title: The Arg389Gly β1-adrenoceptor gene polymorphism influences the acute effects of β-adrenoceptor blockade on contractility in the human heart.
abstract: BACKGROUND
  The β(1)-adrenoceptor (β(1)AR) mediates cardiostimulatory effects of catecholamines in the heart. The Arg389Gly polymorphism of the β(1)AR gene has recently been shown to determine the responsiveness to catecholamines in vitro, and we previously reported that dobutamine induced an augmented contractile response in humans homozygous for the Arg389 allele. The aim of the present study was to evaluate whether the Arg389Gly β(1)AR gene polymorphism influences the responsiveness to β-blocker treatment on cardiac contractility.
  
  
  METHODS
  We investigated 30 healthy male volunteers who were genotyped for the Arg389Gly polymorphism and subjected to modified dobutamine stress-echocardiography (DSE) with and without pretreatment with metoprolol controlled release/extended release (CR/XL). Fractional shortening (FS) as a parameter for left-ventricular contractility and heart rate were measured. To control for pre- and afterload effects, rate corrected velocity of circumferential fiber shortening (Vcfc) was calculated.
  
  
  RESULTS
  Homozygous Arg389 carriers had a significantly higher increase in contractility upon dobutamine stimulation than individuals carrying the Gly389 allele. Pretreatment with metoprolol CR/XL prior to DSE blunted the dobutamine-induced increase of FS and Vcfc in homozygous Arg389 carriers to the level of subjects carrying the Gly389 allele. In the latter group, metoprolol had a modest effect on the dobutamine-induced increase in FS at low concentrations of dobutamine, and no significant effect at peak stress (40 μg/kg/min of dobutamine).
  
  
  CONCLUSIONS
  The responsiveness to β-blockers with respect to cardiac contractility is determined by the Arg389Gly β(1)AR gene polymorphism. These findings offer a molecular explanation for interindividual differences in the responsiveness to β-blocker treatment in humans.
authors.affiliation: Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Kerpener Str. 62, 50937, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Huntgeburth
authors.forename: Karl
authors.initials: K
authors.lastname: La Rosée
authors.forename: Henrik
authors.initials: H
authors.lastname: ten Freyhaus
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Petra
authors.initials: P
authors.lastname: Schnabel
authors.forename: Martin
authors.initials: M
authors.lastname: Hellmich
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D000328:Adult; D001120:Arginine / Q000235:genetics; D025401:Echocardiography, Stress; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000235:genetics
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D018342:Receptors, Adrenergic, beta-1; D001120:Arginine; D008790:Metoprolol; D005998:Glycine