Mechanisms Underlying Nebivolol‐induced Endothelial Nitric Oxide Synthase Activation in Human Umbilical Vein Endothelial Cells

Ladage, Dennis; Brixius, Klara; Hoyer, Heike; Steingen, Caroline; Wesseling, Andreas; Malan, Daniela; Bloch, Wilhelm; Schwinger, Robert H. G.

doi:10.1111/j.1440-1681.2006.04424.x

Cited by 47 publications

(45 citation statements)

References 22 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

View full text Add to dashboard Cite

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“…It is conceivable that NO bioavailability determines endothelial cell cytoskeleton and elastic properties, as NO may depolymerize actin [20]. On the other hand, increased endothelial cell elasticity may be associated with translocation of eNOS to the cell membrane and hence increase eNOS activity [28]. There is further evidence that endothelial cell elastic properties and NO production are related to each other.…”

Section: Aldosteronementioning

confidence: 86%

“…Thus, reduced stiffness means increased NO production, i.e., improved endothelial function. Indeed, recent studies suggest that functional endothelial cell changes by estradiol receptor activation are associated with translocation of the eNOS and altered expression of the endogenous eNOS inhibitor caveolin [28]. A spherical endothelial cell adapts more easily to changes in vessel wall diameter, i.e., stretches more easily with dilatation of the vessel or increased shear stress.…”

Section: Aldosteronementioning

confidence: 99%

How steroid hormones act on the endothelium—insights by atomic force microscopy

Hillebrand

Hausberg

Lang

et al. 2008

Pflugers Arch - Eur J Physiol

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Vascular actions of steroid hormones have gained increasing importance. Indeed, some steroid hormones favorably influence vascular structure and function, whereas others are detrimental. This review will focus on the endothelial effects of steroid hormones. In the first part, we summarize data from in vivo studies elucidating the regulation of endothelial function by steroid hormones. Accumulating data argue for an improvement of endothelium-derived relaxation and impaired vascular contraction by estradiol, whereas testosterone, progesterone, and aldosterone have contrary effects. In the second part, we present data from novel atomic force microscopy studies performed in living endothelial cells under the influence of steroid hormones. These studies provide insight into structural and functional alterations of endothelial cells characterized by changes in volume, apical surface, and stiffness. We summarize the available evidence that changes in shape of endothelial cells translate into changes of endothelial cell stiffness. Under the influence of estradiol, endothelial cells become spherical with consecutive improvement of elasticity, whereas aldosterone flattens endothelial cell-shape leading to increased stiffness. Both, endothelial cell shape and stiffness are major determinants of endothelial nitric oxide production. These studies emphasize the great potential of atomic force microscopy to investigate the function of living endothelial cells.Keywords Aldosterone . Glucocorticoids . Sex hormones . Atomic force microscopy . Endothelium . Imaging . Nitric oxideResearch over the last two decades has been clearly demonstrating that the vascular endothelium is a target for steroid hormones, e.g., sex hormones, glucocorticoids, and mineralocorticoids [25,35]. Indeed, specific receptors for these steroid hormones have been identified in endothelial cells. Numerous clinical studies demonstrate that the various steroid hormones affect vascular function in different ways. Sex hormonesVascular endothelial cells and vascular smooth muscle cells express receptors for estradiol, progesterone, and testosterone [54,55,66]. The sex hormones bind to specific cytosolic receptors. The resulting complexes are transported into the nucleus and initiate gene transcription (so-called genomic effects). Moreover, sex hormones cause a number of rapid non-genomic effects on vascular endothelial and smooth muscle cells.Several studies report gender differences in vascular function. Vascular contraction was found to be greater in male and ovarectomized female rats than in castrated male and female rats, suggesting an effect of testosterone in favor of vascular contraction and an effect of estradiol in favor of preventing vascular contraction [24]. Specifically, estradiol has been shown to cause endothelium-mediated vasorelaxation, whereas testosterone and progesterone interfere with estradiol-mediated endothelium-dependent vasodilation [25].There is a body of evidence suggesting that sex hormones interfere with the synthesis and b...

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“…Ladage i wsp. udowodnili, że stymulowanie wydzielania NO przez nebiwolol odbywa się poprzez wpływ na receptory b, aktywację syntazy NO oraz -w mniejszym stopniu -wskutek stymulacji receptorów estrogenowych [27]. W pracy Maffei i wsp.…”

Section: Mechanizm Antyoksydacyjnego Działania Nebiwololuunclassified

Protective effect of nebivolol to prevent target organ damage in hypertension

Widecka

2018

Arterial Hypertension

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StreszczeniePowikłania sercowo-naczyniowe (przerost lewej komory, migotanie przedsionków, niewydolność serca, incydenty wieńcowe, starzenie się naczyń i przyspieszona miażdżyca) są główną przyczyną zgonów u chorych z nadciśnieniem tętniczym. Stres oksydacyjny i aortalne ciśnienie centralne odgrywają kluczową rolę w patofizjologii systemu sercowo-naczyniowego oraz powikłań sercowo-naczyniowych. Leki przeciwnadciśnieniowe, nawet w obrębie tej samej klasy, wywierają różny wpływ na wskaźniki sztywności tętnic i funkcję śródbłonka. Nebiwolol jest b-adrenolitykiem trzeciej generacji o działaniu wazodylatacyjnym. W jego funkcji rozszerzającej naczynia pośredniczy szlak śródbłonkowej L-argininy/ /tlenku azotu (NO). Nebiwolol zwiększa biodostępność tlenku azotu. W ostatnich badaniach wykazano, że nebiwolol poprawia elastyczność naczyń w stopniu większym niż konwencjonalne b-adrenolityki (atenolol, metoprolol). Według wytycznych ESH/ESC 2013 niektóre b-adrenolityki o działaniu rozszerzającym naczynia, takie jak celiprolol, karwedilol i nebiwolol, zmniejszają ciśnienie centralne tętna i sztywność tętnic lepiej niż atenolol i metoprolol. Słowa kluczowe: nebiwolol, nadciśnienie, uszkodzenia narządowe, ciśnienie centralne Arterial Hypertens. 2018, vol. 22, no. 1, pages: 1-8 Abstract Clinical organ damage in the cardiovascular (left ventricular hypertrophy, atrial fibrillation, heart failure, coronary events, increased stiffness and atherosclerotic changes) are the major cause of death among patients with hypertension. Oxidative stress and aortic central pressure plays a key role in the pathophysiology of the cardiovascular system and cardiovascular outcome. Antihypertensive agents may, even within the same class, exert variable effects on arterial stiffness variables and endothelial function. Nebivolol is a third-generation b-blocker with vasodilator activity. Its vasodilatory function is mediated by the endothelial L-arginine/NO pathway. Nebivolol increases the bioavailability of NO in the vasculare. In recent studies, nebivolol was demonstrated to improve artery stiffness to a greater extent than impact than conventional b-adrenolitics (atenolol, metoprolol). According to guidelines ESH/ESC some of the vasodilatating b-adrenolitics, such as celiprolol, carvedilol and nebivolol, are reducing central pulse pressure and aortic stiffness better than atenolol or metoprolol.

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Mechanisms Underlying Nebivolol‐induced Endothelial Nitric Oxide Synthase Activation in Human Umbilical Vein Endothelial Cells

Cited by 47 publications

References 22 publications

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

How steroid hormones act on the endothelium—insights by atomic force microscopy

Protective effect of nebivolol to prevent target organ damage in hypertension

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