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 Jr. Burnett

Research output: Contribution to journalArticle

77 Citations (Scopus)

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 2012

Fingerprint

Arrestin
Angiotensin I
Angiotensin Receptors
Furosemide
Heart Failure
Ligands
Kidney
Angiotensin Type 1 Receptor
Natriuresis
Diuresis
Vascular Resistance
Angiotensin II Type 1 Receptor Blockers
Pulmonary Wedge Pressure
Renal Circulation
Atrial Natriuretic Factor
Vasoconstriction
Treatment Failure
GTP-Binding Proteins
Cardiac Myocytes
Angiotensin II

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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

In: Circulation: Heart Failure, Vol. 5, No. 5, 09.2012, p. 627-634.

Research output: Contribution to journalArticle

@article{d602ba98c23645389a0523f2383c1884,
title = "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 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.",
keywords = "β-arrestin, Angiotensin II, Animal models of human disease, Cardiovascular pharmacology, Heart failure, Receptors",
author = "Guido Boerrigter and Soergel, {David G.} and Violin, {Jonathan D.} and Lark, {Michael W.} and Burnett, {John C Jr.}",
year = "2012",
month = "9",
doi = "10.1161/CIRCHEARTFAILURE.112.969220",
language = "English (US)",
volume = "5",
pages = "627--634",
journal = "Circulation: Heart Failure",
issn = "1941-3297",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - 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

AU - Boerrigter, Guido

AU - Soergel, David G.

AU - Violin, Jonathan D.

AU - Lark, Michael W.

AU - Burnett, John C Jr.

PY - 2012/9

Y1 - 2012/9

N2 - 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.

AB - 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.

KW - β-arrestin

KW - Angiotensin II

KW - Animal models of human disease

KW - Cardiovascular pharmacology

KW - Heart failure

KW - Receptors

UR - http://www.scopus.com/inward/record.url?scp=84868668210&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868668210&partnerID=8YFLogxK

U2 - 10.1161/CIRCHEARTFAILURE.112.969220

DO - 10.1161/CIRCHEARTFAILURE.112.969220

M3 - Article

C2 - 22891045

AN - SCOPUS:84868668210

VL - 5

SP - 627

EP - 634

JO - Circulation: Heart Failure

JF - Circulation: Heart Failure

SN - 1941-3297

IS - 5

ER -