Background— 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 (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 βAR and the AT₁R. Selective blockade of βARs 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 β-blockers and angiotensin receptor blockers is through receptor–G protein uncoupling; ie, β-blockers interfere with AT₁R-G_q coupling, and valsartan interferes with βAR-G_s coupling. Finally, we demonstrate that AT₁Rs 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.

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