Biased Agonist Modulation of Carvedilol & Metoprolol in Beta-arrestin Pathway

Congestive Heart failure (CHF) is the leading cause of death in the U.S.A. and is a major cause of death globally. Nearly 6 million patients in the U.S.A. have CHF and ~825,000 new cases of HF are diagnosed annually. The American Heart Association defines HF as a chronic disease in which the heart is not able to pump enough blood to meet the demand of the body. This inability of the heart to pump sufficient blood is due to insufficient contraction. In patients with HF, the principal hallmark is depressed cardiac ejection fraction. Cardiac contractility is mediated through a G-protein coupled receptor (GPCR), the β2-adrenergic receptor (β2-AR) signaling after stimulation by catecholamines, norepinephrine and epinephrine, released from sympathetic nerves. Thus, an increase in β-AR stimulation leads to increase in cardiac contraction. However, in CHF, chronic β2-AR stimulation results in reduced cardiac contractility due to a reduction in the responsiveness of these receptors to agonist stimulation. There are several standard pharmacological treatments of CHF, including β2-AR blockers (carvedilol or metoprolol), angiotensin-converting enzyme inhibitors, and phosphodiesterase inhibitors. Here in this work we used a novel structural complementation assay to show the pharmacology in real time of Carvedilol and Metoprolol. A higher antagonistic effect was observed in the case of Carvedilol in β-arrestin1/2 recruitment. We conclude that the therapeutic effects of these drugs are related to the antagonistic effect only on the G-protein signaling. A β-arrestin2 biased agonist might be a new therapeutic approach to treat heart failure.