The influence of polymorphism at position 16 of the beta2-adrenoceptor on the development of tolerance to beta-agonist.
Polymorphism at position 16 of the beta2-adrenoceptor alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to beta-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 microg 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 beta2-adrenoceptor, the magnitude of between-genotype differences in vivo is unlikely to be significant.
Taylor
D R
DR
Dunedin School of Medicine, University of Otago, New Zealand. robin.taylor@stonebow.otago.ac.nz
Hancox
R J
RJ
McRae
W
W
Cowan
J O
JO
Flannery
E M
EM
McLachlan
C R
CR
Herbison
G P
GP
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000595:Amino Acid Sequence / Q000235:genetics; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004361:Drug Tolerance / Q000235:genetics; D004562:Electrocardiography; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D000068299:Salmeterol Xinafoate; D014202:Tremor / Q000503:physiopathology
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D011943:Receptors, Adrenergic, beta; D000068299:Salmeterol Xinafoate; D000420:Albuterol