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MECHANISMS UNDERLYING NEBIVOLOL‐INDUCED ENDOTHELIAL NITRIC OXIDE SYNTHASE ACTIVATION IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS

1 Nebivolol (NEB) has been shown to be a selective blocker of β1‐adrenoceptors with additional vasodilating properties that are mediated, at least in part, by an endothelial‐dependent liberation of nitric oxide (NO). In the present study, we investigated the underlying mechanisms of NEB‐induced vasodilation. 2 Immunohistochemical staining of endothelial nitric oxide synthase (eNOS) was performed in the absence and presence of NEB in human umbilical vein endothelial cells (HUVEC). In addition, we measured the release of nitric oxide (NO) using diaminofluorescein. Metoprolol (MET) was used for comparison. 3 Nebivolol, but not MET (each at 10 µmol/L), caused a time‐dependent increase in NO release from HUVEC, as demonstrated by an increase in DAF fluorescence at 0 versus 10 min (+234 ± 7 and 55 ± 22% basal, respectively). Blockade of β3‐adrenoceptors by SR 59230A (1 µmol/L) partially reduced the NEB‐induced increase in DAF fluorescence. Complete inhibition of NEB‐induced NO liberation was achieved by the simultaneous blockade of β3‐adrenoceptors and oestrogen receptors (with 1 µmol/L ICI 182,780). 4 Application of NEB significantly increased eNOS translocation and serine 1177 phosphorylation of eNOS. However, NEB did not alter eNOS‐phosphorylation at threonine 495 and at serine 114. 5 In conclusion, the endothelium‐dependent NO liberation induced by NEB is due to stimulation of β3‐adrenoceptors and oestrogen receptors and coincides with eNOS translocation and a phosphorylation at eNOS‐serine 1177. These characteristics of NEB may be beneficial not only when treating patients suffering from cardiovascular disease, but may also prevent further deterioration of endothelial dysfunction.