Published online before print September 8, 2003, doi: 10.1161/01.CIR.0000092166.30360.78
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(Circulation. 2003;108:1611.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Dual Inhibition of ß-Adrenergic and Angiotensin II Receptors by a Single Antagonist
A Functional Role for Receptor–Receptor Interaction In Vivo
From the Departments of Medicine, Cell Biology, and Genetics, Duke University Medical Center, Durham, NC.
Correspondence to Howard A. Rockman, MD, Department of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Research Drive, Durham, NC, 27710. E-mail h.rockman{at}duke.edu
Received July 16, 2003; revision received August 8, 2003; accepted August 8, 2003.
Background— Although the renin–angiotensin and the ß-adrenergic systems are interrelated, a direct interaction between ß-adrenergic receptors (ßARs) 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 ßAR and the AT1R. Selective blockade of ßARs 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 ß-blockers and angiotensin receptor blockers is through receptor–G protein uncoupling; ie, ß-blockers interfere with AT1R-Gq coupling, and valsartan interferes with ßAR-Gs coupling. Finally, we demonstrate that AT1Rs and ßARs 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 ßARs and AT1Rs may have profound consequences on the overall response to drugs that antagonize these receptors.
Key Words: heart failure • signal transduction • receptors, adrenergic, beta • angiotensin • pharmacology
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