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BASIC RESEARCH

Nebivolol and its 4-keto derivative increase nitric oxide in endothelial cells by reducing its oxidative inactivation

Luciano Cominacini, MD^*,*, Anna Fratta Pasini, MD^*, Ulisse Garbin, MD^*, Cristina Nava, MD^*, Anna Davoli, BSc^*, Marco Criscuoli, BSc, Attilio Crea, BSc, Tatsuya Sawamura, MD and Vincenzo Lo Cascio, MD^*

^* Department of Biomedical and Surgical Sciences (Medicina D), University of Verona, Verona, Italy
Department of Preclinical Development of Menarini Ricerche SpA, Firenze, Italy
Department of Pharmacokinetics and Metabolism of Menarini Ricerche SpA, Pomezia, Italy
Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan

Manuscript received December 31, 2002; revised manuscript received June 6, 2003, accepted June 10, 2003.

^* Reprint requests and correspondence: Dr. Luciano Cominacini, Dipartimento di Scienze Biomediche e Chirurgiche (Medicina D), Università di Verona, Ospedale Policlinico, 37134 Verona, Italy.
comina{at}medicinad.univr.it

OBJECTIVES: The objective of the present study was to elucidate the vasodilator mechanisms of nebivolol, a high selective ß₁-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 (O₂^·–), 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 O₂^·– (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.

Abbreviations and Acronyms   BAECs = bovine aortic endothelial cells   BLOX-1-CHO cells = CHO-K1 cells stably expressing bovine LOX-1   bLOX-1 mAb = anti-bovine LOX-1 monoclonal antibody   CAD = coronary artery disease   CHO-K1 cells = Chinese hamster ovary-K1 cells   eNOS = endothelial nitric oxide synthase   hLOX-1 mAb = anti-human LOX-1 monoclonal antibody   HUVECs = human umbilical vein endothelial cells   LDL = low-density lipoprotein   LOX-1 = lectin-like ox-LDL receptor-1   MAPK = mitogen-activated protein kinase   NO = nitric oxide   O2·– = superoxide   ox = oxidized   PKC = protein kinase C   ROS = reactive oxygen species

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