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.

• Authors: Guido Boerrigter, David G Soergel, Jonathan D Violin, Michael W Lark, John C Burnett Jr
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 5 Issue 5 Pg. 627-34 (Sep 01 2012) ISSN: 1941-3297 [Electronic] United States
• PMID: 22891045 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Arrestins
• Diuretics
• Ligands
• Oligopeptides
• Receptor, Angiotensin, Type 1
• beta-Arrestins
• Furosemide
• Atrial Natriuretic Factor
• Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH

Topics

• Angiotensin II Type 1 Receptor Blockers (administration & dosage, pharmacology)
• Animals
• Arrestins (metabolism)
• Arterial Pressure (drug effects)
• Atrial Natriuretic Factor (blood)
• Cardiac Pacing, Artificial
• Disease Models, Animal
• Diuresis (drug effects)
• Diuretics (administration & dosage, pharmacology)
• Dogs
• Drug Therapy, Combination
• Furosemide (administration & dosage, pharmacology)
• Glomerular Filtration Rate (drug effects)
• Heart (drug effects, physiopathology)
• Heart Failure (drug therapy, metabolism, physiopathology)
• Infusions, Intravenous
• Kidney (drug effects, metabolism, physiopathology)
• Ligands
• Male
• Natriuresis (drug effects)
• Oligopeptides (administration & dosage, pharmacology)
• Pulmonary Wedge Pressure (drug effects)
• Receptor, Angiotensin, Type 1 (drug effects, metabolism)
• Renal Circulation (drug effects)
• Signal Transduction (drug effects)
• Time Factors
• Urodynamics (drug effects)
• Vascular Resistance (drug effects)
• beta-Arrestins