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

Guido Boerrigter, David G. Soergel, Jonathan D. Violin, Michael W. Lark, John C. Burnett

Research output: Contribution to journalArticle

81 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)627-634
Number of pages8
JournalCirculation: Heart Failure
Volume5
Issue number5
DOIs
StatePublished - Sep 1 2012

Keywords

  • Angiotensin II
  • Animal models of human disease
  • Cardiovascular pharmacology
  • Heart failure
  • Receptors
  • β-arrestin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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