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

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Abstract
Nebivolol, in contrast to other selective beta1-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 beta receptor blockade with nebivolol may improve endothelial function in hyperlipidemia and whether this is attributable to reductions in vascular oxidative stress. 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. 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.