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

Abstract

Background Enhanced arginine vasopressin (AVP) levels are associated with increased mortality during end-stage human heart failure (HF), and cardiac AVP type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulated βAR responsiveness and in doing so contributes to HF development. Methods and Results Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca2+ mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/GRK-dependent manner. Conclusions This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated HF and elevated AVP.

Bcl-2–associated athanogene 3 protects the heart from ischemia/reperfusion injury

“…Tissues were quickly frozen in liquid nitrogen and stored at -80°C until use. Membrane proteins were prepared as described previously (38). In brief, tissue was lysed in buffer (Cell Signaling Technologies) containing protease and phosphatase inhibitor cocktail (ThermoScientific) and homogenized with beads in a Bullet Blender (Next Advance).…”

“…In brief, tissue was lysed in buffer (Cell Signaling Technologies) containing protease and phosphatase inhibitor cocktail (ThermoScientific) and homogenized with beads in a Bullet Blender (Next Advance). NMVCs were rinsed with ice-cold PBS, collected, and lysed in buffer (38). After centrifugation at 13,000 g for 5 minutes at 4°C, the supernatant was collected and protein levels were determined by Bradford assay (Bio-Rad).…”

“…Global LV function was evaluated in all mice after light sedation (2% isoflurane) using a VisualSonics Vevo 770 imaging system and a 707 scan head (VisualSonics Inc.) as described previously (38). The LV ejection fraction (EF) was calculated using the formula EF% = [(LVEDV -LVESV)/LVEDV]×100; where LVEDV and LVESV are LV end-diastolic volume and LV end-systolic volume, respectively.…”

Inverse agonism: the classic concept of GPCRs revisited [Review]

“…Recognition of the deleterious effects of overactivation of the renin-angiotensin system (RAS) and AT1-Gq/G13 signaling [28][29][30], in addition to desensitization of cardioprotective βAR-Gs signaling [31][32][33], has made RAS a major therapeutic target, whether systemically or regionally [34,35]. In many randomized, controlled trials, ACE inhibitor (ACEi) reduced morbidity and mortality more than comparators in patients with congestive heart failure and coronary heart disease [36][37][38][39][40].…”

Letter by Mentzelopoulos et al Regarding Article “β-Adrenergic Receptor–Mediated Cardiac Contractility Is Inhibited Via Vasopressin Type 1A-Receptor–Dependent Signaling”

“…The difference in times to drug administration may also constitute a major reason for the failure of favorable animal study results on the vasopressin-epinephrine combination 1,5 to translate successfully into the clinical setting. 3,5 In accordance with this interpretation, a previous study reported that the mean time to first drug administration in animal cardiac arrest studies was 9.5 minutes, as opposed to 19.4 minutes in human studies of out-of-hospital cardiac arrest.…”