Dual Inhibition of β-Adrenergic and Angiotensin II Receptors by a Single Antagonist

<jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> Although the renin–angiotensin and the β-adrenergic systems are interrelated, a direct interaction between β-adrenergic receptors (βARs) and angiotensin II type 1 receptors (AT <jats:sub>1</jats:sub> Rs) has not been identified. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> Here, we provide evidence for a functional and physiological interaction between 2 G protein–coupled receptors: the βAR and the AT <jats:sub>1</jats:sub> R. Selective blockade of βARs in mouse cardiomyocytes inhibits angiotensin-induced contractility with an IC <jats:sub>50</jats:sub> 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 β-blockers and angiotensin receptor blockers is through receptor–G protein uncoupling; ie, β-blockers interfere with AT <jats:sub>1</jats:sub> R-G <jats:sub>q</jats:sub> coupling, and valsartan interferes with βAR-G <jats:sub>s</jats:sub> coupling. Finally, we demonstrate that AT <jats:sub>1</jats:sub> Rs and βARs 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. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> We show that direct interactions between βARs and AT <jats:sub>1</jats:sub> Rs may have profound consequences on the overall response to drugs that antagonize these receptors. </jats:p>