title: Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.
abstract: BACKGROUND
  Stimulation of beta(1)- and beta(2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta(3)AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects.
  
  
  RESULTS
  To better understand the role of beta(3)ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human beta(3)AR (TGbeta(3) mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous beta(1)- and beta(2)ARs, isoproterenol resulted in an increase in contractility in the TGbeta(3) mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human beta(3)AR agonist L-755,507 significantly increased contractility in the TGbeta(3) mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGbeta(3) mice was investigated in terms of beta(3)AR-G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGbeta(3) mice with L-755,507 resulted in a pertussis toxin-insensitive 1.33-fold increase in [(35)S]GTPgammaS loading and a 1.6-fold increase in adenylyl cyclase activity.
  
  
  CONCLUSIONS
  Cardiac overexpression of human beta(3)ARs results in positive inotropy only on stimulation with a beta(3)AR agonist. Overexpressed beta(3)ARs couple to G(s) and activate adenylyl cyclase on agonist stimulation.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Kohout
authors.forename: H
authors.initials: H
authors.lastname: Takaoka
authors.forename: P H
authors.initials: PH
authors.lastname: McDonald
authors.forename: S J
authors.initials: SJ
authors.lastname: Perry
authors.forename: L
authors.initials: L
authors.lastname: Mao
authors.forename: R J
authors.initials: RJ
authors.lastname: Lefkowitz
authors.forename: H A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D004452:Echocardiography; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; C112650:L 755507; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000262:Adenylyl Cyclases; D007545:Isoproterenol