INFLUENCE OF ALBUTEROL, CROMOLYN SODIUM AND IPRATROPIUM BROMIDE ON THE AIRWAY AND CIRCULATING MEDIATOR RESPONSES TO ALLERGEN BRONCHIAL PROVOCATION IN ASTHMA

Abstract

The effect of pharmacologic agents on mast cell mediator release was investigated in vivo. Eight atopic asthmatic subjects with airways relatively unreactive to nonspecific stimuli (geometric mean PC20 methacholine, 4.0 mg/ml) underwent single-concentration allergen challenge before (control) or after inhaling albuterol 200 .mu.g, cromolyn sodium 20 mg, or 0.9% sodium chloride placebo. Six of the same subjects also underwent allergen challenge after pretreatment with ipratroplum bromide, 1 mg. Airway responses to pharmacologic agents and bronchial challenge were measured by change in both specific airway conductance (SGaw) and FEV1. Mast cell mediator release was monitored by serial change in plasma histamine and, in addition, serum neutrophil chemotactic factor (NCF) on the placebo, albuterol, and cromolyn sodium challenge days. Control and placebo allergen challenges were associated with repeatable mean maximal falls in SGaw (48.5 versus 49.6%) and FEV1 (25.7 versus 25.5%). The mean increments in plasma histamine were not significantly different on the control (0.17 to 0.44 ng/ml) or placebo challenge days (0.18 to 0.64 ng/ml), with maximal levels occurring 5 min after challenge. A sustained increase in NCF was identified on the placebo challenge day (155.0% above baseline). Pretreatment with albuterol abolished any significant bronchoconstriction, with mean maximal falls in SGaw and FEV1 after challenge of 7.5 and 1.4%, respectively. These changes in airway caliber were not associated with any significant increment in mean plasma histamine (0.17 to 0.22 ng/ml) or serum NCF (4.1% increase). Cromolyn sodium pretreatment, while attenuating the airway response, was still associated with significant falls in SGaw (22.7%) and FEV1 (7.3%) and increases in plasma histamine (0.18 to 0.27 ng/ml). The increment in plasma histamine at 5 min was, however, significantly less than on the placebo challenge day (p < 0.05). In contrast, changes in NCF were significantly abolished at all time points after challenge with cromolyn sodium pretreatment (maximal increase, 15.3%). Ipratropium bromide pretreatment, while producing comparable bronchodilatation to albuterol, had no significant effect on the airway or mediator responses to challenge. These findings indicate that albuterol is a potent inhibitor of mast cell degranulation in vivo, and this may be an important facet of its mode of action in asthma. These studies with albuterol confirm in vitro findings. Cromolyn sodium has also been found to inhibit mast cell degranulation in vivo but is less efficacious than albuterol in this respect.