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

Publication ,  Journal Article
Barki-Harrington, L; Luttrell, LM; Rockman, HA
Published in: Circulation
September 30, 2003

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.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

September 30, 2003

Volume

108

Issue

13

Start / End Page

1611 / 1618

Location

United States

Related Subject Headings

  • Valsartan
  • Valine
  • Tetrazoles
  • Signal Transduction
  • Receptors, Angiotensin
  • Receptors, Adrenergic, beta
  • Receptor, Angiotensin, Type 1
  • Propranolol
  • Myocytes, Cardiac
  • Myocardial Contraction
 

Citation

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Barki-Harrington, L., Luttrell, L. M., & Rockman, H. A. (2003). Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo. Circulation, 108(13), 1611–1618. https://doi.org/10.1161/01.CIR.0000092166.30360.78
Barki-Harrington, Liza, Louis M. Luttrell, and Howard A. Rockman. “Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo.Circulation 108, no. 13 (September 30, 2003): 1611–18. https://doi.org/10.1161/01.CIR.0000092166.30360.78.
Barki-Harrington, Liza, et al. “Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo.Circulation, vol. 108, no. 13, Sept. 2003, pp. 1611–18. Pubmed, doi:10.1161/01.CIR.0000092166.30360.78.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

September 30, 2003

Volume

108

Issue

13

Start / End Page

1611 / 1618

Location

United States

Related Subject Headings

  • Valsartan
  • Valine
  • Tetrazoles
  • Signal Transduction
  • Receptors, Angiotensin
  • Receptors, Adrenergic, beta
  • Receptor, Angiotensin, Type 1
  • Propranolol
  • Myocytes, Cardiac
  • Myocardial Contraction