Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo.

Published

Journal Article

BACKGROUND: Although the renin-angiotensin and the beta-adrenergic systems are interrelated, a direct interaction between beta-adrenergic receptors (betaARs) and angiotensin II type 1 receptors (AT1Rs) has not been identified. METHODS AND RESULTS: Here, we provide evidence for a functional and physiological interaction between 2 G protein-coupled receptors: the betaAR and the AT1R. Selective blockade of betaARs in mouse cardiomyocytes inhibits angiotensin-induced contractility with an IC50 that is similar to its inhibition of isoproterenol-mediated contractility. Furthermore, administration of the angiotensin receptor blocker valsartan to intact mice results in a significant reduction in the maximal response to catecholamine-induced elevation of heart rate. The mechanism for this transinhibitory effect of beta-blockers and angiotensin receptor blockers is through receptor-G protein uncoupling; ie, beta-blockers interfere with AT1R-Gq coupling, and valsartan interferes with betaAR-Gs coupling. Finally, we demonstrate that AT1Rs and betaARs form constitutive complexes that are not affected by ligand stimulation. As a result of these interactions, a single receptor antagonist effectively blocks downstream signaling and trafficking of both receptors simultaneously. CONCLUSIONS: We show that direct interactions between betaARs and AT1Rs may have profound consequences on the overall response to drugs that antagonize these receptors.

Full Text

Duke Authors

Cited Authors

  • Barki-Harrington, L; Luttrell, LM; Rockman, HA

Published Date

  • September 30, 2003

Published In

Volume / Issue

  • 108 / 13

Start / End Page

  • 1611 - 1618

PubMed ID

  • 12963634

Pubmed Central ID

  • 12963634

Electronic International Standard Serial Number (EISSN)

  • 1524-4539

Digital Object Identifier (DOI)

  • 10.1161/01.CIR.0000092166.30360.78

Language

  • eng

Conference Location

  • United States