title: The Gln27Glu beta2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo.
abstract: Studies performed have shown that the Arg16Gly allele in beta-adrenoceptors (beta2AR) enhances susceptibility to agonist-induced down-regulation, while the Gln27Glu polymorphism diminishes it. In this study, we tested whether similar phenotypes occur in vivo. We assessed 32 volunteers (mean age 25 +/- 2 years) with different genotypes (group A: wild-type beta2AR, n = 16; group B: homozygous Glu27, n = 10; group C: homozygous Gly16, n = 6) for the effect of 2 weeks treatment with 3 x 5 mg/day oral terbutaline on terbutaline infusion-induced increases in heart rate and contractility (i.e. shortening of heart rate-corrected duration of electromechanical systole, QS2c). At baseline, terbutaline infusion increased heart rate and contractility similarly among subjects in the three groups. Treatment with oral terbutaline for 14 days reduced the ability of intravenous (i.v.) terbutaline to increase heart rate and contractility. The extent of this reduction was similar but the time course of desensitization differed among the three groups. While in groups A and C terbutaline infusion-induced increases in heart rate and contractility were reduced within 24 h after oral ingestion of terbutaline, a significant effect on response to terbutaline infusion was not evident for the first 3 days of terbutaline treatment in group B. The Arg16Gly and the Gln27Glu variants of the beta2AR do not alter the extent of agonist-induced beta2AR desensitization in vivo but Glu27 homozygotes develop desensitization more slowly. This result may have implications for cardiac side-effects in patients who are Glu27 homozygotes and who receive beta2AR agonist therapy.
authors.affiliation: Institute of Pharmacology, University of Halle, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Bruck
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.forename: Rainer
authors.initials: R
authors.lastname: Büscher
authors.forename: Anke
authors.initials: A
authors.lastname: Ulrich
authors.forename: Joachim
authors.initials: J
authors.lastname: Radke
authors.forename: Paul A
authors.initials: PA
authors.lastname: Insel
authors.forename: Otto-Erich
authors.initials: OE
authors.lastname: Brodde
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D000328:Adult; D017931:DNA Primers / Q000737:chemistry; D004351:Drug Resistance; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D013726:Terbutaline / Q000008:administration & dosage
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D017931:DNA Primers; D018343:Receptors, Adrenergic, beta-2; D018698:Glutamic Acid; D013726:Terbutaline; D005998:Glycine