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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:615.)
© 2003 American Heart Association, Inc.

Vascular Biology

Nebivolol Prevents Vascular NOS III Uncoupling in Experimental Hyperlipidemia and Inhibits NADPH Oxidase Activity in Inflammatory Cells

Hanke Mollnau; Eberhard Schulz; Andreas Daiber; Stephan Baldus; Matthias Oelze; Michael August; Maria Wendt; Ulrich Walter; Carolin Geiger; Rahul Agrawal; Andrei L. Kleschyov; Thomas Meinertz; Thomas Münzel

From the Abteilung für Kardiologie, Universitäts-Krankenhaus Eppendorf, University of Hamburg; Department of Clinical Biochemistry and Pathobiochemistry (U.W.), University of Würzburg; and Berlin Chemie (R.A.), Berlin, Germany.

Correspondence to Thomas Münzel, MD, Abteilung für Kardiologie, Universitäts-Krankenhaus Eppendorf, Martinistr 52, D-20246 Hamburg, Germany. E-mail muenzel{at}uke.uni-hamburg.de

Objectives— Nebivolol, in contrast to other selective ß₁-adrenergic receptor antagonists like atenolol, improves endothelial function in patients with oxidative stress within vascular tissue. With the present studies we sought to determine whether ß receptor blockade with nebivolol may improve endothelial function in hyperlipidemia and whether this is attributable to reductions in vascular oxidative stress.

Methods and Results— Watanabe heritable hyperlipidemic rabbits (WHHL) were treated with nebivolol (10 mg/kg per day for 8 weeks). New Zealand white rabbits (NZWR) served as controls. Nebivolol improved endothelial function, reduced vascular superoxide and vascular macrophage infiltration, and prevented NO synthase uncoupling in WHHL. Nebivolol treatment did not modify the expression of sGC or cGK-I but improved cGK-I activity (assessed by the phosphorylation state of the VAsodilator Stimulated Phosphoprotein at serine²³⁹, P-VASP). NAD(P)H oxidase activity in whole blood and isolated neutrophils was dose-dependently inhibited by nebivolol, whereas atenolol, metoprolol, and carvedilol were markedly less effective.

Conclusions— Nebivolol therapy effectively prevents NO synthase III uncoupling and prevents activation of the neutrophil NAD(P)H oxidase and infiltration of inflammatory cells. These novel antioxidative stress actions of this compound may explain partly the beneficial effects on endothelial function in patients with enhanced vascular oxidative stress.

Key Words: nebivolol • NO synthase • superoxide • neutrophils • NADPH oxidase

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