Effect of dl-nebivolol, its enantiomers and metabolites on the intracellular production of superoxide and nitric oxide in human endothelial cells

Evangelista, Stefano; Garbin, Ulisse; Pasini, Anna Fratta; Stranieri, Chiara; Boccioletti, Veronica; Cominacini, Luciano

doi:10.1016/j.phrs.2006.12.008

Cited by 47 publications

(45 citation statements)

References 33 publications

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“…dl-Nebivolol was reported to possess an intrinsic β2/β3 agonistic activity, 5,[38][39][40] leading to Akt-dependent phosphorylation of eNOS in Ser1177 in endothelial cells 41 ; therefore, we assessed phosphorylated eNOS in platelets. dl-Nebivolol and l-nebivolol enhanced eNOS phosphorylation at serine1177, 1 of the phosphorylation sites involved in eNOS activation in platelets.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Momi

Caracchini

Falcinelli

et al. 2014

ATVB

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H ypertension is associated with an increased risk of arterial thrombotic events, such as stroke and myocardial infarction, 1 in which platelets are deeply involved. Previous studies have shown that β-adrenoceptor blockers reduce platelet activation and aggregation, 2 but this does not seem to be a class effect because not all β-blockers share this property. 3 dl-Nebivolol (a racemic mixture of d-and l-nebivolol) is a third-generation β 1 adrenoceptor-selective antagonist that, besides its β-blockade-mediated hypotensive effect, possesses direct vasodilatory properties through a mechanism involving the l-arginine/nitric oxide (NO) pathway. 4,5 Of the 2 enantiomers forming the racemic mixture of dl-nebivolol, d-nebivolol, which has an ≈200-fold greater affinity for β 1 -adrenoceptors than that of l-nebivolol, seems to be mainly responsible of selective β-blockade, 6 whereas the l-form is the main effector of the endothelium-dependent vasorelaxant effect. 7,8 dl-Nebivolol exerts its vasodilatory action by activating endothelial nitric oxide synthase (eNOS) and by preventing eNOS uncoupling, thus enhancing NO production. 9 Endothelium-derived NO is a powerful inhibitor of platelet activation and an antithrombotic agent. 10,11 Besides endothelium, eNOS is present in other cells, including platelets, [12][13][14] and several in vitro and in vivo observations in animals and in humans suggest that platelet-derived NO plays a significant anti-inflammatory and antithrombotic role. [15][16][17][18][19] dl-Nebivolol was previously reported to inhibit ADP-and collagen-induced aggregation of human platelets in vitro, 20 an effect prevented by the previous exposure of platelets to a NOS inhibitor, such as L-NG-nitroarginine methyl ester, and enhanced by preincubation with l-arginine, the substrate of NOS, suggesting that the antiplatelet effect of dl-nebivolol is mediated by an enhanced release of NO from platelets. 4 © 2014 American Heart Association, Inc. Objective-dl-Nebivolol, a selective β1-adrenergic receptor antagonist, besides its hypotensive activity exerts vasodilatory and platelet inhibitory effects in vitro by a mechanism involving nitric oxide (NO). Our aim was to evaluate whether nebivolol exerts in vivo antithrombotic effects, to unravel the mechanism of this action and to clarify the relative roles of its 2 enantiomers: d-and l-nebivolol. Methods and Results-In wild-type mice, dl-nebivolol, l-nebivolol, and d-nebivolol, but not bisoprolol, reduced mortality consequent to platelet pulmonary thromboembolism induced by the intravenous injection of collagen plus epinephrine (−44%, −45%, −29%, respectively; P<0.05), whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were effective. dl-Nebivolol, l-and d-nebivolol reduced photochemical damage-induced femoral artery thrombosis in wild-type mice, whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were active. Moreover, dl-nebivolol and l-nebivolol increased plasma, urinary-, and platelet-derived nitrites and nitrates (NOx), NO degradation products, in ...

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Section: Discussionmentioning

confidence: 99%

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Momi

Caracchini

Falcinelli

et al. 2014

ATVB

Self Cite

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“…4 It could be argued that a partial limitation of this study may be the lack of identification of metabolites of nebivolol. Actually, some metabolites of nebivolol 6,35,36 and sera from mice 37 and humans 11 treated with nebivolol were already shown to have similar pattern of activity on NO availability in endothelial cells as compared with nebivolol itself.…”

Section: Effect Of Serum Derived From Hypertensive Patients Untreatedmentioning

confidence: 98%

Nebivolol Treatment Reduces Serum Levels of Asymmetric Dimethylarginine and Improves Endothelial Dysfunction in Essential Hypertensive Patients

Pasini¹,

Garbin²,

Stranieri³

et al. 2008

American Journal of Hypertension

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“…In addition, nebivolol also increases . NO release from the endothelium, thus attenuating oxidative stress effects on endothelium-dependent vasodilation [309,310]. The calcium channel blocker lacidipine has also been demonstrated…”

Section: Antihypertensive Treatments With Direct and Indirect Antioximentioning

confidence: 99%

“…In addition, other agents belonging to the beta-blocker or calcium channel blocker drug classes have also been shown to exert antioxidant effects unrelated to their blood pressure lowering action. The beta-blockers carvedilol and nebivolol appear to possess ROS scavenging properties as well as inhibitory effects on ROS production, such as the inhibition of Nox activation [308,309]. In addition, nebivolol also increases .…”

Section: Antihypertensive Treatments With Direct and Indirect Antioximentioning

confidence: 99%

Lipid Peroxidation and Antioxidants in Arterial Hypertension

Sousa¹,

Afonso²,

Albino‐Teixeira³

et al. 2012

Lipid Peroxidation

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Effect of dl-nebivolol, its enantiomers and metabolites on the intracellular production of superoxide and nitric oxide in human endothelial cells

Cited by 47 publications

References 33 publications

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Nebivolol Treatment Reduces Serum Levels of Asymmetric Dimethylarginine and Improves Endothelial Dysfunction in Essential Hypertensive Patients

Lipid Peroxidation and Antioxidants in Arterial Hypertension

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