Abstract 18566: V1A Receptor Overexpression in the Murine Heart Depresses the Inotropic Response to Catecholamines

Abstract

Background: — Circulating levels of arginine vasopressin (AVP), a vasoconstrictor, are elevated in patients with heart failure. In the heart, AVP induces effects through the V1A receptor. The goal of this study was to better define the role of AVP in cardiac contractile dysfunction in the diseased heart. We utilized an inducible, cardiac-specific V1A receptor overexpression (V1A-OE) mouse model to explore the effects of AVP signaling in cardiac myocytes. Methods and Results: — Isolated WT and V1A-OE hearts were studied using a Langendorff apparatus. A fluid-filled balloon was inserted into the LV to record isovolumic ventricular pressure. Each heart underwent a 20min equilibration period, followed by administration of ISO or IBMX for 3min each. ISO [10 -5 ] had significantly smaller inotropic effects in V1A-OE (n=8) compared to WT hearts (n=5) (LVDP% V1A-TG: 129±14.04% increase vs. WT: 191.5±20.80%). WT hearts (n=4) pretreated with exogenous AVP [10 -9 ] also had significantly smaller inotropic responses to ISO [10 -5 ] (LVDP% WT+AVP: 118.8±12.30). The phosphodiesterase inhibitor IBMX [10 -5 ] had enhanced contractility in WT (n=5) significantly more than in V1A-OE (n=5) (LVDP% V1A-OE: 99.40±6.61 vs. WT 149.4±8.135). Western blot analysis showed reduced levels of phospholamban (PLB) phosphorylation at Serine-16, a PKA phosphorylation site, in the V1A-OE+IBMX compared to WT+IBMX. Conclusions: — These results suggest that V1A overexpression reduces myocardial inotropic regulation by inhibiting PKA-induced phosphorylation of Ca 2+ regulatory proteins that are involved in β-adrenergic regulation of cardiac contractility. Increased AVP signaling plays a role in the depression of cardiac contractility in heart failure and AVP antagonists may improve heart function by enhancing cardiac contractility reserve.