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.
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.


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.
Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Guido
G
Boerrigter
David G
DG
Soergel
Jonathan D
JD
Violin
Michael W
MW
Lark
John C
JC
Burnett
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D062186:Arterial Pressure / Q000187:drug effects; D009320:Atrial Natriuretic Factor / Q000097:blood; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004359:Drug Therapy, Combination; D005665:Furosemide / Q000008:administration & dosage / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008024:Ligands; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014563:Urodynamics / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D000071557:beta-Arrestins
D047228:Angiotensin II Type 1 Receptor Blockers; D019390:Arrestins; D004232:Diuretics; D008024:Ligands; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; D005665:Furosemide; D009320:Atrial Natriuretic Factor; C555534:Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH