Chest
Volume 96, Issue 6, December 1989, Pages 1285-1291
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Clinical Investigations
Is There Loss of a Protective Muscarinic Receptor Mechanism in Asthma?

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We Investigated the hypothesis that prior airway muscarinic receptor stimulation (with aerosolized methacholine) would modify the bronchoconstrictor response to histamine, which is, in part, vagally mediated. On four different experiment days, the following combinations of methacholine and histamine inhalation challenges were performed in 15 subjects (nine normal and six asthmatic) in a random fashion: methacholine-histamine, histamine-methacholine; methacholine-methacholine and histamine-histamine. Cumulative provocative dose of each agonist which caused a 50 percent decrease in SGaw was estimated (PD50). The second challenge was performed approximately 1 hour after the first challenge, when SGaw had returned to baseline. In normal subjects, prior muscarinic stimulation with methacholine suppressed the subsequent bronchoconstrictor response to histamine (mean±SE PD50 histamine increased from 13.7±3.1 to 28.4±7.2 breath units), without modifying the bronchoconstrictor response to methacholine. In asthmatic subjects, prior methacholine exposure failed to modify the bronchoconstrictor responses to histamine and methacholine. In contrast, prior challenge with histamine did not modify the subsequent bronchoconstrictor responses to histamine and methacholine in both normal and asthmatic subjects. Pretreatment with ipratropium bromide attenuated the histamine-induced bronchoconstriction, suggesting that airway effects of histamine, in part, are vagally mediated. These data suggest that prior muscarinic stimulation has a protective effect on histamine-induced bronchoconstriction in normal subjects and the absence of this inhibitory effect in asthmatic patients may represent loss of a protective muscarinic receptor mechanism.

Section snippets

Subjects

Fifteen nonsmoker subjects (ten men and five women) without a recent history of upper respiratory tract infection were included in the study. Six subjects had a history of mild asthma; their ages ranged from 25 to 52 years (mean 37). The remaining nine subjects had no personal or family history of atopy. Their ages ranged from 22 to 38 years (mean 30). The asthmatic subjects were asymptomatic at the time of the study, and had not received inhaled beta agonists for at least 12 hours prior to

Baseline Pulmonary Function

These results are shown in Table 1. Asthmatic subjects had evidence of mild airway obstruction as shown by significantly lower SGaw, FEV1 and forced vital capacity. The SGaw was comparable on different experiment days within each group. The mean±SE post-diluent values of SGaw on experiment days 2–5 were 0.21±0.02, 0.21±0.02, 0.20±0.02, and 0.19±0.01 s·cmH2O−1, respectively, for normal subjects, and 0.11±0.03, 0.13±0.02, 0.11±0.02 and 0.12±0.02 s·mH2O−1, respectively, for asthmatic patients.

In

Discussion

The results of this study demonstrate that prior stimulation of airway muscarinic receptors by inhaled methacholine causes a suppression of bronchoconstrictor response to histamine. Suppression of bronchoconstrictor response to histamine by prior muscarinic receptor stimulation was only observed in normals and not in subjects with bronchial asthma. Our study also demonstrates that suppression of histamine responses was specific and only observed after prior muscarinic receptor stimulation. This

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    Manuscript received June 12; revision accepted July 13.

    Division of Clinical Pharmacology; recipient of a scholarship from Universidad de Buenos Aires, Argentina.

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