Nebivolol and its 4-keto derivative increase nitric oxide in endothelial cells by reducing its oxidative inactivation.
OBJECTIVE
The objective of the present study was to elucidate the vasodilator mechanisms of nebivolol, a high selective beta(1)-receptor antagonist with antioxidant properties.


BACKGROUND
Oxidative inactivation of nitric oxide (NO) is regarded as an important cause of its decreased biological activity.


METHODS
Oxidative stress was induced through the binding of oxidized (ox)-low-density lipoprotein (LDL) to its specific endothelial receptor, called "lectin-like oxidized LDL receptor-1" (LOX-1), in bovine and human endothelial cells and in Chinese hamster ovary cells stably expressing bovine LOX-1 (BLOX-1-CHO cells). Reactive oxygen species (ROS), superoxide (O(2)(*-)), and NO were measured in cells by flow cytometry.


RESULTS
Nebivolol and its 4-keto derivative prevented in a dose-dependent manner the increase of ROS (p < 0.001) and O(2)(*-) (p < 0.001) in bovine aortic endothelial cells (BAECs), human umbilical vein endothelial cells (HUVECs), and BLOX-1-CHO cells stimulated with ox-LDL. Atenolol had no effect. The incubation of HUVECs and BAECs with ox-LDL reduced basal and bradykinin-induced NO and nitrite concentration (p from <0.001 to <0.01). Nebivolol and its 4-keto derivative prevented the reduction of basal and stimulated NO and nitrite concentration (p from <0.001 to <0.01) while atenolol had no effect. The preincubation of BAECs with blocking anti-LOX-1 monoclonal antibody (LOX-1 mAb) significantly counteracted the effect of ox-LDL on stimulated generation of NO (p < 0.001), but the effect was significantly lower than that of nebivolol and its 4-keto derivative alone (p < 0.01).


CONCLUSIONS
In conclusion, the findings of the present study indicate that nebivolol increases NO also by decreasing its oxidative inactivation.
Cominacini
Luciano
L
Department of Biomedical and Surgical Sciences, Medicina D, University of Verona, Verona, Italy. comina@medininad.univr.it
Fratta Pasini
Anna
A
Garbin
Ulisse
U
Nava
Cristina
C
Davoli
Anna
A
Criscuoli
Marco
M
Crea
Attilio
A
Sawamura
Tatsuya
T
Lo Cascio
Vincenzo
V
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002417:Cattle; D018929:Cell Culture Techniques; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D004983:Ethanolamines / Q000494:pharmacology*; D006801:Humans; D000068577:Nebivolol; D009569:Nitric Oxide / Q000096:biosynthesis*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D004983:Ethanolamines; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D000068577:Nebivolol; D013481:Superoxides; D009569:Nitric Oxide