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

ABSTRACT: Vasopressin type 1A receptor (V1AR) expression is elevated in chronic human heart failure (HF) and contributes to cardiac dysfunction in animal models, in part via reduced ?-adrenergic receptor (?AR) responsiveness. Although cardiac V1AR overexpression and V1AR stimulation are each sufficient to decrease ?AR activity, it is unknown whether V1AR inhibition conversely augments ?AR responsiveness. Further, although V1AR has been shown to contribute to chronic progression of HF, its impact on cardiac function following acute ischaemic injury has not been reported. Using V1AR knockout (V1AR KO) mice we assessed the impact of V1AR deletion on cardiac contractility at baseline and following ischaemic injury, ?AR sensitivity and cardiomyocyte responsiveness to ?AR 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 ischaemic 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 ?-blocker sensitivity, suggesting increased basal ?AR activity, and indeed levels of left ventricular cAMP, as well as phospholamban (PLB) and cardiac troponin I (cTnI) phosphorylation were elevated compared with control mice. At the cellular level, myocytes isolated from V1AR KO mice demonstrated increased responsiveness to ?AR stimulation consistent with the finding that acute pharmacological V1AR inhibition enhanced ?AR-mediated contractility in control myocytes. Therefore, although V1AR deletion does not protect the heart from the rapid development of cardiac dysfunction following acute ischaemic injury, its effects on ?AR activity suggest that acute V1AR inhibition could be utilized to promote myocyte contractile performance.

SUBMITTER: Wasilewski MA 

PROVIDER: S-EPMC5334456 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature