title: Characterization of nitric oxide release by nebivolol and its metabolites.
abstract: BACKGROUND
  Nebivolol is a selective beta(1)-adrenergic receptor antagonist that causes a direct vasodilator effect attributed to the action on vascular nitric oxide (NO). This study aimed to investigate whether nebivolol or its metabolites induces NO production and to explore the mechanisms underlying this pharmacologic effect.
  
  
  METHODS
  Conductance and resistance arteries from Wistar-Kyoto rats (WKY) (n = 33) incubated with the fluorescent probe diaminofluorescein-2 (DAF-2) were stimulated with increasing concentrations of nebivolol or its enantiomers and metabolites, and NO release was histologically evaluated.
  
  
  RESULTS
  Nebivolol induced a dose-dependent increase in NO levels in the endothelium of both arteries. Levels of NO were significantly increased at 10(-6)mol/L and reached a plateau state at 10(-5)mol/L. Induction of NO is not a general action of beta-adrenoceptor antagonists, as atenolol had no effects. Nebivolol action on NO release was mainly caused by the D-isomer. Moreover NO production is also maintained after hepatic metabolism, as the three main metabolites of nebivolol were able to induce a significant increase in endothelial NO release. Finally, nebivolol-activated calcium mobilization is crucial to NO production.
  
  
  CONCLUSIONS
  Our study shows the effects of D-nebivolol and its metabolites on endothelial NO production in both conductance and resistance arteries, and clarifies that this effect is realized through a calcium-dependent mechanism.
authors.affiliation: Department of AngioCardioNeurology, La Sapienza University, Rome, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.forename: Alessandra
authors.initials: A
authors.lastname: Aretini
authors.forename: Roberta
authors.initials: R
authors.lastname: Poulet
authors.forename: Umberto
authors.initials: U
authors.lastname: Bettarini
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Gentile
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cifelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001578:Benzopyrans / Q000737:chemistry / Q000493:pharmacokinetics*; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004983:Ethanolamines / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007536:Isomerism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D014665:Vasodilator Agents; D000068577:Nebivolol; D009569:Nitric Oxide; D002118:Calcium