Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo.
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.
Duke Scholars
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Related Subject Headings
- Valsartan
- Valine
- Tetrazoles
- Signal Transduction
- Receptors, Angiotensin
- Receptors, Adrenergic, beta
- Receptor, Angiotensin, Type 1
- Propranolol
- Myocytes, Cardiac
- Myocardial Contraction
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Valsartan
- Valine
- Tetrazoles
- Signal Transduction
- Receptors, Angiotensin
- Receptors, Adrenergic, beta
- Receptor, Angiotensin, Type 1
- Propranolol
- Myocytes, Cardiac
- Myocardial Contraction