β-adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling

Douglas G Tilley; Weizhong Zhu; Valerie D Myers; Larry A Barr; Erhe Gao; Xue Li; Jianliang Song; Rhonda L Carter; Catherine A Makarewich; Daohai Yu; Constantine D Troupes; Laurel A Grisanti; Ryan C Coleman; Walter J Koch; Steven R Houser; Joseph Y Cheung; Arthur M Feldman

doi:10.1161/CIRCULATIONAHA.114.010434

β-adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling

Circulation. 2014 Nov 11;130(20):1800-11. doi: 10.1161/CIRCULATIONAHA.114.010434. Epub 2014 Sep 9.

Authors

Douglas G Tilley¹, Weizhong Zhu², Valerie D Myers², Larry A Barr², Erhe Gao², Xue Li², Jianliang Song², Rhonda L Carter², Catherine A Makarewich², Daohai Yu², Constantine D Troupes², Laurel A Grisanti², Ryan C Coleman², Walter J Koch², Steven R Houser², Joseph Y Cheung², Arthur M Feldman²

Affiliations

¹ 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.
² 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.).

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.

Methods and 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.

Keywords: cardiomyopathies; myocardial failure; myocardium; receptors, adrenergic, beta; vasopressin type 1A receptor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidiuretic Hormone Receptor Antagonists / pharmacology
Arginine Vasopressin / pharmacology
Calcium Signaling / drug effects
Cardiomyopathy, Hypertrophic / complications
Cardiomyopathy, Hypertrophic / physiopathology*
Cats
Cell Line, Tumor
Colforsin / pharmacology
Cyclic AMP / biosynthesis
G-Protein-Coupled Receptor Kinases / physiology
GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
Genes, Reporter
HEK293 Cells
Heart Failure / etiology
Heart Failure / physiopathology
Humans
Indoles / pharmacology
Isoproterenol / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutagenesis, Site-Directed
Myocardial Contraction / drug effects
Myocardial Contraction / physiology*
Pyrrolidines / pharmacology
Receptors, Adrenergic, beta / physiology*
Receptors, Vasopressin / biosynthesis
Receptors, Vasopressin / genetics
Receptors, Vasopressin / physiology*
Recombinant Fusion Proteins / metabolism
Rolipram / pharmacology
Second Messenger Systems / drug effects
Second Messenger Systems / physiology*

Substances

Antidiuretic Hormone Receptor Antagonists
Indoles
Pyrrolidines
Receptors, Adrenergic, beta
Receptors, Vasopressin
Recombinant Fusion Proteins
Arginine Vasopressin
Colforsin
relcovaptan
Cyclic AMP
G-Protein-Coupled Receptor Kinases
GTP-Binding Protein alpha Subunits, Gq-G11
Rolipram
Isoproterenol

Abstract

Publication types

MeSH terms

Substances

Grants and funding