Nebivolol prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits NADPH oxidase activity in inflammatory cells.
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.
Mollnau
Hanke
H
Abteilung für Kardiologie, Universitäts-Krankenhaus Eppendorf, University of Hamburg, Hamburg, Germany.
Schulz
Eberhard
E
Daiber
Andreas
A
Baldus
Stephan
S
Oelze
Matthias
M
August
Michael
M
Wendt
Maria
M
Walter
Ulrich
U
Geiger
Carolin
C
Agrawal
Rahul
R
Kleschyov
Andrei L
AL
Meinertz
Thomas
T
Münzel
Thomas
T
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
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