β-Adrenergic Receptor-Mediated Cardiac Contractility Is Inhibited via Vasopressin Type 1A-Receptor-Dependent Signaling

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 -adrenergic receptor (AR) responsiveness. This led us to hypothesize that V1AR signaling regulates AR responsiveness and in doing so contributes to development of heart failure. Methods and Results Transaortic constriction resulted in decreased cardiac function and AR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased AR ligand affinity, as well as AR-induced Ca2+ mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of AR 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 AR may be informative for the treatment of patients with acute decompensated heart failure and elevated arginine vasopressin.