Nebivolol Therapy Research Articles

The evolution of endothelial dysfunction according to the length of the implanted stent on the background of nebivolol therapy

Abstract Introduction The development of atherosclerosis is the driving cause for arterial interventions using coronary stents. Long-stent implantation can increase the vascular injury thereby contributing to the progression of endothelial dysfunction (ED) by the degradation and reduction bioavailability of the nitric oxide (NO) - thus increasing the risk of major cardiovascular events. Purpose Evaluation the evolution of endothelial dysfunction biomarker depending on the length of the stent implanted on the background of nebivolol therapy. Methods The study included 100 patients with stable angina pectoris II–III functional class (age 59.72±0.59 years) undergoing PCI with stent implantation who started the treatment with nebivolol 5mg per day tangent to the conventional treatment and were exposed to PCI with stent implantation, depending on the stent’s length they were divided in three groups: I group - 14 patients with implanted stent’s length ≤15 mm, II group - 57 subjects with implanted stent’s length =15-30 mm and the III group -29 cases where the implanted stent’s length was ≥30 mm. In all the groups was appreciated in blood the endothelial dysfunction’s marker - NO. This marker was assessed preprocedural, postprocedural (after 24 hours) and at intervals of one month, 3,6,12 months after coronary angioplasty, the NO level being compared between these groups and the reference pattern consisting of 20 healthy people. Results The circulating level of nitric oxide determined in I group -61,28±6,92 μM/L and in the II group -56.6±3.03 μM/L and the III group52.39±3.35 was compromised at the preprocedural stage versus the reference pattern - 78.67±2.72 μM/L. During the post- PCI period (first 24 hours), the biomarker level’s was reduced in I group -52.35±1.66 μM/ L, II group -53.74±2.77 μM/L and III group - 52.98±2.91 μM/L. After one month after the intervention on the backroung of the treatment with nebivolol, was recorded a gaing of the NO value in I group - 64.97±5.35 μM/L, II group -63.15±3.99 μM /L and the III group-59.38±4.46 μM/L. The NO serum concentration during the period 3 and 6 months continued to increase in all groups vs the reference pattern. At the 12-month period, the NO level remained high in all the studied groups versus the baseline: I group 99.2±1.1 μM / L (p>0.05), II group-97.96±2.2 μM/L (p<0.001) and the III group -97.65±1.9 μM/L (p<0.001). Conclusion The stent’s length = 15-30 mm and ≥30 mm reveals the presence of an expanded atherosclerotic process, the substrate of which is constituted by the endothelial dysfunction, this being confirmed by the low preprocedural level of NO. The stent implantation procedure induced the accentuation of endothelial dysfunction, and the 12-month nebivolol treatment favored the increase of NO serum concentraon in all groups by 24.9% vs the reference pattern and by 73.3% vs baseline.

Effects of Nebivolol therapy on hemodynamic parameters and lipid profile compared to other beta blockers in patients with essential hypertension: a systematic review and meta-analysis.

Besides being commonly used to treat high blood pressure, beta blockers are a family of drugs that are primarily used to regulate irregular cardiac rhythms. Nebivolol is a third generation of beta blockers, which is highly cardioselective, about three times as selective as bisoprolol. In this study, we aimed to evaluate Nebivolol's effectiveness and safety in comparison to other beta blockers. We searched the online databases PubMed, ScienceDirect, and Cochrane Library for relevant RCTs evaluating Nebivolol's effect on hypertension management. Relative risk (WRR) and weighted mean difference (WMD), with a 95% confidence interval (CI) were utilized to quantify the impact of nebivolol medication in the treatment of hypertension using a random effects model. Twelve RCTs are included in the study, the patient numbers in every attempt ranged from 42-273 and 1456 patients in all were included in this review. Nebivolol does not significantly reduce SBP, DBP and HR compared to other beta blockers (WMD -0.57 mmHg, 95% CI [-1.55; 0.42 mmHg] p=0.12; WMD -0.27 mmHg, 95% CI [-1.36; 0.82 mmHg] p=0.63 ; WMD 0.10 BPM, 95% CI [-4.11;1.31 BPM] p=0.96, respectively). Patients treated with Nebivolol has significantly lower LDL-C (WMD -8.88 mg/dL, 95% CI [-15.28; -2.48 mg/dL] p=0.007) and significantly higher HDL-C (WMD 2.30 mg/dL, 95% CI [0.75; 3.84 mg/dL] p=0.004. According to this study's findings, nebivolol is well tolerated and decreases LDL-C. And higher HDL-C than other beta blocker agents. This review does not recommend nebivolol as first-line treatment in hypertension as Nebivolol does not significantly reduce blood pressure and HR of patients.

Influence of bisoprolol and nebivolol on the regulatory-adaptive status of patients with diastolic chronic heart failure

Background. Chronic heart failure (CHF) is the most common outcome of cardiovascular disease, of hypertension disease (HD). Beta-blockers contribute to the correction of hypertension, reduce heart remodeling, slow the progression of CHF. At the same time, bisoprolol and nebivolol differing pharmacochemical properties can have a multidirectional effect on the regulatory-adaptive status (RAS).
 Aim. To determine the effect of bisoprolol or nebivolol therapy on the RAS of patients with diastolic CHF on the background of HD III stage.
 Material and methods. The study involved 68 patients with diastolic CHF who were randomized into two groups for treatment with bisoprolol or nebivolol. As part of the combination therapy, patients were administered quinapril was prescribed (13.52.5 mg/day, n=34 and 12.82.8 mg/day, n=34), and if indicated, acetylsalicylic acid, atorvastatin. Initially and after 24 weeks of therapy were carried out: quantitative assessment of RAS, echocardiography, treadmill test, six-minute walking test, subjective assessment of quality of life, determination of the level of N-terminal propeptide of brain natriuretic hormone in blood plasma, daily monitoring of blood pressure.
 Results. Both schemes of combined therapy comparably improved the structural and functional state of the heart, controlled arterial hypertension. In comparison with bisoprolol, nebivolol differed positive impact on RAS, more increased tolerance to physical activity and improved quality of life.
 Conclusion. In patients with diastolic CHF and HD III stage, the use of nebivolol in combination therapy may be preferable due to the positive effect on RAS, in comparison with bisoprolol.

The influence of nebivolol plus ramipril vs nebivolol combined with amlodipine and ramipril on oxidative stress in patients undegroing coronary angioplasty

Background and Aims: Evaluate the efficacy of nebivolol therapy on the level of the biomarkers of the oxidative stress - superoxidedismutase (SOD) and malondialdehyde (MDA) in patients exposed to angioplasty (PCI).

Effects of nebivolol combined with ramipril vs nebivolol associated amlodipine and ramipril on biomarker of endothelial dysfunction in pacients with angina pectoris and essential hypertension

Aim: Evaluate the efficacy of nebivolol therapy associated with ramipril vs nebivolol combined with amlodipine and ramipril in patients with APS and EH undergoing PCI.

A comparative study of effects of nebivolol and atenolol on blood pressure and lipid profile in patients of mild to moderate hypertension

Background: Beta blockers have been used in the treatment of hypertension, since last four decades and are widely accepted as the first-line treatment for hypertension. Nebivolol, a third generation β-blocker has highest β1 selectivity and is devoid of intrinsic sympathomimetic activity. Along with peripheral vasodilatation and nitric oxide (NO)-induced benefits such as antioxidant activity and reversal of endothelial dysfunction, nebivolol promotes better protection from cardiovascular events. The objective of the study was to compare the effects of atenolol and nebivolol on both blood pressure and lipid profile in patients of mild to moderate hypertension.Methods: This was a prospective, randomized, parallel, open labelled study. Patients were recruited from the medicine out-patient department (OPD) and cardiology OPD. A total of 100 patients were enrolled in the study. 50 patients were allocated to atenolol group and 50 patients to nebivolol group. BP and baseline investigations such as lipid profile were performed. Tests to determine lipid profile were performed on the first visit (Week 0) and at 24 weeks. Continuous variables between the two treatment groups were analyzed by unpaired t-test. Efficacy endpoints within the group were analyzed by using paired t-test.Results: All the lipid levels except HDL-C were increased with atenolol therapy. At 24 weeks, atenolol therapy led to increase in LDL-C, VLDL-C, TC and TG which was highly significant (p<0.0001). HDL levels were decreased at 24 weeks which was also statistically highly significant (p<0.0001). The mean values of lipids in nebivolol group at baseline and at 24 weeks. At 24 weeks, nebivolol therapy led to changes in LDL-C, VLDL-C, HDL-C, TC and TG which was not statistically significant (p>0.05).Conclusions: From study it can be concluded that atenolol and nebivolol are equally effective in reducing BP but atenolol worsens lipid profile as compared to nebivolol.

Nebivolol and Endothelial Dysfunction in Patients With Essential Hypertension: A Reputation Saver of β‐Blockers?

We have read with great interest the recently published article by Neuman and coworkers1 in which they hypothesized that nebivolol, a selective β1-antagonist that stimulates nitric oxide (NO), improves endothelial function in African Americans with hypertension when compared with metoprolol. In that well-designed study, the authors found evidence for NO bioavailability at rest during treatment with both nebivolol and metoprolol succinate in hypertensive African American patients, with a clear trend for a greater contribution of NO during nebivolol therapy. Moreover, after combined blockade of NO and endothelium-derived hyperpolarizing factor (EDHF), there was significantly greater vasoconstriction during nebivolol compared with metoprolol therapy, suggesting a greater contribution of both NO and EDHF combined to resting vasomotor tone during nebivolol treatment. Moreover, the contribution of NO to exercise-induced vasodilation was greater during treatment with nebivolol compared with metoprolol succinate. Nebivolol is a third-generation, β1-adrenergic receptor antagonist that has vasodilatory properties both in animals and humans independent of β1-receptor antagonism and related to β3-receptor agonist effects.2-5 It is a racemic mixture of D- and L-enantiomers, of which D-nebivolol is considered to be a highly selective β-adrenergic receptor antagonist.5-8 It was demonstrated that nebivolol stimulates NO release through both β3-receptor and adenosine triphosphate–dependent, P2Y-receptor activation.3, 9-12 In a well-designed clinical study, Tzemos and coworkers13 analyzed whether nebivolol could improve endothelial dysfunction in patients with essential hypertension. They showed that nebivolol/bendrofluazide increased both stimulated and basal endothelial NO release, whereas, for the same degree of blood pressure control, atenolol/bendrofluazide had no effect on NO bioactivity; therefore, they concluded that nebivolol may offer additional vascular protection in treating hypertension.13 Moreover, Oelze and coworkers14 demonstrated that nebivolol but not metoprolol improved endothelial function and reduced vascular oxidative stress in an experimental model of AngII-induced hypertension. These effects were associated with a normalization of the expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits Nox1, Nox2, p22phox, p47phox, p67phox, and Rac1 and an inhibition of NOS III uncoupling in a rat hypertension model. More importantly, they found that nebivolol but not metoprolol inhibited activation of vascular NADPH oxidase and were able to dissociate an already assembled and active membrane-associated NADPH oxidase complex. These observations indicate that nebivolol, in addition to its β1-receptor–blocking and NO-releasing effects, possesses substantial inhibitory effects on vascular oxidative stress, all of which may beneficially influence endothelial dysfunction because of oxidative stress in the setting of arterial hypertension.14 It is well-known that essential hypertension is associated with endothelial dysfunction, and with greater oxidative stress producing free oxygen radicals that contribute to the decrease in NO bioavailibility. Elevated plasma levels of malondialdehyde, a final product of lipid peroxidation and an index of oxidative stress, have been demonstrated in patients with essential hypertension.15, 16 Concordantly, our study group previously found that nebivolol, differently from metoprolol, improved oxidative stress and insulin sensitivity, decreased plasma sP-selectin, and increased adiponectin levels in hypertensive patients.17 From that standpoint, we concluded that nebivolol may significantly improve endothelial dysfunction in hypertensive patients. However, our study population had no African American patients, unlike the patient population from the study by Neumann and coworkers. In conclusion, nebivolol has beneficial effects on endothelial function mainly by increasing NO bioavailability. We strongly believe that although standard β-blockers are falling out of favor nowadays, perhaps the new generation of β-blockers such as nebivolol may “rescue” the reputation of these agents in the near future. There are no conflicts of interest to declare.

Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction.

BackgroundMore than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties.ObjectivesTo evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF.MethodsTwenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months.ResultsAfter treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters.ConclusionDespite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity.

THE EFFECT OF NEBIVOLOL ON BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN WITH MILD HYPERTENSION

Aim. To study the effects of nebivolol on bone mineral density (BMD) in postmenopausal women with mild hypertension (HT) and osteopenia. Material and methods. Postmenopausal women (n=56) aged 50-65 years with mild HT фтв osteopenia were included into the randomized controlled study and divided in two groups (28 patients in each). During 12 months patients of the main group received treatment with nebivolol (5-7.5 mg/day) and patients of the control group received treatment with atenolol (12.5-25 mg/day). Clinical and anthropometric examinations, blood pressure measurements, ECG registrations were performed in all patients initially and after 12 months of treatment. Quantitative estimation of BMD was performed by dual energy X-ray absorptiometry with osteodensitometry DELPHI W manufactured by HOLOGIC company (USA) in the lumbar spine (L1-L4), femoral neck and proximal femur in the anterior-posterior projection. In addition, calcium and bone metabolism indices were determined: ionized calcium, total alkaline phosphatase, C-telopeptide of type I collagen (CTX). Results. Therapy of mild HT with nebivolol during 12 months showed increase in BMD in the spine according to the T-test from -1.7±0.4 SD to -1.4±0.53 SD (p<0.001), while in atenolol group this index decreased from -1.5±0.7 SD to -1.6±0.64 SD (p<0.001). When evaluating T-test of the femoral neck the index changed in the main group from - 1.4±0.44 SD to -1.27±0.5 SD (p=0.015), in the control group - from -1.3±0.64 SD to -1.5±0.65 SD (p=0.0005). In the study group T-test of proximal femur changed from -0.58±0.4 SD to -0.49±0.4 SD (p=0.003), and in the control group - from -0.8±0.84 SD to -0.83±0.93 SD (p=0.3). The dynamics of the BMD due to 12 month therapy in all investigated bone segments distinguished significantly between study and control groups. Nebivolol therapy group showed reduction in CTX level from 0.367±0.16 to 0.294±0.12 ng/ml (p<0.001), whereas the control group showed increase in this parameter from 0.369±0.15 to 0.499±0.18 ng/ml (p<0.001). The dynamics of the CTX levels distinguished significantly between groups (p<0.001). Conclusion. The study demonstrated the positive effect of nebivolol on BMD, whereas atenolol had no effect on bone mass.

Digital plethysmography and arginine metabolism in prehypertension: effect of nebivolol therapy.

Prehypertension is an important phenotype for cardiovascular risk and development of established hypertension. To better understand the early circulatory changes in this group, the authors studied 34 patients with prehypertension (blood pressure 120-139/80-89 mm Hg) using digital plethysmography for measurement of blood flow and reactive hyperemic index (RHI). Arterial augmentation index (AI) was also measured. Because prehypertension is associated with endothelial dysfunction and decreased availability of nitric oxide (NO), indices of arginine metabolism (l-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, and l-citrulline) were measured. Nebivolol (5 mg/d), a vasodilating β1 -antagonist with β3 -agonist activity, was studied in a double-blind fashion for 8 weeks. Nebivolol increases the bioavailability of NO. Prehypertension was associated with normal RHI and baseline digital blood flow. AI was abnormal and associated with diastolic blood pressure. ADMA concentration was increased at baseline. After 8 weeks of nebivolol therapy, RHI, ADMA, symmetric dimethylarginine, and AI showed no significant change, but digital blood flow and l-citrulline levels were significantly increased. Prehypertension is associated with increased ADMA and evidence of increased arterial stiffness and preserved RHI. Nebivolol therapy is associated with digital vasodilation and increased NO production, as depicted by increased levels of l-citruline and mean digital blood flow.

Long-term safety of nebivolol and valsartan combination therapy in patients with hypertension: an open-label, single-arm, multicenter study

Long-term safety of nebivolol and valsartan combination therapy in patients with hypertension: an open-label, single-arm, multicenter study

Both Carvedilol and Nebivolol May Improve Platelet Function and Prothrombotic State in Patients With Nonischemic Heart Failure

It is unclear whether carvedilol and nebivolol will produce different effects on platelet function and prothrombotic state in heart failure (HF). Thus, we compared their effects on these functions in patients with nonischemic HF. We included 61 patients with symptomatic nonischemic HF having ejection fraction ≤40%. The patients were randomized to carvedilol (n = 31) or nebivolol (n = 30). Analyses were made at baseline, 3, and 6 months. At 6 months, mean platelet volume (MPV) was significantly lowered by both carvedilol and nebivolol therapy. However, MPV tended to be lower in the carvedilol group (7.7 ± 1.0 vs 8.0 ± 0.7 fL, P = .05). Fibrinogen and d-dimer levels were significantly decreased in but comparable in both the groups. Carvedilol and nebivolol have similar beneficial effects on platelet function and prothrombotic state in patients with nonischemic HF.

Topical effects of nebivolol on wounds in diabetic rats

ObjectiveRecently, it has reported that nebivolol might be useful in the treatment of diabetes mellitus foot ulcers. The aim of this study was to examine treatment of the wounds in streptozotocin-induced diabetic rats with topical nebivolol. MethodsTwo 15×15mm-sized wounds were created in 56 streptozotocin-induced rats. A total of 56 diabetic wounds were studied in eight groups (n=7). No treatment was administered to the first and second groups. The third and fourth groups consisted of diabetic rats that were administered 1:1 mixture of lanolin and vaseline for 7 and 14days, respectively. Five percent nebivolol plus 1:1 mixture of lanolin and vaseline was administered to rats in the fifth and sixth groups for 7 and 14days, respectively, and 10% nebivolol plus 1:1 mixture of lanolin and vaseline was administered to rats in the seventh and eighth groups for 7 and 14days, respectively. On days 7 and 14, wound healing was observed, and the percent of wound healing was determined by measuring its size and histopathologic examination. The ratio was calculated by the formula, healing ratio (%)=100×(1−wound area/initial wound area). Statistical analysis was performed by ANOVA with Tukey’s HSD test and Mann–Whitney U test, using SPSS 15.0 software. ResultsOn days 7 and 14, rates of wound healing in the fifth, sixth, seventh, and eighth groups were 57.42%, 89.16%, 60.80%, and 91.80%, respectively. Multiple comparison showed that rates of wound healing were significantly higher in rats administered 5% and 10% nebivolol than those in rats administered a mixture of lanolin and vaseline and in the untreated group (P<0.05). ConclusionTopical nebivolol therapy may be useful for wound healing in diabetic rats. Further studies are needed to support these data.

Differential approach in selecting beta-adrenoblocker therapy for patients with chronic heart failure and anaemia

Currently, beta-adrenoblockers (β-AB) are regarded as one of the major medication classes in the treatment of patients with chronic heart failure (CHF). In several international studies, β -AB therapy of CHF patients was associated with reduced levels of haemoglobin (Hb) and development of new anaemia cases. Anaemia is known as an adverse prognostic factor in CHF. Aim. To study the effects of β -AB therapy on the anaemia clinical course among CHF patients. Material and methods. The study included 90 ambulatory patients with Functional Class (FC) II-IV CHF and anaemia. The participants were divided into 3 equally sized groups (n=30 per group) and treated with carvedilol, metoprolol, or nebivolol for 6 months. Results. By the end of the follow-up, baseline Hb levels increased in the nebivolol group (p=0,028), and were also significantly higher than in the other two groups. In the carvedilol group, the levels of haematocrit (Ht) and glomerular filtration rate (GFR) significantly decreased (p=0,017 and 0,06, respectively). In the metoprolol group, no substantial changes of laboratory parameters were observed. The maximal reduction in baseline CHF FC was registered in the patients receiving nebivolol (p=0,037). A significant improvement in myocardial contractility, based on the echocardiography data, was registered in the carvedilol and nebivolol groups. Conclusion. Nebivolol therapy was associated with a significantly more pronounced reduction in pro-BNP levels, compared to carvedilol or metoprolol treatment (p&lt;0,001). The nebivolol group also demonstrated the most pronounced improvement in quality of life of CHF patients (p&lt;0,001). These findings suggest that nebivolol could be recommended as a medication of choice in patients with CHF and anaemia.

Lowering blood pressure with β-blockers in peripheral artery disease: the importance of comorbidity

Lowering blood pressure with β-blockers in peripheral artery disease: the importance of comorbidity

Nebivolol Exerts Beneficial Effects on Endothelial Function, Early Endothelial Progenitor Cells, Myocardial Neovascularization, and Left Ventricular Dysfunction Early After Myocardial Infarction Beyond Conventional β1-Blockade

The aim of this study was to investigate whether nebivolol has added effects on left ventricular (LV) dysfunction and remodeling early after myocardial infarction (MI) beyond its β₁-receptor-blocking properties. Nebivolol is a third-generation selective β₁-adrenoreceptor antagonist that stimulates endothelial cell nitric oxide (NO) production and prevents vascular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Both endothelial NO synthase-derived NO production and NADPH oxidase activation are critical modulators of LV dysfunction early after MI. Mice with extensive anterior MI (n = 90) were randomized to treatment with nebivolol (10 mg/kg/day), metoprolol-succinate (20 mg/kg/day), or placebo for 30 days starting on day 1 after surgery. Infarct size was similar among the groups. Both β₁-adrenergic receptor antagonists caused a similar decrease in heart rate. Nebivolol therapy improved endothelium-dependent vasorelaxation and increased early endothelial progenitor cells 4 weeks after MI compared with metoprolol and placebo. Nebivolol, but not metoprolol, inhibited cardiac NADPH oxidase activation after MI, as detected by electron spin resonance spectroscopy analysis. Importantly, nebivolol, but not metoprolol, improved LV dysfunction 4 weeks after MI (LV ejection fraction: nebivolol vs. metoprolol vs. placebo: 32 ± 4% vs. 17 ± 6% vs. 19 ± 4%; nebivolol vs. metoprolol: p < 0.05) and was associated with improved survival 4 weeks post-MI compared with placebo. Nebivolol had a significantly more pronounced inhibitory effect on cardiomyocyte hypertrophy after MI compared with metoprolol. Nebivolol improves LV dysfunction and survival early after MI likely beyond the effects provided by conventional β₁-receptor blockade. Nebivolol induced effects on NO-mediated endothelial function, early endothelial progenitor cells and inhibition of myocardial NADPH oxidase likely contribute to these beneficial effects of nebivolol early after MI.

Effects of nebivolol therapy on endothelial functions in cardiac syndrome X

Endothelial dysfunction is major pathophysiologic mechanism in cardiac syndrome X (CSX), which causes a decrease in plasma nitrite oxide (NO) levels. It was demonstrated that nebivolol improves endothelial function and increases NO release. Despite this pathophysiologic relation, the effect of nebivolol therapy on endothelial function in patients with CSX is unknown. The aim of this study is to evaluate the effect of nebivolol on patients in CSX. Thirty-eight patients who were diagnosed with CSX were prospectively enrolled in the study. The treatment group consisted of 20 patients and the control group consisted of 18 patients. An oral 5-mg dose of nebivolol was given daily and maintained for 4 weeks in the treatment group. Ultrasonographic parameters (brachial artery flow-mediated dilatation [FMD], brachial artery lumen diameters) and inflammatory markers (high-sensitivity C-reactive protein [hsCRP], von Willebrand factor [vWf], and fibrinogen) were measured at baseline and end of the 4 weeks. Brachial baseline lumen diameter, brachial lumen diameter after reactive hyperemia, and FMD were 4.61 +/- 0.49 mm, 4.87 +/- 0.53 mm, and 5.6% +/- 2.3% at baseline. After the nebivolol therapy, there was a significant increase in both brachial artery baseline lumen diameter and lumen diameter after reactive hyperemia (P < 0.001 and P = 0.002). However, there was no significant change in FMD (5.6% +/- 2.2% vs 5.3% +/- 2.1%, P not significant). Levels of hsCRP, vWf, and fibrinogen were significantly decreased (hsCRP: 3.4 +/- 0.49 mg/dl vs 2.97 +/- 0.74 mg/dl, P = 0.001; vWf: 107 +/- 62 vs 86 +/- 58, P = 0.004; fibrinogen: 341 +/- 89 mg/dl vs 299 +/- 87 mg/ dl, P = 0.01) in the treatment group. Nebivolol therapy may have a favorable effect on endothelial function in CSX. Further studies are needed to confirm the clinical significance of nebivolol therapy in CSX.

Nebivolol Attenuates Maladaptive Proximal Tubule Remodeling in Transgenic Rats

Background/Aims: The impact of nebivolol therapy on the renal proximal tubular cell (PTC) structure and function was investigated in a transgenic (TG) rodent model of hypertension and the cardiometabolic syndrome. The TG Ren2 rat develops nephropathy with proteinuria, increased renal angiotensin II levels and oxidative stress, and PTC remodeling. Nebivolol, a β₁-antagonist, has recently been shown to reduce albuminuria, in part, through reductions in renal oxidative stress. Accordingly, we hypothesized that nebivolol therapy would attenuate PTC damage and tubulointerstitial fibrosis. Methods: Young Ren2 (R2-N) and SD (SD-N) rats were treated with nebivolol (10 mg/kg/day) or vehicle (R2-C; SD-C) for 3 weeks. PTC structure and function were tested using transmission electron microscopy and functional measurements. Results: Nebivolol treatment decreased urinary N-acetyl-β-D-glucosaminidase, tubulointerstitial ultrastructural remodeling and fibrosis, NADPH oxidase activity, 3-nitrotyrosine levels, and increased megalin and lysosomal-associated membrane protein-2 immunostaining in PTCs. Ultrastructural abnormalities that were improved with therapy included altered canalicular structure, reduced endosomes/lysosomes and PTC vacuoles, basement membrane thickening, and mitochondrial remodeling/fragmentation. Conclusion: These observations support the notion that nebivolol may improve PTC reabsorption of albumin and other glomerular filtered small molecular weight proteins in association with the attenuation of oxidative stress, tubulointerstitial injury and fibrosis in this rat model of metabolic kidney disease.

Nebivolol

Nebivolol is a third-generation beta-adrenergic receptor antagonist (beta-blocker) with high selectivity for beta(1)-adrenergic receptors. In addition, it causes vasodilatation via interaction with the endothelial L-arginine/nitric oxide (NO) pathway. This dual mechanism of action underlies many of the haemodynamic properties of nebivolol, which include reductions in heart rate and blood pressure (BP), and improvements in systolic and diastolic function. With respect to BP lowering, the NO-mediated effects cause a reduction in peripheral vascular resistance and an increase in stroke volume with preservation of cardiac output. Flow-mediated dilatation and coronary flow reserve are also increased during nebivolol administration. Other haemodynamic effects include beneficial effects on pulmonary artery pressure, pulmonary wedge pressure, exercise capacity and left ventricular ejection fraction. In addition, nebivolol does not appear to have adverse effects on lipid metabolism and insulin sensitivity like traditional beta-blockers. The documented beneficial haemodynamic effects of nebivolol are translated into improved clinical outcomes in patients with hypertension or heart failure. In patients with hypertension, the incidence of bradycardia with nebivolol is often lower than that with other currently available beta-blockers. This, along with peripheral vasodilatation and NO-induced benefits such as antioxidant activity and reversal of endothelial dysfunction, should facilitate better protection from cardiovascular events. In addition, nebivolol has shown an improved tolerability profile, particularly with respect to events commonly associated with beta-blockers, such as fatigue and sexual dysfunction. Data from SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure) showed that significantly fewer nebivolol versus placebo recipients experienced the primary endpoint of all-cause mortality or cardiovascular hospitalization. The benefits of nebivolol therapy were shown to be cost effective. Thus, nebivolol is an effective and well tolerated agent with benefits over and above those of traditional beta-blockade because of its effects on NO release, which give it unique haemodynamic effects, cardioprotective activity and a good tolerability profile.

HEMODYNAMIC AND METABOLIC EFFECTS OF NEBIVOLOL IN LOCOMOTIVE CREW STAFF WITH NEWLY DIAGNOSED ARTERIAL HYPERTENSION

Aim. To evaluate influence of long-term monotherapy with nebivolol on blood pressure (BP) (office BP; self-monitoring BP, pre-trip BP monitoring, ambulatory BP monitoring (ABPM)) and metabolic blood profile in locomotive crew staff with newly diagnosed arterial hypertension (HT). Material and methods. Locomotive crew engineers and their assistants (n=50; age 20-55 y.o.) with newly diagnosed HT 1-2 degree with moderate-to-high cardiovascular risk were included into the open prospective uncontrolled study. The study duration was 12 months. The office BP level, heart rate were evaluated initially, in 12 weeks and 12 months of treatment; pre-trip BP level – one time per month; ABPM and blood biochemical tests (glucose and lipid profile) - initially and in 12 months of therapy. Data of BP self-moni￾toring, nebivolol treatment compliance and safety was also evaluated. Results. Long-term monotherapy with nebivolol allowed reaching the target level of office BP, self-monitoring BP, ABPM. Nebivolol provided BP control both in working days and in week end. Efficacy of nebivolol monotherapy was 88%. Nebivolol therapy improved basic ABPM indicators (load pressure, variability, daily rhythm), pulse BP, heart rate. Nebivolol had no significant negative metabolic effects, 78% of patients demonstrated sufficient compliance with nebivolol treatment. Adverse reaction (bradycardia) was observed in 2 (4%) patients. Conclusion. Nebivolol has high antihypertensive efficacy, metabolic neutrality and good safety profile in the locomotive crew staff with newly diagnosed HT.