Is nebivolol, which is classified as a β1‐adrenegic receptor antagonist, a biased agonist?

Nebivolol (NEB) is a β1‐adrenergic receptor (β1‐AR) antagonist (β‐blocker) with the greatest β1‐AR selectivity in human myocardium compared to other β‐blockers such as bisoprolol, metoprolol, and carvedilol (CAR). Both NEB and CAR are third generation β‐blockers and are considered vasodilatory β‐blockers. CAR is identified as a biased agonist of the β1‐AR, activating G‐protein‐independent β‐arrestin‐dependent epidermal growth factor receptor (EGFR) transactivation; however, it remains unclear if NEB is a biased agonist. Since determining if NEB is a biased agonist can unravel alternate signaling pathways that contribute to NEB‐mediated modulation of critical signaling in cardiovascular diseases, we tested the hypothesis that NEB functions as a biased agonist. Treatment with NEB induced rapid internalization of β‐ARs in HL‐1 cardiac myocytes and MEFs (k = 1.1 ± 0.3 and 0.7 ± 0.1 min −1 at 1 μM, respectively). Moreover, similar to CAR, NEB increased phosphorylation of the EGFR and extracellular regulated kinase (ERK) in a time dependent manner. Taken together, these data parallel previous studies demonstrating that CAR is a biased agonist; thus, indicating that NEB is a biased agonist. This work was supported by a VA VISN 15 grant (BTA) and Merritt award (JRS), as well as a Forest Laboratories research grant to LP and NIH R01HL073101 to JRS.