In dogs with experimental heart failure, adding TRV120027 to furosemide preserved natriuresis and diuresis while significantly reducing mean arterial pressure, vascular resistances, and PCWP (P<0.05).
Does TRV120027 added to furosemide improve hemodynamics and renal function in experimental heart failure?
In a canine model of heart failure, the novel β-arrestin biased ligand TRV120027 added to furosemide reduced cardiac preload and afterload while preserving renal function.
p-value: p=<0.05
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 infusion. After a washout, a postinfusion 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 postinfusion clearance with F+T. Glomerular filtration 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.
Boerrigter et al. (Tue,) conducted a other in Experimental heart failure (n=12). TRV120027 plus furosemide vs. Furosemide (1 mg/kg per hour) plus saline was evaluated on Diuresis, natriuresis, and hemodynamics (mean arterial pressure, vascular resistances, pulmonary capillary wedge pressure) (p=<0.05). In dogs with experimental heart failure, adding TRV120027 to furosemide preserved natriuresis and diuresis while significantly reducing mean arterial pressure, vascular resistances, and PCWP (P<0.05).