The Influence of Polymorphism at Position 16 of the β₂-Adrenoceptor on the Development of Tolerance to β-Agonist

Abstract

Polymorphism at position 16 of the β₂-adrenoceptor alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to (3-agonist in homozygous Gly-16 patients with patients harboring the “wild” genotype (homozygous Arg-16) during regular treatment with salmeterol. In a prospective, randomized, double blind, placebo controlled, cross over study, 20 subjects with mild to moderate asthma (10 Gly-16, 10 Arg-16) received 2 weeks of treatment with inhaled salmeterol 100 μg b.i.d. Thereafter, dose responses to inhaled salbutamol were constructed for forced expiratory volume in 1 sec (FEV₁), heart rate, QTc interval, serum potassium and glucose, and finger tremor. The protective effect of salbutamol against adenosine monophosphate (AMP) challenge was also measured. Salmeterol resulted in a significant reduction in the area under curve (AUC) for FEV₁ (p = 0.01), heart rate (p = 0.01), QTc interval (p = 0.01), and tremor (p = 0.05), and in the maximum responses for FEV₁ (p = 0.05), heart rate (p = 0.02), and glucose (p = 0.02). The protective effect of salbutamol against AMP was reduced by 3.61 doubling doses (p < 0.001). However, differences between Gly-16 and Arg-16 patients were small and nonsignificant. Thus, although tolerance is influenced in vitro by polymorphism of the β₂-adrenoceptor, the magnitude of between genotype differences in vivo is unlikely to be significant.

Key Words:

• Beta₂-adrenoceptor
• Polymorphism
• Tolerance
• Beta agonist