Dual inhibition of β-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 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 IC ₅₀ 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 AT ₁Rs 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.