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Nebivolol acts as a beta3‐adrenergic receptor agonist in a mouse model of oxygen‐induced retinopathy
Author(s) -
Dal Monte M.,
Amato R.,
Locri F.,
Cammalleri M.
Publication year - 2017
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2017.0f084
Subject(s) - nebivolol , agonist , vasodilation , pharmacology , endocrinology , medicine , nitric oxide , neovascularization , antagonist , retinal , adrenergic agonist , angiogenesis , chemistry , receptor , blood pressure , ophthalmology
Purpose Nebivolol is a β1‐adrenergic receptor (AR) antagonist with vasodilatory properties. Nebivolol, but not the β1‐AR antagonist atenolol, has been found to ameliorate endothelial dysfunction. There is no clear evidence about the molecular target of the vasodilatory action of nebivolol, but several studies seem to indicate that the activation of β3‐ARs may mediate such vasodilation. In the present study, we evaluated the possible activity of nebivolol as β3‐AR agonist in a mouse model of oxygen‐induced retinopathy (OIR) using β1/β2‐AR knockout (KO) mice. These mice are quite resistant to retinal hypoxia, with reduced neovascularization in respect to their wild type (WT) controls. Methods The OIR model was established in KO and WT. Nebivolol was subcutaneously administered at 0.1, 1 or 10 mg/kg once daily between PD12 and PD16, before animal sacrifice at PD17. The effects of nebivolol on retinal neovascularization, VEGF levels and nitric oxide (NO) production were assessed by CD31 immunohistochemistry, real time RT‐PCR and ELISA, and the Griess method, respectively. Results In OIR, nebivolol minimally affected retinal neovascularization in WT while dose‐dependently induced pathologic angiogenesis in KO mice. In addition, nebivolol dose‐dependently increased VEGF levels in KO. The NO pathway was likely to be involved in the angiogenic effects of nebivolol. Conclusions The weak effects of nebivolol in the WT retina indicate that β1‐ and/or β2‐ARs play a pivotal role in retinal angiogenesis and that the angiogenic role of β3‐ARs may be unraveled only in the absence of the two other subtypes and when adequately stimulated. The present study indicates that nebivolol may stimulate β3‐ARs in the mouse retina suggesting this drug as a possible candidate as β3‐AR agonist.