of airway responsiveness as provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second by the Mefar dosimeter protocol gave a close and predictable relationship with provocative concentration of methacholine causing a 20% fall in expiratory volume in one second assessed using the tidal breathing method. Airway hyperresponsiveness as determined by the accepted criterion of provocative concentration of methacholine causing a 20% fall in expiratory volume in one second #8 mg . mL -1 was best correlated with provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second <0.5 mg by Mefar dosimeter. Eur Respir J 2000; 15: 181±184.