Selectively engaging ß-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance.
J Pharmacol Exp Ther
; 335(3): 572-9, 2010 Dec.
Article
de En
| MEDLINE
| ID: mdl-20801892
ABSTRACT
Biased G protein-coupled receptor ligands engage subsets of the receptor signals normally stimulated by unbiased agonists. However, it is unclear whether ligand bias can elicit differentiated pharmacology in vivo. Here, we describe the discovery of a potent, selective ß-arrestin biased ligand of the angiotensin II type 1 receptor. TRV120027 (Sar-Arg-Val-Tyr-Ile-His-Pro-D-Ala-OH) competitively antagonizes angiotensin II-stimulated G protein signaling, but stimulates ß-arrestin recruitment and activates several kinase pathways, including p42/44 mitogen-activated protein kinase, Src, and endothelial nitric-oxide synthase phosphorylation via ß-arrestin coupling. Consistent with ß-arrestin efficacy, and unlike unbiased antagonists, TRV120027 increased cardiomyocyte contractility in vitro. In rats, TRV120027 reduced mean arterial pressure, as did the unbiased antagonists losartan and telmisartan. However, unlike the unbiased antagonists, which decreased cardiac performance, TRV120027 increased cardiac performance and preserved cardiac stroke volume. These striking differences in vivo between unbiased and ß-arrestin biased ligands validate the use of biased ligands to selectively target specific receptor functions in drug discovery.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Pression sanguine
/
Angiotensine-II
/
Phénomènes physiologiques cardiovasculaires
/
Transduction du signal
/
Arrestines
/
Récepteur de type 1 à l'angiotensine-II
Langue:
En
Journal:
J Pharmacol Exp Ther
Année:
2010
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique