Cardiorenal Actions of TRV120027, a Novel ß-Arrestin–Biased Ligand at the Angiotensin II Type I Receptor, in Healthy and Heart Failure Canines

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 ␣q 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 g/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. (Circ Heart Fail. 2011;4:770-778.)

β-arrestin–biased signaling through the β 2 -adrenergic receptor promotes cardiomyocyte contraction

“…promote cardiomyocyte contraction along with activation of antiapoptotic signaling (37,38). To date, a comparable ligand has not been reported for β-adrenergic receptors.…”

“…As G-protein-dependent signaling has been attributed to cardiomyocyte death, the use of a β-arrestin-biased agonist could be an advantageous therapeutic approach (34). Beyond its inability to activate G-protein signaling, evidence has suggested that β-arrestinbiased signaling promotes cardiomyocyte survival signaling along with induction of cardiomyocyte contractility (3,(35)(36)(37)(38). Indeed, a β-arrestin-biased agonist for the angiotensin II type 1A receptor (AT1 A R), TRV027, has demonstrated the ability to promote β-arrestin-dependent cardiac contraction in vivo and is currently in clinical trials for the treatment of heart failure (37, 38).…”

Biased Signaling Favoring Gi over β-Arrestin Promoted by an Apelin Fragment Lacking the C-terminal Phenylalanine

“…Stimulation by Ang II or [Sar 1 , Ile 4 , Ile 8 ] Ang II of AT1a receptor led to positive inotropic and lusitropic responses in wild-type cardiomyocytes, whereas this response was abolished in ␤-arrestin 2 knock-out cardiomyocytes (61). The therapeutic potential of such compounds has been illustrated by the development of TR120027, a AT1a receptor ␤-arrestin-biased agonist, which improved cardiac performance and had cardioprotective activity by blocking the G protein-mediated vasoconstriction while increasing the cardiac contractility through ␤-arrestin signaling (62,63). The activation of ApelinR ␤-arrestin-mediated signaling could have also a biological role because only apelin fragments that fully activate ␤-arrestin induced a decrease in arterial BP (14).…”

The Renin-Angiotensin System: Is there a limit to where it goes?

“…In this sense, TRV120027 targets the AT1R in such a way that blocks of the G-protein mediated adverse effects of Ang II while simultaneously unmasks beneficial pharmacology mediated by beta-arrestin. Its benefits to heart and kidney were already clearly demonstrated in animal models by us and others [10][11][12].…”