Dose-related effects of formoterol on airway responsiveness to adenosine 5′-monophosphate and histamine

Abstract

Inhaled short-acting β2-agonists provide greater protection against airway responsiveness (AR) to the mast-cell stimulus, adenosine 5′-monophosphate (AMP), than to histamine, a direct spasmogen. Both terbutaline and albuterol exhibit this mast-cell stabilizing property in a dose-dependent manner. A single dose of the long-acting β2-agonist formoterol has also been reported to have a mast cell-stabilizing effect, whereas salmeterol has not. To explore the dose-related actions of the long-acting β2-agonist formoterol on AR, the authors compared the acute effects of three doses of formoterol and terbutaline on AR to AMP and histamine. In a double-blind, randomized, placebo-controlled, cross-over study, 25 mild, steroid naive, asthmatic subjects attended on 10 occasions. At each visit, subjects inhaled either a single dose of terbutaline (500 μg), formoterol (6, 12 or 24 μg) or a matched placebo, administered via Turbuhaler®, 30 min prior to challenge with both AMP and histamine. Each dose of β2-agonist reduced AR to AMP and histamine. The bronchoprotective effects of formoterol (6 μg) and terbutaline (500 μg) were similar in magnitude in reducing AR to histamine (mean±SD: 3.6±0.3 and 3.1±0.3 doubling doses (DD)) and AR to AMP (3.5±0.5 and 3.3±0.4 DD, respectively). Overall, formoterol reduced AR to both spasmogens in a dose-dependent manner. In addition, formoterol (12 and 24 μg) provided a significantly greater protective effect against AMP than against histamine challenge. It decreased AR by 5.7±0.6 and 6.3±0.7 DD against AMP and 4.3±0.4 and 4.8±0.43 DD against histamine, respectively. The results of this study indirectly demonstrated an in vivo dose-dependent mast-cell stabilizing effect of formoterol, in addition to functional antagonism on airway smooth muscle. This property of β2-agonists may have clinical benefits in asthma management.