Premium
Genotype‐dependent time course of lymphocyte β 2 ‐adrenergic receptor down‐regulation
Author(s) -
Bruck Heike,
Leineweber Kirsten,
Beilfuß Anja,
Weber Melanie,
Heusch Gerd,
Philipp Thomas,
Brodde OttoErich
Publication year - 2003
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(03)00188-7
Subject(s) - terbutaline , medicine , endocrinology , lymphocyte , chemistry , agonist , cyclic adenosine monophosphate , atenolol , analysis of variance , receptor , genotype , adrenergic receptor , t lymphocyte , isoprenaline , repeated measures design , iodocyanopindolol , beta (programming language) , asthma , intrinsic activity , in vitro , biochemistry , stimulation , blood pressure , gene , statistics , mathematics , computer science , programming language
Background Volunteers homozygous for Glu27 β 2 ‐adrenergic receptor (β 2 AR) polymorphism have delayed onset of agonist‐induced desensitization of cardiac β 2 AR responses. Methods and results To determine whether this can also be demonstrated for Glu27Glu β 2 AR natively expressed in circulating lymphocytes, we assessed the effects of 2 weeks of oral treatment with 3 × 5 mg/d terbutaline on lymphocyte β 2 AR density (determined by [−]‐[iodine 125]iodocyanopindolol binding) and responsiveness (assessed as [−]‐isoproterenol hydrochloride [INN, isoprenaline] [1 nmol/L to 1 μmol/L]–induced lymphocyte cyclic adenosine monophosphate increases) in 23 healthy volunteers (13 with wild‐type β 2 AR [group A], 5 homozygous for Glu27 with Gly16Gly or Arg16Gly [group B], and 5 homozygous for Gly16 with Gln27Gln or Gln27Glu [group C]). Before terbutaline treatment, lymphocyte β 2 AR density and isoproterenol‐induced lymphocyte cyclic adenosine monophosphate accumulation were not significantly different in the genotype groups; 2 weeks of terbutaline treatment significantly decreased lymphocyte β 2 AR density and responsiveness in the 3 genotype groups to a nearly identical extent, and no differences were observed. In time‐course studies, however, in groups A and C lymphocyte β 2 AR showed significant ( P < .05, repeated‐measures ANOVA) down‐regulation as early as 24 hours after the first terbutaline intake, whereas in group B significant ( P < .05, repeated‐measures ANOVA) β 2 AR decreases were observed only 72 hours after the first terbutaline intake. Thus the time course of lymphocyte β 2 AR down‐regulation in group B was significantly ( P < .01, 2‐way ANOVA) different from that in groups A and C. Conclusion The extent of lymphocyte β 2 AR down‐regulation after long‐term terbutaline treatment in volunteers homozygous for the Gly16 or Glu27 β 2 AR polymorphism was genotype‐independent and was nearly identical to that in wild‐type β 2 AR volunteers. However, the onset of β 2 AR down‐regulation was delayed in volunteers homozygous for the Glu27 β 2 AR polymorphism. Clinical Pharmacology & Therapeutics (2003) 74 , 255–263; doi: 10.1016/S0009‐9236(03)00188‐7