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

Abstract

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. (Circ Heart Fail. 2012;5:627-634.)Key Words: animal models of human disease ◼ heart failure ◼ cardiovascular pharmacology ◼ angiotensin II ◼ receptors ◼ β-arrestin

Biased Agonism as a Mechanism for Differential Signaling by Chemokine Receptors

“…In general, biased agonists targeting 7TMRs have been generated synthetically and display distinct physiologic profiles from endogenous, balanced agonists, suggesting a role for these compounds as novel drugs (23,24). However, it has been unclear whether biased agonism is an "accident" of 7TMR complexity that has only been exploited by synthetic drugs or whether it is a property that is utilized by endogenous systems as an added layer for specificity in signaling (25).…”

The β-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors

“…For example, a ␤arr-biased AT 1 R agonist has markedly different physiologic effects from the endogenous agonist angiotensin II (68). Although angiotensin II causes vasoconstriction, cardiac hypertrophy, and increased cardiac contractility, the ␤arr-biased agonist causes vasodilation and does not cause cardiac hypertrophy, but still increases cardiac contractility via ␤arr-mediated phosphorylation of tropomyosin and other contractile proteins (69).…”

New therapeutic pathways in the RAS

“…TRV120027 is the first biased ARB in clinical development and is currently being evaluated in a phase II clinical study for the treatment of heart failure. 7,8 …”