Yates_1997_Am.J.Respir.Crit.Care.Med_156_988

There is increasing evidence for the development of tolerance to the bronchoprotective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli in asthma. With short-acting beta 2-agonists, this is more readily demonstrable using indirectly acting agents such as adenosine monophosphate (AMP), which may act via mast cell degranulation, than using methacholine (MCh), implying more rapid mast cell than smooth muscle desensitization. Desensitization may be greater with the long-acting beta 2-agonist, salmeterol, given its greater duration of receptor occupancy. In a double-blind, placebo-controlled crossover study, we investigated the effect of regular salmeterol on the protection conferred by albuterol using MCh- and AMP-induced bronchoconstriction. Sixteen mild asthmatic subjects not using inhaled glucocorticoids were randomized to treatment for 2 wk with inhaled salmeterol (50 micrograms b.i.d. via diskhaler) or identical placebo. Provocative concentrations of MCh and AMP causing a 20% fall in FEV1 (PC20) were measured 15 min after 200 micrograms albuterol, both before and after treatment. Mean MCh PC20 after albuterol decreased significantly after 2 wk of salmeterol treatment (mean 2.2 mg/ml before to 1.1 +/- 1.2 mg/ml after) compared with placebo (2.9 +/- 1.3 mg/ml before to 2.6 +/- 1.3 mg/ml after; p < 0.05), but this fell just short of statistical significance when analyzed as change in doubling dilutions (1.1 +/- 0.4 versus 0.18 +/- 0.4; p = NS). Mean PC20 to AMP was not significantly affected (mean 27.5 +/- 1.5 mg/ml prior to salmeterol treatment and 9.5 +/- 1.5 mg/ml after treatment; p = NS compared with placebo). Thus, regular salmeterol treatment led to loss of bronchoprotection by albuterol to MCh but not to AMP challenge, implying an absence of mast cell beta 2-adrenoceptor downregulation with regular salmeterol therapy.