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Abstract
Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β2-AR, and likely β1-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β1- and/or β2-ARs.
Highlights
Nebivolol is classified as a third generation b-adrenoceptor antagonist (b-blocker) that has a higher affinity for b1adrenoceptors (b1-ARs) compared to b2-ARs and b3-ARs [1,2]
As there is still debate regarding the role of the b3-AR in nebivolol-mediated signaling, the expression of b-ARs in mouse embryonic fibroblasts (MEFs) and HL-1 cardiac myocyte cells were examined via qPCR
The primer pairs were able to amplify all b-ARs subtypes in the mouse aorta (Fig. 1A) and no statistical difference was observed between the receptors the b3-AR tended to have lower expression. b1-ARs were found only in the HL-1 cells, and b2-ARs were found in both MEFs and HL-1 cells (Fig. 1B). b3AR message was below detection levels in both MEFs and HL-1 cells even after 40 cycles of PCR under the conditions used in this study
Summary
Nebivolol is classified as a third generation b-adrenoceptor (bAR) antagonist (b-blocker) that has a higher affinity for b1adrenoceptors (b1-ARs) compared to b2-ARs and b3-ARs [1,2]. The mechanism is unknown, a leading theory is that nebivolol induces vasodilation via b3-ARs [5,6,7,8]. Recent evidence argues against a mechanism involving human b3-ARs [9], and nebivolol’s reported affinity for b3-ARs (Ki , 1.5 mM) is much weaker than for b2-ARs (Ki , 30 nM) and b1-ARs (Ki , 0.8 nM) [9,10]. Because of the ratios of agonist to antagonist utilized the most recent reports regarding nebivolol acting through b3-ARs [5] leaves open the possibility that nebivolol could act, at least in part, via b1-ARs or b2-ARs. The b3-AR is not the only theorized target receptor; an alternative theory is that metabolites of nebivolol induce vasodilation through b2-ARs [12]
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