Cardiorenal actions of TRV120027, a novel ß-arrestin-biased ligand at the angiotensin II type I receptor, in healthy and heart failure canines: a novel therapeutic strategy for acute heart failure.

Abstract

BACKGROUND:

The angiotensin II type 1 receptor (AT1R) plays a key role in regulating cardiorenal function. Classic "unbiased" AT1R antagonists block receptor coupling to both G(αq) and ß-arrestin-mediated signals, which desensitize G-protein signaling as well as transduce G-protein-independent signals. TRV120027 is a novel ß-arrestin-biased AT1R ligand, which engages ß-arrestins while blocking G-protein signaling. At the AT1R, TRV120027 can inhibit angiotensin II-mediated vasoconstriction, whereas, through ß-arrestin coupling, increase cardiomyocyte contractility. We defined for the first time the acute cardiorenal actions of TRV120027 in healthy and heart failure (HF) canines.

METHODS AND RESULTS:

Healthy and HF canines (induced by tachypacing) were anesthetized. After instrumentation and equilibration, a 30-minute baseline clearance was performed, followed by further clearance with escalating doses of intravenous TRV120027 (0.01, 0.1, 1, 10, and 100 μg/kg per minute) and a 30-minute washout. In healthy canines, TRV120027 decreased pulmonary capillary wedge pressure and systemic and renal vascular resistances, while increasing cardiac output, renal blood flow, glomerular filtration rate, and urinary sodium excretion. In HF canines, TRV120027 decreased mean arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure, systemic and renal vascular resistances and increased cardiac output and renal blood flow. Glomerular filtration rate and urinary sodium excretion were maintained.

CONCLUSIONS:

We report for the first time the cardiorenal actions of the novel ß-arrestin-biased AT1R ligand TRV120027. In both normal and HF canines, TRV120027 demonstrated cardiac unloading actions while preserving renal function. With this beneficial pharmacological profile, TRV120027 represents a novel strategy for the treatment of HF.

• Authors: Guido Boerrigter, Michael W Lark, Erin J Whalen, David G Soergel, Jonathan D Violin, John C Burnett Jr
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 4 Issue 6 Pg. 770-8 (Nov 2011) ISSN: 1941-3297 [Electronic] United States
• PMID: 21835984 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arrestins
• Ligands
• Oligopeptides
• Receptor, Angiotensin, Type 1
• beta-Arrestins
• Sodium
• Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH

Topics

• Animals
• Arrestins (metabolism)
• Blood Pressure (drug effects, physiology)
• Cardiac Output (drug effects, physiology)
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Glomerular Filtration Rate (drug effects, physiology)
• Heart (drug effects, physiopathology)
• Heart Failure (drug therapy, metabolism, physiopathology)
• Kidney (drug effects, physiopathology)
• Ligands
• Male
• Oligopeptides (pharmacology, therapeutic use)
• Receptor, Angiotensin, Type 1 (metabolism)
• Sodium (urine)
• Treatment Outcome
• Vascular Resistance (drug effects, physiology)
• beta-Arrestins