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

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. 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. We show that direct interactions between betaARs and AT1Rs may have profound consequences on the overall response to drugs that antagonize these receptors.