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 beta-adrenergic systems are interrelated, a direct interaction between beta-adrenergic receptors (betaARs) and angiotensin II type 1 receptors (AT(1)Rs) has not been identified. Methods and Results - Here, we provide evidence for a functional and physiological interaction between 2 G protein - coupled receptors: the betaAR and the AT(1)R. 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 AT(1)R-G(q) coupling, and valsartan interferes with betaAR-G(s) coupling. Finally, we demonstrate that AT(1)Rs 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. Conclusions - We show that direct interactions between betaARs and AT(1)Rs may have profound consequences on the overall response to drugs that antagonize these receptors.