Nebivolol Administration Research Articles

Protective effect of nebivolol on rat ovary exposed to deltamethrin toxicity.

We aimed to investigate the antioxidant activity of nebivolol against possible damage to the ovarian tissue due to the application of deltamethrin as a toxic agent, by evaluating histopathological proliferating cell nuclear antigen (PCNA) and tumor necrosis factor-alpha (TNF-α) signal molecules immunohistochemically. The animals were divided into three groups as control, deltamethrin and deltamethrin + nebivolol groups. Vaginal smears were taken after the animals were mated and detected on the first day of pregnancy. After the sixth day, deltamethrin (0.5 mL of 30 mg/kg BW undiluted ULV), and 2 mL of sterile nebivolol solution were administered intraperitoneally every day for 6-21 periods. After routine histopathological follow-up, the ovarian tissue was stained with hematoxylin and eosin stain. Control group showed normal histology of ovarium. In deltamethrin group, hyperplasic cells, degenerative follicles, pyknotic nuclei, inflammation and hemorrhagic areas were observed. Nebivolol treatment restored these pathologies. Deltamethrin treatment increased TNF-α and PCNA reaction. However, nebivolol decreased the expression. It was thought that deltamethrin toxicity adversely affected follicle development by inducing degeneration and apoptotic process in preantral and antra follicle cells, and nebivolol administration might reduce inflammation and slow down the apoptotic signal in the nuclear phase and regulate reorganization.

The impact of nebivolol, carvedilol and propranolol on pulmonary microhemodynamics in case of experimental pulmonary thromboembolism in rabbits

BACKGROUND: Beta-adrenoblockers nebivolol, carvedilol and propranolol are used in clinical cardiology for the treatment of patients with ischemic heart disease. Pulmonary thromboembolism can develop in such patients. However, its unknown, what will be the pulmonary microcirculatory changes in case of pulmonary thromboembolism after pretreatment with beta-blockers.
 AIM: The comparative analysis of the pulmonary microhemodynamics changes following experimental pulmonary thromboembolism in rabbits after pretreatment with nebovolol, carvedilol and propranolol.
 MATERIAL AND METHODS: In 35 isolated perfused rabbit lungs we investigated the changes of pulmonary microcirculation in case of experimental pulmonary thromboembolism after pretreatment with 1-blocker nebivolol, combined blocker of 1- and 1, 2-adrenoceptors carvedilol, and blocker of 1, 2-adrenoceptors propranolol.
 RESULTS: After administration of 1, 2-adrenoceptors blocker propranolol and 1-blocker nebivolol the most of the pulmonary microcirculatory parameters increased. Combined 1-, 1, 2-blocker carvedilol caused mainly vasodilatory effects of the pulmonary arterial vessels, however, the pulmonary venous resistance increased. Pulmonary thromboembolism after pretreatment with beta-blockers caused pronounced increase of pulmonary artery pressure, precapillary and pulmonary vascular resistance. In that case after pretreatment with carvedilol capillary filtration coefficient was increased two times more than after propranolol administration; after pretreatment with nebivolol capillary filtration coefficient increased less, than after propranolol administration.
 CONCLUSIONS: Acute pulmonary embolism caused less pronounced increasing of capillary filtration coefficient in case of nebivolol administration, than after pretreatment with carvedilol and propranolol.

Efficacy and safety of nebivolol in Korean patients with hypertension by age and sex: a subanalysis from the BENEFIT-KOREA study

BackgroundBENEFIT-KOREA (BEnefits after 24 weeks of NEbivolol administration For essential hypertensIon patients wiTh various comorbidities and treatment environments in Korea) study, an observational study in South Korea, demonstrated the efficacy and safety of nebivolol in Asian patients with essential hypertension with and without comorbidities in real-world settings. We present a subanalysis of the efficacy and safety of nebivolol across age and sex in the BENEFIT-KOREA cohort.MethodsAdult South Korean patients with essential hypertension participated in the prospective, single-arm, open, observational BENEFIT-KOREA study; 3011 patients received nebivolol as monotherapy or add-on therapy. Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP), and pulse rate at 12 and 24 weeks were evaluated. Participants were divided into three age groups—young males and females: < 50 years; middle-aged males and females: ≥50 years to < 70 years; and older males and females: ≥70 years.ResultsThe mean age of study participants was 63.5 ± 12.9 years; majority were between 50 and 69 years of age and 40.4% were females. A significant decrease was observed in mean SBP, DBP, and pulse rate from baseline at 12 and 24 weeks in males and females across all age groups analyzed (all P < 0.001 vs. baseline), with no significant difference in mean reduction in SBP and DBP from baseline between sex within the age groups. Majority of reported adverse events were mild. The incidence of adverse events was lower in young participants versus middle-aged and older participants.ConclusionsOur subanalysis from the real-world BENEFIT-KOREA study in Asian patients with essential hypertension demonstrated the efficacy and safety of once-daily nebivolol across age groups with no between-sex differences.Trial registrationName of the registry: clinicaltrials.gov. Trial registration number: NCT03847350. Date of registration: February 20, 2019 retrospectively registered.

Role of β3-Adrenoceptor Activation in Changes of Pulmonary Microhemodynamics after Experimental Pulmonary Thromboembolism.

Changes in pulmonary microhemodynamics during modelling of pulmonary thromboembolism against the background of nebivolol and mirabegron pretreatment were studied in isolated perfused rabbit lungs. In both cases, the pulmonary artery pressure and precapillary and pulmonary vascular resistance increased to a greater extent than in control animals, but the increase in capillary hydrostatic pressure was less pronounced. The postcapillary resistance did not change in pulmonary embolism against the background of nebivolol administration and increased in case of mirabegron pretreatment; capillary filtration coefficient after nebivolol pretreatment increased less markedly than after mirabegron administration. The increase in capillary filtration coefficient after activation of β3-adrenoceptors with the specified drugs depended on the ratio of constriction of pulmonary veins, capillary hydrostatic pressure, and endothelial permeability.

Nitric oxide mediated the effects of nebivolol in cardiorenal syndrome.

Objective(s):Despite several proposed mechanisms for the pathophysiology of cardiorenal syndrome (CRS), the exact mechanism remains unclear. Nitrosative stress has been argued as a key mechanism recently. Nebivolol is a beta-blocker with nitric oxide (NO)-releasing effect. In the present study, NO-mediated effects of two different treatment regimes of nebivolol in CRS were studied. Materials and Methods:Rats were divided into: sham-operated (sham-control), myocardial infarction (MI)-induced, (MI-control) early nebivolol-treated (MI-neb1) and late nebivolol-treated (Mı-neb2) groups. The effects of nebivolol were assessed both in the early and late period of MI by histologic, hemodynamic and biologic studies.Results:Developed MI model was in line with the heart failure with preserved ejection fraction. Focal and total tubular damage findings were observed in MI-control group both in early and late period of MI. In parallel, subclinical functional damage was transformed into chronic renal dysfunction in this group. Increased inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) together with decreased neuronal NOS (nNOS) levels were in parallel with the increased inflammation and nitrosative stress biomarkers. Nebivolol effectively prevented both subclinical and clinical nephropathy. There was no statistical difference between the nebivolol treatment regimes.Conclusion:The beneficial effects of nebivolol were closely related to the reduction of nitrosative damages as well as hemodynamic alterations. The NO-mediated effects were: prevention of nitrosative damage by decreasing iNOS, preservation of nNOS in order to maintain glomerular filtration rate (GFR), and restoration of eNOS in the late period of MI. On contrary to our previous work, early nebivolol administration had a similar effect with delayed administration of nebivolol on CRS.

Complex assessment of blood pressure regulation system in hypertension patients

Introduction: There are almost no studies characterizing the integrative level of blood pressure (BP) regulation.&#x0D; Materials and methods: 277 people of both genders aged 58.6±6.4 with stage II hypertension disease were randomized into six groups. The monotherapy of hypertension disease was conducted in five groups, using nebivolol, lisinopril, indapamide, amlodipine, and losartan. The sixth group had a combined therapy (lisinopril/indapamide). The therapy effectiveness was assessed at four levels of blood pressure regulation, using the following methods: 1) laser Doppler flowmetry, determination of the level of tumor necrosis factor-α and interleukin-10; 2) echocardiography and Doppler sonography, ultrasound examination of the renal blood flow, ECG, Holter monitoring of ECG; 3) an examination of the heart rate variability level and a quantitative assessment of beta-adrenoreception of erythrocyte cell membranes; 4) the regulatory and adaptive status was assessed, using the method of cardio-respiratory synchronism.&#x0D; Results and discussion: A more significant BP decrease was revealed during a combination therapy (by 20.4% of the baseline daily value). At the integrative level, an index of the regulatory and adaptive status (iRAS) increased in the treatment with lisinopril/indapamide combination (by 40.5%), amlodipine (by 40.5%), losartan (by 35.3%), and lisinopril (by 30.2%). Nebivolol administration resulted in a 13.5% decrease in iRAS. Indapamide therapy had no significant effect on iRAS.&#x0D; Conclusion: A comprehensive assessment of the blood pressure regulation system makes it possible to control the effectiveness of the therapy not only on a target organ or function, but also on the condition of the organism as an integral system.

REAL WORLD EFFICACY OF NEBIVOLOL IN COMBINATION WITH RENIN ANGIOTENSIN SYSTEM BLOCKADE AND/OR CALCIUM ANTAGONIST, A SUB-STUDY OF PROSPECTIVE, MULTICENTER OBSERVATIONAL STUDY

Objective: Beta blocker is generally not recommended for antihypertensive combination therapy with ACE inhibitor or angiotensin receptor blocker (RAS blockers) because inhibition of renin is the overlapped. And with respect to vasodilating property, there is also few study for the efficacy when nebivolol is combined with RAS blockers (A) or with RAS blocker + calcium antagonist combination (A+C) as the third drug. Design and method: As a sub-study of the open, non-controlled, prospective, multicenter observational study to identify BEnefits after 24 weeks of NEbivolol administration For essential hypertensIon patients wiTH various co-morbidities and treatment environments in KOREA (BENEFIT-KOREA), 294 subjects (A group, n = 178; A+C group, n = 116) were analyzed. After nebivolol 5 mg was added for combination therapy, 162 (A+N group) and 97 subjects (A+C+N group) completed the follow up at week 24. Treatment success was defined as achieved systolic and diastolic blood pressures (SBP/DBP) below 140/90 mmHg. Results: Age was 64.4 ± 13.1. Female was 40.1% and the elderly aged > = 65 was 56.8%. Baseline systolic and diastolic blood pressures (SBP/DBP) were 143.6 ± 16.6/83.6 ± 11.5 mmHg for A+N group and 147.3 ± 14.6/84.9 ± 12.6 mmHg for A+C+N group (p = 0.1552/0.4551 for SBP/DBP). At week 24, SBP/DBP were 130.6 ± 13.6/76.0 ± 11.0 mmHg for A+N group and 137.6 ± 16.0/78.4 ± 11.9 mmHg for A+C+N group (p = 0.0036/0.1019 for SBP/DBP). SBP/DBP reductions at 24 weeks were −13.0 ± 19.2/−7.6 ± 12.2 mmHg (p < 0.0001, each) for A+N group and −9.7 ± 16.7/−6.4 ± 11.2 mmHg (p < 0.0001, each) for A+C+N group. There was no significant difference in SBP reductions between A+N group vs. A+C+N group (p = 0.1583). Treatment success rates were significantly improved (36.5% and 25.9% at baseline and 78.4% and 63.9% at week 24 for group A+N and group A+C+N, respectively) (McNemar p values < 0.0001, each group). Conclusions: Nebivolol(N) was demonstrated to be effective in combination therapy of A+N as well as of A+C+N. Nitric oxide mediated vasodilation may have different mechanisms from class A drugs and/or class C. For the difference in the efficacy between A+N versus A+C+N, a larger study is needed.

Abstract P336: Efficacy and Safety of Vasodilator Beta-Blocker in Elderly Hypertensive Patients: Result From BEFIT-KOERA Study

Purpose: Beta-blockers are efficacious in young hypertensive patients with sympathetic activation. Elderly patients have been known to be at higher risk of hypotension, bradycardia, and other side-effects of beta-blockers when compared with younger patients. This study was to evaluate efficacy and safety of vasodilator beta-blocker in elderly hypertensive patients. Methods: BENEFIT-KOREA study (BEnefits after 24 weeks of NEbivolol administration For essential hypertensIon patients wiTh various co-morbidities and treatment environments in KOREA) was a open labeled non-controlled, prospective, multicenter observational study enrolled total 3,140 subjects [1,871 male(59.6%), mean age=63.5±12.9 years old]. We evaluated efficacy and safety of vasodilator beta-blocker in elderly patients. Results: Subjects of more than 65 years old [n=1,655, 839 male (49.3%), mean age=73.6±5.8] were analyzed. Table shows that vasodilator beta-blocker is effective in reduction of blood pressure, mean arterial pressure and pulse pressure in elderly patients regardless of add-on or switched to beta-blocker. Adverse drug reaction rate was not different between age group (n=19, 1.15% vs. n=17, 1.15%). Table shows lipid profile and body mass index were not aggravated after 24-week treatment of vasodilator beta-blocker. Conclusion: Vasodilator beta-blocker is efficacious and safe without metabolic derangement in elderly patients regardless of prescription patterns. These drug effects in elderly are comparable to in younger patients.

Nebivolol attenuates cerebral vasospasm both by increasing endothelial nitric oxide and by decreasing oxidative stress in an experimental subarachnoid haemorrhage

Objective: Evidence suggests that reduction of nitric oxide (NO) bioavailability due to oxidative stress plays a central role in the pathophysiology of cerebral vasospasm after subarachnoid haemorrhage (SAH). To prevent SAH-induced cerebral vasospasm, therefore we used nebivolol hydrochloride as a NO–mediated vasodilator and an antioxidant drug in an experimental rat model of SAH.Materials and methods: Forty female Wistar rats were divided into control, SAH, SAH plus placebo, and SAH plus nebivolol groups. Starting six hours after inducing SAH, 5 mg/kg of nebivolol hydrochloride and of pharmaceutical excipients of nebivolol was given orally once daily for five days to SAH plus nebivolol and SAH plus placebo groups, respectively. The lumen diameter and vessel wall thickness of the basilar artery were measured in brain sections. The serum and brain supernatant levels of nitric oxide (NO) were analysed. The brain supernatant levels of intrinsic antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured as markers of the antioxidant status.Results: Nebivolol administration attenuated cerebral vasospasm both by increasing NO levels and by decreasing oxidative stress. Our study also demonstrated that nebivolol administration reverses SAH created imbalance between SOD and GSH-Px by increasing GSH-Px activity relative to SOD.Conclusions: Nebivolol attenuates the cerebral vasospasm after SAH both increasing NO levels and decreasing oxidative stress. Therefore, it may promise to prevent SAH-induced cerebral vasospasm as an anti-spasmodic and anti-oxidant agent.

Effect of Atenolol or Nebivolol Administration on Blood Pressure Variability and its Impact on White Organ Damage in Spontaneously Hypertensive Rats

Effect of Atenolol or Nebivolol Administration on Blood Pressure Variability and its Impact on White Organ Damage in Spontaneously Hypertensive Rats

Pharmacokinetic and Pharmacodynamic Profile of Nebivolol in an Animal Model of Metabolic Syndrome

The cardiovascular and pharmacokinetic effects of nebivolol were evaluated in hypertensive fructose-fed and control rats,analyzing the effect of intravenously administered nebivolol 3 or 10 mg/kg on blood pressure, heart rate, and short-term andbeat-to-beat blood pressure variability. The enantioselective pharmacokinetic profile of d- and l-nebivolol enantiomers wasevaluated. Short-term and beat-to-beat blood pressure variability was assessed using standard deviation and blood pressurespectral analysis, respectively. The hypertensive state altered the pharmacokinetics of nebivolol, evidenced by reduction ofnebivolol clearance in the fructose group compared to the control group after administration of the highest dose. The antihypertensiveeffect of nebivolol was similar in both groups, while the bradycardic effect was greater in control rats. Althoughno significant differences were found in beat-to-beat blood pressure variability, short-term blood pressure variability showedgreater reduction after nebivolol administration in fructose-fed rats compared to control normotensive animals (-57.9%±11.8%vs.-19.6%±9.2%; p<0.05). In conclusion, although nebivolol reduces blood pressure and blood pressure variability in bothgroups, no significant differences were found in the pharmacokinetics and cardiovascular effects of fructose-fed rats, exceptfor lower bradycardic efficacy and greater reduction in short-term blood pressure variability.

Nebivolol to attenuate the effects of hyper-homocysteinaemia in rats

ObjectiveThis study investigated the prophylactic effect of nebivolol against hyper-homocysteinaemia (hHcy) induced oxidative stress in brain, heart, liver and kidney tissues and histomorphometric changes in the thoracic aorta. MethodsTwenty-four adult male Wistar rats were divided into a control, nebivolol, hHcy and nebivolol + hHcy group. hHcy was induced by oral administration of l-methionine (1 g/kg/day) for 28 days. 10 mg/kg/day nebivolol was administered orally for 28 days. Malondialdehyde (MDA) and glutathione (GSH) levels and catalase (CAT) and superoxide dismutase (SOD) activities in the tissues were determined. The total cross-sectional area (TCSA), luminal cross-sectional area (LCSA) and intima-media thickness (IMT) were measured in the thoracic aorta. ResultsHomocysteine (Hcy) levels were lower in the nebivolol + hHcy group than in the hHcy group. Nebivolol treatment significantly decreased high MDA levels in the brain, heart and liver tissues. The level of GSH was higher in the brain, heart and kidney tissues of the nebivolol + hHcy group (P < 0.001). The activity of CAT increased only in the kidney tissue of the nebivolol + hHcy group (P < 0.01), and the activity of SOD was significantly increased in all the tissues in this group. Increased TCSA and IMT in the nebivolol + hHcy group were significantly decreased after nebivolol administration. The LCSA was significantly higher in the hHcy group than the control group, probably due to outward vascular remodelling. ConclusionNebivolol treatment may be useful in different clinical scenarios where hHcy affects physiopathological pathways.

Abstract 20202: Pharmacodynamic Interactions Between Nebivolol and Valsartan in Healthy Volunteers

Introduction: Combining different classes of antihypertensive drugs is more effective for achieving blood pressure (BP) control than increasing the dose of monotherapies. An aim of this study was to investigate pharmacodynamic (PD) interactions between nebivolol, a β1 selective, vasodilatory beta blocker and valsartan, an angiotensin II type 1 receptor blocker. Methods: This was a single-center, randomized, open-label, multiple-dose, three-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into one of six treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol 20 mg, valsartan 320 mg, or nebivolol 20 mg plus valsartan 320 mg. Outcomes included changes in BP, heart rate (HR), plasma angiotensin II, plasma renin activity (PRA), and 24-hour urinary aldosterone. Results: The drop in least square mean values of systolic and diastolic BP was significantly greater following the concomitant administration of nebivolol and valsartan than either monotherapy alone. The mean HR after treatment with nebivolol alone, as well as after the combined treatment, was consistently lower than valsartan monotherapy. A sharp increase in mean Day 7 PRA and plasma angiotensin II occurred in subjects receiving valsartan alone and this was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at Day 7 was substantially decreased after combined treatment, as compared to either monotherapy treatment. All treatments were safe and well tolerated. Conclusions: Nebivolol and valsartan co-administration led to greater reductions in BP compared to either monotherapy. Nebivolol attenuated valsartan-induced increases in angiotensin II levels and PRA and reduced urinary aldosterone levels. Hence, these mechanisms for BP lowering are complementary and provide a rationale for further investigation of this combination in patients with essential hypertension.

Abstract 633: Pharmacodynamic Interactions Between Nebivolol and Valsartan in Healthy Volunteers

Background: Combining different classes of antihypertensive drugs is more effective for achieving blood pressure (BP) control than increasing the dose of monotherapies. An aim of this study was to investigate pharmacodynamic (PD) interactions between nebivolol, a β1 selective, vasodilatory beta blocker and valsartan, an angiotensin II type 1 receptor blocker. Methods: This was a single-center, randomized, open-label, multiple-dose, three-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into one of six treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol 20 mg, valsartan 320 mg, or nebivolol 20 mg plus valsartan 320 mg. Outcomes included changes in BP, heart rate (HR), plasma angiotensin II, plasma renin activity (PRA), and 24-hour urinary aldosterone. Results: The drop in least square mean values of systolic and diastolic BP was significantly greater following the concomitant administration of nebivolol and valsartan than either monotherapy alone. The mean HR after treatment with nebivolol alone, as well as after the combined treatment, was consistently lower than valsartan monotherapy. A sharp increase in mean Day 7 PRA and plasma angiotensin II occurred in subjects receiving valsartan alone and this was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at Day 7 was substantially decreased after combined treatment, as compared to either monotherapy treatment. All treatments were safe and well tolerated. Conclusion: Nebivolol and valsartan co-administration led to greater reductions in BP compared to either monotherapy. Nebivolol attenuated valsartan-induced increases in angiotensin II levels and PRA and reduced urinary aldosterone levels. Hence, these mechanisms for BP lowering are complementary and provide a rationale for further investigation of this combination in patients with essential hypertension.

Nebivolol protects against myocardial infarction injury via stimulation of beta 3-adrenergic receptors and nitric oxide signaling.

Nebivolol, third-generation β-blocker, may activate β3-adrenergic receptor (AR), which has been emerged as a novel and potential therapeutic targets for cardiovascular diseases. However, it is not known whether nebivolol administration plays a cardioprotective effect against myocardial infarction (MI) injury. Therefore, the present study was designed to clarify the effects of nebivolol on MI injury and to elucidate the underlying mechanism. MI model was constructed by left anterior descending (LAD) artery ligation. Nebivolol, β3-AR antagonist (SR59230A), Nitro-L-arginine methylester (L-NAME) or vehicle was administered for 4 weeks after MI operation. Cardiac function was monitored by echocardiography. Moreover, the fibrosis and the apoptosis of myocardium were assessed by Masson's trichrome stain and TUNEL assay respectively 4 weeks after MI. Nebivolol administration reduced scar area by 68% compared with MI group (p<0.05). Meanwhile, nebivolol also decreased the myocardial apoptosis and improved the heart function after MI (p<0.05 vs. MI). These effects were associated with increased β3-AR expression. Moreover, nebivolol treatment significantly increased the phosphorylation of endothelial NOS (eNOS) and the expression of neuronal NOS (nNOS). Conversely, the cardiac protective effects of nebivolol were abolished by SR and L-NAME. These results indicate that nebivolol protects against MI injury. Furthermore, the cardioprotective effects of nebivolol may be mediated by β3-AR-eNOS/nNOS pathway.

Tempol-nebivolol therapy potentiates hypotensive effect increasing NO bioavailability and signaling pathway

Nebivolol is a third generation beta blocker with endothelial nitric oxide synthase (eNOS) agonist properties. Considering the role of reactive oxygen species (ROS) in the uncoupling of eNOS, we hypothesized that the preadministration of an antioxidant as tempol, could improve the hypotensive response of nebivolol in normotensive animals increasing the nitric oxide (NO) bioavailability by a reduction of superoxide (O2•−) basal level production in the vascular tissue.Male Sprague Dawley rats were given tap water to drink (control group) or tempol (an antioxidant scavenger of superoxide) for 1 week. After 1 week, Nebivolol, at a dose of 3 mg/kg, was injected intravenously to the control group or to the tempol-treated group. Mean arterial pressure, heart rate, and blood pressure variability were evaluated in the control, tempol, nebivolol, and tempol nebivolol groups, as well as, the effect of different inhibitor as Nβ-nitro-l-arginine methyl ester (L-NAME, a Nitric oxide synthase blocker) or glybenclamide, a KATP channel inhibitor. Also, the expression of α,β soluble guanylate cyclase (sGC), phospho-eNOS, and phospho-vasodilator-stimulated phosphoprotein (P-VASP) were evaluated by Western Blot and cyclic guanosine monophosphate (cGMP) levels by an enzyme-linked immunosorbent assay (ELISA) commercial kit assay.We showed that pretreatment with tempol in normotensive rats produces a hypotensive response after nebivolol administration through an increase in the NO bioavailability and sGC, improving the NO/cGMP/protein kinase G (PKG) pathway compared to that of the nebivolol group.We demonstrated that tempol preadministration beneficiates the response of a third-generation beta blocker with eNOS stimulation properties, decreasing the basal uncoupling of eNOS, and improving NO bioavailability. Our results clearly open a possible new strategy therapeutic for treating hypertension.

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.

Effect of the long-term administration of nebivolol on clinical symptoms, exercise capacity and left ventricular function in patients with heart failure and preserved left ventricular ejection fraction: background, aims and design of the ELANDD study

The SENIORS trial demonstrated that nebivolol has beneficial effects in patients with heart failure. However, the role of beta-blocker therapy in patients with heart failure and preserved left ventricular ejection fraction (HFPEF) is still unsettled. To assess the long-term effects of administration of nebivolol, compared to placebo, on the clinical symptoms, exercise capacity and parameters of left ventricular (LV) function in patients with HFPEF. The Effect of Long-term Administration of Nebivolol on clinical symptoms, exercise capacity and left ventricular function in patients with Diastolic Dysfunction (ELANDD) study is a prospective multicenter European trial in 120 patients with HFPEF randomised to nebivolol or placebo. HFPEF is defined as symptoms or signs of heart failure, a LV ejection fraction >45% and evidence of diastolic LV dysfunction by Doppler echocardiography. Procedures include a baseline clinical examination, 6-min walk test (6MWT), electrocardiography, Doppler echocardiography and Minnesota QoL questionnaire. Nebivolol or placebo is started at 2.5 mg/day and gradually uptitrated to 10 mg/day. After initiation of the study, patients are assessed at 1, 2, 5 and 6 weeks (titration phase) and at weeks 12 and 26. The primary endpoint is the change from baseline in the 6MWT distance with nebivolol versus placebo. Sample size calculations are based on an anticipated 15% difference (70 m) in the 6MWT distance between nebivolol and placebo-treated patients. This study will allow the collection of data regarding the possible clinical benefits and the effects on LV function of nebivolol administration in patients with HFPEF.

Nebivolol, a Vasodilating Selective β1-Blocker, Is a β3-Adrenoceptor Agonist in the Nonfailing Transplanted Human Heart

The present study was to assess whether nebivolol could activate beta(3)-adrenergic receptors (ARs) in the human heart. Nebivolol is a third-generation beta-blocker used in the treatment of heart failure. It associates selective beta(1)-adrenergic antagonist properties with endothelial and nitric oxide (NO)-dependent vasodilation. Several studies reported that this vasodilation could result from an activation of beta(3)-ARs, but no data are available in the heart. The effect of nebivolol (0.1 nmol/l to 10 micromol/l) upon the developed peak tension was tested in endomyocardial biopsies from human nonrejecting transplanted hearts. Tension was recorded at steady state using a mechanoelectric force transducer. Nebivolol induced a concentration-dependent decrease in peak tension (maximum effect obtained at 10 micromol/l: -55 +/- 4%, n = 6), which was similar to that obtained with a preferential beta(3)-AR agonist, BRL 37344 (maximum effect obtained at 1 micromol/l: -45 +/- 2%, n = 12). The nebivolol effect was not modified by 10 micromol/l nadolol, a beta(1,2)-AR antagonist, but was significantly reduced in the presence of 1 micromol/l L-748,337, a selective beta(3)-AR antagonist, and after pre-treatment with 100 micromol/l N(G)-monomethyl-L-arginine, an NOS inhibitor. Our study demonstrated that nebivolol activated beta(3)-AR in the human ventricle. The NO-dependent negative inotropic effect of nebivolol associated with its vasodilating properties previously described in human microcoronary arteries could improve the energetic balance in heart. Those effects could explain the improvement of hemodynamic parameters obtained in patients with heart failure after nebivolol administration as previously described in clinical trials.

Long-term nebivolol administration reduces renal fibrosis and prevents endothelial dysfunction in rats with hypertension induced by renal mass reduction

D/L-Nebivolol is a lypophilic beta1-adrenergic antagonist which is devoid of intrinsic sympathomimetic activity and can increase nitric oxide (NO) bioavailability with its subsequent vasodilating properties. The purpose of the present work was to assess the effect of long-term nebivolol administration on both renal damage and endothelial dysfunction induced by renal mass reduction (RMR) in rats. Atenolol, which does not increase NO bioavailability, was included in the study as a comparative beta-adrenoceptor antagonist. Rats were subjected to both right nephrectomy and surgical removal of two-thirds of the left kidney in order to retain approximately one-sixth of the total renal mass. One week after ablation, rats were distributed randomly according to the following experimental groups: control group containing RMR rats without treatment; RMR rats treated daily with nebivolol for 6 months (drinking water, 8 mg/kg per day); and RMR rats treated daily with atenolol for 6 months (drinking water, 80 mg/kg per day). A group of sham-operated animals was also included. Administration of either nebivolol or atenolol similarly reduced arterial pressure in comparison with RMR untreated animals; however, animals receiving nebivolol presented lower levels of collagen type I expression as well as lower glomerular and interstitial fibrosis than those receiving atenolol. Urinary excretion of oxidative stress markers were also lower in animals receiving nebivolol than in rats treated with atenolol. Furthermore, nebivolol prevented RMR-induced endothelial dysfunction more efficiently than atenolol. Nebivolol protects against renal fibrosis, oxidative stress and endothelial dysfunction better than equivalent doses, in terms of arterial pressure reduction, of atenolol in a hypertensive model of renal damage induced by RMR.