Vasopressin type 1A receptor deletion enhances cardiac contractility, -adrenergic receptor sensitivity and acute cardiac injury-induced dysfunction

V1AR expression is elevated in chronic human heart failure and contributes to cardiac dysfunction in animal models, in part via reduced βAR responsiveness. While cardiac V1AR overexpression and V1AR stimulation are each sufficient to decrease βAR activity, it is unknown whether V1AR inhibition conversely augments βAR responsiveness. Further, although V1AR has been shown to contribute to chronic progression of heart failure, its impact on cardiac function following acute ischemic injury has not been reported. Using V1AR KO mice we assessed the impact of V1AR deletion on cardiac contractility at baseline and following ischemic injury, βAR sensitivity and cardiomyocyte responsiveness to βAR stimulation. Strikingly, baseline cardiac contractility was enhanced in V1AR KO mice and they experienced a greater loss in contractile function than control mice following acute ischemic injury, although the absolute levels of cardiac dysfunction and survival rates did not differ. Enhanced cardiac contractility in V1AR KO mice was associated with augmented β-blocker sensitivity, suggesting increased basal βAR activity, and indeed levels of left ventricular cAMP, as well as phospholamban and cardiac troponin I phosphorylation were elevated versus control mice. At the cellular level, myocytes isolated from V1AR KO mice demonstrated increased responsiveness to βAR stimulation consistent with the finding that acute pharmacological V1AR inhibition enhanced βAR-mediated contractility in control myocytes. Therefore, while V1AR deletion does not protect the heart from the rapid development of cardiac dysfunction following acute ischemic injury, its effects on βAR activity suggest that acute V1AR inhibition could be utilized to promote myocyte contractile performance.