Loss of Salmeterol Bronchoprotection against Exercise in Relation to ADRB2 Arg16Gly Polymorphism and Exhaled Nitric Oxide

Abstract

Rationale: b 2 -Agonists are the treatment of choice for exerciseinduced bronchoconstriction (EIB) and act through specific receptors (ADRB2). Arg16Gly polymorphisms have been shown to affect responses to regular use of b 2 -agonists. Objectives: To evaluate the influence of the Arg16Gly receptor polymorphism on salmeterol bronchoprotection in EIB and assess predictors of bronchoprotection. Methods: A prospective, genotype-blinded, randomized trial was performed in 26 subjects (12 Arg16Arg and 14 Gly16Gly) with EIB who were not on controller therapy. Subjects were administered salmeterol, 50 mg twice a day for 2 weeks, and underwent an exercise challenge 9 hours after the first and last drug dose. In addition to genotype, FEV 1 , response to salmeterol, degree of EIB, and exhaled nitric oxide (FE NO ) at baseline were examined for their association with loss of bronchoprotection (LOB). Measurements and Main Results:The maximum exercise-induced FEV 1 fall was 27.9 6 1.4% during the run-in period, 8.1 6 1.2% (70.3 6 4.1% bronchoprotection) after the first salmeterol dose, and 22.8 6 3.2% (18.9 6 11.5% bronchoprotection) after 2 weeks of salmeterol (P ¼ 0.0001). The Arg16Gly polymorphisms were not associated with the LOB in response to salmeterol. FE NO values at baseline were significantly related to the LOB (r ¼ 0.47; P ¼ 0.01). Mean change was a 74 6 13% LOB in subjects with FE NO levels greater than 50 ppb and a 7 6 16% gain in bronchoprotection in those with FE NO levels less than 25 ppb (P ¼ 0.01). Conclusions:The LOB that occurs with chronic long-acting b 2 -agonists use is not affected by ADRB2 Arg16Gly polymorphisms. High FE NO was associated with marked LOB. Use of long-acting b 2 -agonists before achieving a reduction in FE NO may need to be avoided. Clinical trial registered with www.clinicaltrials.gov (NCT 00595361).Keywords: asthma; b 2 -agonist; nitric oxide; pharmacogenetics; tolerance Inhaled b 2 -adrenergic agonists are widely used and have been proved to be the most effective treatment available to acutely prevent and reverse the bronchial obstruction that occurs after physical activity (1). Both short-acting and long-acting b 2 -agonists (SABA and LABA) administered in a standard dose immediately before exercise have been shown to reduce the fall in FEV 1 by 70-80% most subjects (2).However, daily treatment may lead to tolerance to the bronchoprotective effect (3). This effect has been documented in response to direct (methacholine and adenosine monophosphate [AMP]) (4) and indirect (allergen and exercise) stimuli (5, 6), occurring as early as 7 days after regular use and even in the face of concomitant use of inhaled corticosteroids (ICS) (3). The loss of bronchoprotection (LOB) has been reported to range from 49% to 72% of the initial observed effect (3) with some subjects retaining near complete bronchoprotection and others developing a paradoxical increase in bronchoconstriction to the provocative stimulus.It has been speculated this phenomenon may be caused by receptor down-regulation, redu...

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