Nebivolol acts as a beta3‐adrenergic receptor agonist in a mouse model of oxygen‐induced retinopathy

Abstract

PurposeNebivolol 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.MethodsThe 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.ResultsIn 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.ConclusionsThe 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.