Characterization of nitric oxide release by nebivolol and its metabolites.
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.
Maffei
Angelo
A
Department of AngioCardioNeurology, La Sapienza University, Rome, Italy.
Vecchione
Carmine
C
Aretini
Alessandra
A
Poulet
Roberta
R
Bettarini
Umberto
U
Gentile
Maria Teresa
MT
Cifelli
Giuseppe
G
Lembo
Giuseppe
G
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
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D014665:Vasodilator Agents; D000068577:Nebivolol; D009569:Nitric Oxide; D002118:Calcium