title: Nebivolol prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits NADPH oxidase activity in inflammatory cells.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Abteilung für Kardiologie, Universitäts-Krankenhaus Eppendorf, University of Hamburg, Hamburg, Germany.
authors.forename: Hanke
authors.initials: H
authors.lastname: Mollnau
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Michael
authors.initials: M
authors.lastname: August
authors.forename: Maria
authors.initials: M
authors.lastname: Wendt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Carolin
authors.initials: C
authors.lastname: Geiger
authors.forename: Rahul
authors.initials: R
authors.lastname: Agrawal
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Kleschyov
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinertz
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D017849:Animals, Inbred Strains; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D017869:Cyclic GMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004983:Ethanolamines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006162:Guanylate Cyclase; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008840:Microfilament Proteins; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D000068577:Nebivolol; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D000071756:Soluble Guanylyl Cyclase; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D015815:Cell Adhesion Molecules; D004983:Ethanolamines; D008055:Lipids; D008840:Microfilament Proteins; D010750:Phosphoproteins; D018342:Receptors, Adrenergic, beta-1; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D000098662:Vasodilator-Stimulated Phosphoprotein; D000068577:Nebivolol; D013481:Superoxides; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase