Vasopressin type 1A receptor deletion enhances cardiac contractility, β-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 β-adrenergic receptor (βAR) responsiveness. Although 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 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, 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 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 β-blocker sensitivity, suggesting increased basal βAR 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 βAR stimulation consistent with the finding that acute pharmacological V1AR inhibition enhanced βAR-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 βAR activity suggest that acute V1AR inhibition could be utilized to promote myocyte contractile performance.

Leukocyte Cytoskeleton Polarization Is Initiated by Plasma Membrane Curvature from Cell Attachment

“…Briefly, Mice were anaesthetized with inhalation of 1.5-2% isoflurane, and the left ventricular (LV) wall thickness, LV end-systolic diameter, and LV end-diastolic diameter were measured. Percentage of fractional shortening (FS%) and ejection fraction (EF%) were calculated as described (Wasilewski et al, 2016). The measurements were performed before the surgery and at 24 hr after heart I/R.…”

Ganoderic acid A protects neural cells against NO stress injury in vitro via stimulating β adrenergic receptors

“…Some drugs acting on adrenergic receptors, such as AD and isoproterenol, can induce myocardial injury [ 20 , 21 ]. Reduced β-adrenergic receptor (β-AR) responsiveness could improve liver damage and myocardial injury [ 22 ], and a β2-adrenergic receptor (β2-AR) agonist could aid in the recovery of ischemia–reperfusion injury [ 23 ]. SNP is a donor of NO; therefore, we established an excessive NO damage model induced by SNP to study the role of the adrenergic system in nerve injury [ 24 – 27 ].…”

Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling

“…The density of βAR on cardiac membranes, prepared as previously described 13 , or NRVM were determined by saturation binding experiments. Cardiac membranes (25 μg of protein) or single cell suspensions (1×10 5 cells) of NRVM were incubated with [ 125 I]-cyanopindolol ([ 125 I]-CYP; 200 pM; PerkinElmer) in binding buffer (75 mM Tris, pH 7.4, 2 mM EDTA, 12.5 mM MgCl 2 , 1 μg/mL aprotinin, 1 μg/mL leupeptin).…”