TRV120027, a novel β-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure

Background: TRV120027 is a novel β-arrestin biased ligand of the angiotensin II type 1 receptor; it antagonizes canonical G-protein-mediated coupling while, in contrast to classical angiotensin II type 1 receptor antagonists, it engages β-arrestin-mediated signaling. Consequently, TRV120027 inhibits angiotensin II-mediated vasoconstriction while, via β-arrestin coupling, it increases cardiomyocyte contractility. We hypothesized that TRV120027 would elicit beneficial cardiorenal actions when added to furosemide in experimental heart failure. Methods and Results: Two groups of anesthetized dogs (n=6 each) with tachypacing-induced heart failure were studied. After a baseline clearance, 1 group (F+V) received furosemide (1 mg/kg per hour) plus saline for 90 minutes, whereas the other (F+T) received the same dose of furosemide plus TRV120027 (0.3 and 1.5 μg/kg per minute for 45 minutes each);2 clearances were done during drug influsion. After a washout, a postinflusion clearance was done; ^*P <0.05 between groups. F+V and F+T increased diuresis and natriuresis to a similar extent during drug administration, but urine flow^* and urinary sodium excretion^* were higher in the postinflusion clearance with F+T. Glomerular fltration rate was preserved in both groups. Renal blood flow increased with F+T but this was not significant versus F+V. Compared with F+V, F+T decreased mean arterial pressure^*, systemic ^* and pulmonary^* vascular resistances, and atrial natriuretic peptide^*. Pulmonary capillary wedge pressure^* decreased to a larger extent with F+T than with F+V. Conclusions: When added to furosemide, TRV120027, a novel β-arrestin biased angiotensin II type 1 receptor ligand, preserved furosemide-mediated natriuresis and diuresis, while reducing cardiac preload and afterload. These results provide support for TRV120027 as a promising novel therapeutic for the treatment of heart failure.