1. β-adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling.
- Author
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Tilley DG, Zhu W, Myers VD, Barr LA, Gao E, Li X, Song J, Carter RL, Makarewich CA, Yu D, Troupes CD, Grisanti LA, Coleman RC, Koch WJ, Houser SR, Cheung JY, and Feldman AM
- Subjects
- Animals, Antidiuretic Hormone Receptor Antagonists pharmacology, Arginine Vasopressin pharmacology, Calcium Signaling drug effects, Cardiomyopathy, Hypertrophic complications, 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, Pyrrolidines pharmacology, Receptors, Vasopressin biosynthesis, Receptors, Vasopressin genetics, Recombinant Fusion Proteins metabolism, Rolipram pharmacology, Second Messenger Systems drug effects, Cardiomyopathy, Hypertrophic physiopathology, Myocardial Contraction physiology, Receptors, Adrenergic, beta physiology, Receptors, Vasopressin physiology, Second Messenger Systems physiology
- 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., (© 2014 American Heart Association, Inc.)
- Published
- 2014
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