Nebivolol and its 4-keto derivative increase nitric oxide in endothelial cells by reducing its oxidative inactivation

Cominacini, Luciano; Pasini, Anna Fratta; Garbin, Ulisse; Nava, Cristina; Davoli, A.; Criscuoli, Marco; Crea, Attilio; Sawamura, Tatsuya; Cascio, Vincenzo Lo

doi:10.1016/j.jacc.2003.06.011

Cited by 80 publications

(52 citation statements)

References 39 publications

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“…Moreover, reactive oxygen radicals were reduced in a model with hypercholesteremic rabbits by reducing O 2- [25,27] in the vessel wall. Nebivolol possesses several antioxidative characteristics, it directly interacts with reactive oxygen radicals [24,25]. In a rat model of angiotensin II-mediated hypertension it could be shown that nebivolol induced a dissociation of p67 (phox) and Rac1, and additionally an inhibition of NADPH oxidase activity in rat heart membranes.…”

Section: Discussionmentioning

confidence: 99%

Influence of Nebivolol and Metoprolol on Inflammatory Mediators in Human Coronary Endothelial or Smooth Muscle Cells. Effects on Neointima Formation After Balloon Denudation in Carotid Arteries of Rats Treated with Nebivolol

Wolf

Sauter

Preyer

et al. 2007

Cell Physiol Biochem

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Objective and Background: Inflammation plays a critical role in all stages of atherogenesis. Proliferating vascular smooth muscle cells (SMC) and endothelial cells (EC) enhancing the inflammatory response, both contribute to the progression of atherosclerosis. Anti-proliferative, anti-inflammatory and anti-oxidative therapy seems to be a promising therapeutic strategy. The aim of this study was to assess the anti-proliferative and anti-inflammatory effect of the β-blocker nebivolol in comparison to metoprolol in vitro and to find out whether nebivolol inhibits neointima formation in vivo. Methods and Results: Real-time-RT-PCR revealed a decrease in VCAM-1, ICAM-1, PDGF-B, E-selectin and P-selectin mRNA expression in human coronary artery EC and SMC incubated with nebivolol for 72 hours while metoprolol did not have this effect. Nebivolol reduced MCP-1 and PDGF-BB protein in the culture supernatant of SMC and EC, respectively. Sprague-Dawley rats were treated with nebivolol for 0 or 35 days before and 28 days after carotid balloon injury. Immunohistological analyses showed that pre-treatment with nebivolol was associated with a decreased number of SMC layers and macrophages and an increased lumen area at the site of the arterial injury. The intima area was reduced by 43% after pre-treatment. Conclusion: We found that nebivolol reduced the expression of proinflammatory genes in endothelial cells and vascular smooth muscle cells in vitro whereas metoprolol did not. In vivo, nebivolol inhibited neointima formation by reducing SMC proliferation and macrophage accumulation.

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Section: Discussionmentioning

confidence: 99%

Influence of Nebivolol and Metoprolol on Inflammatory Mediators in Human Coronary Endothelial or Smooth Muscle Cells. Effects on Neointima Formation After Balloon Denudation in Carotid Arteries of Rats Treated with Nebivolol

Wolf

Sauter

Preyer

et al. 2007

Cell Physiol Biochem

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“…In addition to salt sensitivity, the 4a/b polymorphism has been shown to determine the efficacy of nevibolol, a betablocker that in addition increases the production of NO. [44][45][46][47] Nebivolol is known to increase NO levels 46 possibly by inhibiting NO oxidation. 47 Nebivolol improved left ventricular hypertrophy and endothelial dysfunction in subjects carrying the b/b eNOS genotype, but failed to do so in those with the 4a/b genotype.…”

Section: Ethnicity and Enos Polymorphismsmentioning

confidence: 99%

“…[44][45][46][47] Nebivolol is known to increase NO levels 46 possibly by inhibiting NO oxidation. 47 Nebivolol improved left ventricular hypertrophy and endothelial dysfunction in subjects carrying the b/b eNOS genotype, but failed to do so in those with the 4a/b genotype. 45 The diminished production of NO reported in subjects with the 4a/b mutation may prevent the beneficial effects of nebivolol.…”

Section: Ethnicity and Enos Polymorphismsmentioning

confidence: 99%

Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

et al. 2004

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Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, Po0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; Po0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.

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“…Endothelial dysfunction in the brachial artery is related to the presence of endothelial dysfunction in the coronary arteries; while it is a predictor of cardiovascular events in patients with CAD. 13) Endothelial function measured by means of flow-mediated dilatation (FMD) of the brachial artery is also significantly impaired in patients with SCF.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Nebivolol on Flow-Mediated Dilation in Patients With Slow Coronary Flow

et al. 2009

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SummarySlow coronary flow (SCF) is the phenomenon of slow progression of angiographic contrast in the coronary arteries in the absence of stenosis in the epicardial vessels in some patients presenting with chest pain. There are no definite treatment modalities for patients with SCF. Our aim was to investigate the efficacy of nebivolol in patients with slow coronary flow by monitoring its effects on endothelial function and different markers of inflammation. Forty-two patients (16 females, 26 males; mean age, 55 ± 10) with slow coronary flow (SCF) were included in the study. After baseline assessment, the patients were administered nebivolol 5 mg once daily. After 12 weeks of nebivolol therapy, the biochemical and ultrasonographic examinations were repeated. Chest pain relief was detected in 38 patients after treatment (90%). Systolic and diastolic blood pressure and high sensitive CRP were significantly decreased after nebivolol therapy. Among brachial artery dilation variables that reflect endothelial function, basal resistive index (RI), post-flow mediated dilation RI, and post-nitrate mediated dilation RI were significantly decreased after therapy. Nebivolol is effective at improving endothelial function in patients with SCF. It controls chest pain, decreases CRP, and has favorable effects on brachial artery dilation variables in patients with coronary slow flow. (Int Heart J 2009; 50: 545-553)

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Nebivolol and its 4-keto derivative increase nitric oxide in endothelial cells by reducing its oxidative inactivation

Abstract: In conclusion, the findings of the present study indicate that nebivolol increases NO also by decreasing its oxidative inactivation.

Cited by 80 publications

References 39 publications

Influence of Nebivolol and Metoprolol on Inflammatory Mediators in Human Coronary Endothelial or Smooth Muscle Cells. Effects on Neointima Formation After Balloon Denudation in Carotid Arteries of Rats Treated with Nebivolol

Influence of Nebivolol and Metoprolol on Inflammatory Mediators in Human Coronary Endothelial or Smooth Muscle Cells. Effects on Neointima Formation After Balloon Denudation in Carotid Arteries of Rats Treated with Nebivolol

Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

Efficacy of Nebivolol on Flow-Mediated Dilation in Patients With Slow Coronary Flow

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