Genotype-dependent time course of lymphocyte beta 2-adrenergic receptor down-regulation.
BACKGROUND
Volunteers homozygous for Glu27 beta(2)-adrenergic receptor (beta(2)AR) polymorphism have delayed onset of agonist-induced desensitization of cardiac beta(2)AR responses.


RESULTS
To determine whether this can also be demonstrated for Glu27Glu beta(2)AR natively expressed in circulating lymphocytes, we assessed the effects of 2 weeks of oral treatment with 3 x 5 mg/d terbutaline on lymphocyte beta(2)AR density (determined by [-]-[iodine 125]iodocyanopindolol binding) and responsiveness (assessed as [-]-isoproterenol hydrochloride [INN, isoprenaline] [1 nmol/L to 1 micromol/L]-induced lymphocyte cyclic adenosine monophosphate increases) in 23 healthy volunteers (13 with wild-type beta(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 beta(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 beta(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 beta(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) beta(2)AR decreases were observed only 72 hours after the first terbutaline intake. Thus the time course of lymphocyte beta(2)AR down-regulation in group B was significantly (P <.01, 2-way ANOVA) different from that in groups A and C.


CONCLUSIONS
The extent of lymphocyte beta(2)AR down-regulation after long-term terbutaline treatment in volunteers homozygous for the Gly16 or Glu27 beta(2)AR polymorphism was genotype-independent and was nearly identical to that in wild-type beta(2)AR volunteers. However, the onset of beta(2)AR down-regulation was delayed in volunteers homozygous for the Glu27 beta(2)AR polymorphism.
Bruck
Heike
H
Department of Pathophysiology and Nephrology, University of Essen Medical School, Germany.
Leineweber
Kirsten
K
Beilfuss
Anja
A
Weber
Melanie
M
Heusch
Gerd
G
Philipp
Thomas
T
Brodde
Otto-Erich
OE
D000318:Adrenergic beta-Agonists / Q000493:pharmacokinetics; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000328:Adult; D001665:Binding Sites; D003062:Codon / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D020120:Iodocyanopindolol / Q000493:pharmacokinetics; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011110:Polymorphism, Genetic / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis* / Q000235:genetics*; D013726:Terbutaline / Q000493:pharmacokinetics
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D003062:Codon; D018343:Receptors, Adrenergic, beta-2; D020120:Iodocyanopindolol; D000242:Cyclic AMP; D013726:Terbutaline