Characterization of Nitric Oxide Release by Nebivolol and Its Metabolites

Angelo Maffei, Carmine Vecchione, Alessandra Aretini, Roberta Poulet, Umberto Bettarini, Maria Teresa Gentile, Giuseppe Cifelli, Giuseppe Lembo

Research output: Contribution to journalArticlepeer-review


Background: Nebivolol is a selective β1-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 β-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. Conclusion: 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.

Original languageEnglish
Pages (from-to)579-586
Number of pages8
JournalAmerican Journal of Hypertension
Issue number6
Publication statusPublished - Jun 2006


  • β-adrenoceptor antagonists
  • endothelium
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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