title: β-adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling.
abstract: BACKGROUND
  Enhanced arginine vasopressin levels are associated with increased mortality during end-stage human heart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulates βAR responsiveness and in doing so contributes to development of heart failure.
  
  
  RESULTS
  Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca(2+) mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/G protein receptor kinase-dependent manner.
  
  
  CONCLUSIONS
  This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated heart failure and elevated arginine vasopressin.
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.). douglas.tilley@temple.edu arthur.feldman@tuhs.temple.edu.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Valerie D
authors.initials: VD
authors.lastname: Myers
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Larry A
authors.initials: LA
authors.lastname: Barr
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Jianliang
authors.initials: J
authors.lastname: Song
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Carter
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Makarewich
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Constantine D
authors.initials: CD
authors.lastname: Troupes
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Grisanti
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Coleman
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.affiliation: From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000503:physiopathology*; D002415:Cats; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D054768:G-Protein-Coupled Receptor Kinases / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D017930:Genes, Reporter; D057809:HEK293 Cells; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D017483:Receptors, Vasopressin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D011759:Pyrrolidines; D011943:Receptors, Adrenergic, beta; D017483:Receptors, Vasopressin; D011993:Recombinant Fusion Proteins; D001127:Arginine Vasopressin; D005576:Colforsin; C082134:relcovaptan; D000242:Cyclic AMP; D054768:G-Protein-Coupled Receptor Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020889:Rolipram; D007545:Isoproterenol
keywords: cardiomyopathies; myocardial failure; myocardium; receptors, adrenergic, beta; vasopressin type 1A receptor