Nebivolol, an antihypertensive agent, has new application in inhibiting melanoma.

Repurposing existing drugs for cancer therapy has become an important strategy because of its advantages, such as cost reduction, effect and safety. The present study was designed to investigate the antimelanoma effect and possible mechanisms of action of nebivolol, which is an approved and widely prescribed antihypertensive agent. In this study, we explored the effect of nebivolol on cell proliferation and cell activity in melanoma in vitro and the potential antimelanoma mechanism of nebivolol through a series of experiments, including the analysis of the effects with regard to cell apoptosis and metastasis. Furthermore, we evaluated the antimelanoma effect on xenograft tumor models and inspected the antimelanoma mechanism of nebivolol in vivo using immunohistochemical and immunofluorescence staining assays. As results in this work, in vitro , nebivolol possessed a strong activity for suppression proliferation and cell cycle arrest on melanoma. Moreover, nebivolol significantly induced cell apoptosis in melanoma through a mitochondrial-mediated endogenous apoptosis pathway. Additionally, nebivolol inhibited melanoma cell metastasis. More importantly, nebivolol exhibited significantly effective melanoma xenograft models in vivo , which related to the mechanism of apoptosis induction, proliferation inhibition, metastasis blocking and angiogenesis arrest. Overall, the data of the present study recommend that nebivolol holds great potential in application as a novel agent for the treatment of melanoma.

Assessment of nebivolol efficacy in experimental models of toxoplasmosis: insights into parasite burden reduction and neuronal protection.

This study investigates the efficacy of nebivolol (NBV) in experimental models of toxoplasmosis, focusing on parasite burden reduction and neuronal protection. In the acute model of experimental toxoplasmosis, Swiss mice infected with RH strain tachyzoites received oral NBV chlorhydrate doses of 2 mg/kg/day and 4 mg/kg/day for 8 days. Treatment with NBV significantly reduced parasite burden compared to vehicle and standard drug (PYR) groups. In the chronic model of experimental toxoplasmosis, C57/BL6 mice infected with the ME49 strain received NBV chlorhydrate 41 days post-infection and were evaluated after 10 days of treatment. NBV chlorhydrate effectively reduced cyst number and area, as well as bradyzoite burden compared to controls. Histological analysis demonstrated that NBV chlorhydrate preserved neuronal count, with the 4 mg/kg/day dose yielding counts similar to non-infected mice. Statistical analysis confirmed significant differences compared to control groups. Furthermore, immunohistochemical analysis revealed a significant reduction in iNOS labeling in the brains of mice treated with NBV chlorhydrate, indicating a decrease in nitric oxide production compared to control groups. These findings suggest NBV's potential as a promising candidate for toxoplasmosis treatment, highlighting its ability to reduce parasite burden and protect neuronal integrity. Further research is warranted to elucidate NBV's mechanisms of action and its clinical application in managing toxoplasmosis.

Clinical pharmacokinetics of nebivolol: a systematic review.

Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.

Protective role of nebivolol via AKT1/Hif-1α/eNOS signaling pathway: nephrotoxicity caused by methotrexate in a rat model.

Methotrexate (MTX) is an antineoplastic and anti-inflammatory agent, which is used in severe diseases. Its use should be limited due to side effects such as nephrotoxicity, myelotoxicity, and hepatotoxicity. Nebivolol (NBV), which is a beta-blocker used in the treatment of hypertension, also contributes to vasodilation in tissues by activating the endothelial nitric oxide synthase (eNOS) enzyme. The purpose of this study is to research the effect of NBV on MTX-induced nephrotoxicity through the AKT1/hypoxia-inducible factor 1-alpha (Hif-1α)/eNOS signaling pathway. The rats were randomly divided into three groups of eight each. The groups were control, MTX, and MTX + NBV. A single dose of 20 mg/kg MTX was given intraperitoneally to the rats on the first day of the study and 10 mg/kg NBV was given orally to the treatment group for 7 days. At the end of the study, rats' blood and kidney tissues were taken for histopathological, immunohistochemical, and biochemical examinations. MTX administration significantly decreased the expression levels of AKT1, eNOS, and Hif-1α compared with the control group (p < 0.001 for all), and NBV treatment increased these values compared with the MTX group (p < 0.001 for all). In conclusion, NBV treatment ameliorated the MTX-induced nephrotoxicity via AKT1/Hif-1α/eNOS signaling pathway.

Nebivolol Alleviates Vascular Endothelial Insulin Resistance by Inhibiting Endoplasmic Reticulum Stress.

Vascular endothelial insulin resistance (IR) is an important risk factor in the development of vascular complications in diabetes. Prolonged endoplasmic reticulum stress (ERS) contributes to the development and progression of endothelial IR. The current study assessed the effects and mechanism of nebivolol on vascular IR in Goto-Kakizaki (GK) rats and endothelial IR induced by high glucose (33.3 mmol/L) associated with high insulin (10-7 mol/L) in human aortic endothelial cells (HAECs). Rats were divided into Wistar, Wistar + Neb (Wistar rats treated with nebivolol, 10 mg/kg, ig), GK, and GK + Neb (GK rats treated with nebivolol, 10 mg/kg, ig). GK rats showed hyperglycemia, dyslipidemia, impaired glucose homeostasis, metabolic IR, reduced relaxation to insulin, and lower serum nitric oxide (NO) level. Treatment with nebivolol for 4 months ameliorated insulin's vasorelaxation and NO production, and relieved dyslipidemia in GK rats. Additionally, nebivolol increased glucose uptake and NO level in the endothelial IR group in vitro. Nebivolol increased aortic expressions of IRS-1/PI3K/Akt/eNOS relative proteins and GLUT4 and reduced expressions of ERS markers (ATF6, GRP78, and CHOP, p-JNK/JNK). Furthermore, both nebivolol and TUDCA (ERS inhibitor) alleviated the attenuated IRS-1PI3K/Akt/eNOS pathway and enhanced ERS in HAECs IR. Tunicamycin (ERS inducer) not only induced endothelial IR but also blocked nebivolol's alleviation on the IRS-1PI3K/Akt/eNOS pathway and ERS. Nebivolol ameliorated endothelial IR partially by inhibiting ERS and then regulating the IRS-1/PI3K/Akt/eNOS signal.

BIOCHEMICAL MARKERS OF ENDOTHELIAL DYSFUNCTION, THEIR CHANGES UNDER THE INFLUENCE OF TREATMENT WITH VARIOUS BETA-ADRENOBLOCKERS IN YOUNG MEN WITH MYOCARDIAL INFARCTION.

OBJECTIVE: The aim: Is to determine the levels of markers of endothelial dysfunction in young men with myocardial infarction and their changes during the treatment with beta-blockers with different pharmacological properties. PATIENTS AND METHODS: Materials and methods: 112 male patients of Caucasian race of the Ukrainian population under the age of 50 with MI. Group I received Nebivolol, group II - bisoprolol. RESULTS: Results: During the 6-month follow-up, positive dynamics of NOS-2 and ET-1 was observed. The level of NOS-2 in groups I - II was 4272.3±162.7, 4629.7±161.2 pg/mL, respectively (p<0.05). The dynamics of ET-1 showed significant decrease of its level in all groups. CONCLUSION: Conclusions: Significant changes in markers of endothelial dysfunction, namely NOS3/eNOS, NOS2/iNOS and ET-1, are observed in young male patients of the Ukrainian population with MI. During 6 months of treatment, positive changes were observed in the form of an increase in NOS-3 levels and a significant decrease in ET-1 and NOS-2 levels. The inclusion of Nebivolol in the basic therapy for this group of patients is associated with an additional positive effect on the normalization of levels NO synthase and the reduction of ET-1.

Nebivolol/Valsartan: A Novel Antihypertensive Fixed-Dose Combination Tablet.

DATA SOURCES: A PubMed (1966 to October 2018) search was conducted using the following keywords: nebivolol, valsartan, and hypertension (HTN). Additional sources were identified by references. STUDY SELECTION AND DATA EXTRACTION: Articles written in English were included if they evaluated the pharmacology, pharmacokinetics, efficacy, safety, or place in therapy of nebivolol/valsartan in human subjects. DATA SYNTHESIS: Most patients with HTN require combination therapy; however, ß-adrenergic antagonists and AII type 1 receptor blockers have been considered less effective because of overlapping mechanisms of action. A phase III, randomized trial demonstrated that nebivolol/valsartan produced statistically significant blood pressure (BP) lowering as compared with monotherapy with the individual components or placebo. Substudy analyses confirmed this among subgroups and demonstrated that nebivolol/valsartan decreased plasma renin and aldosterone levels. One trial reported continued BP lowering at 52 weeks. Another study showed that nebivolol/valsartan had similar additivity scores as compared with other antihypertensive combinations. Relevance to Patient Care and Clinical Practice: This review discusses drug information, efficacy, and safety of nebivolol/valsartan and discusses its clinical relevance as a novel combination product in managing patients with HTN. CONCLUSION: Nebivolol/valsartan combination may offer a benefit to patients with an indication for both classes who desire to decrease pill burden. Although BP lowering was statistically significant in comparison to the individual components as monotherapy, the combination does not offer clinically significant benefits that would elevate its place in HTN management.

The influence of nebivolol on the activity of BRL 37344 - the ß3-adrenergic receptor agonist, in the animal model of detrusor overactivity.

AIMS: The cardiotoxic effects of antimuscarinics constitute a significant restriction in their application in elderly people. Overactive bladder syndrome pharmacotherapy using compounds with cardioprotective properties would seem an ideal solution. The main goal of the study was to assess the impacts of nebivolol (NEB) on the activity of BRL 37344 - ß3-adrenergic receptor (ß3AR) agonist, in the animal model of detrusor overactivity. As both these substances can impact on the cardiovascular system, their effect on the parameters of this system and diuresis was also examined. METHODS: Retinyl acetate (RA; 0.75%) solution was used to induce detrusor overactivity in female Wistar rats. BRL and/or NEB were administered intra-arterially during cystometry in a single dose (2.5 or 5, 0.05 or 0.1 mg/kg, respectively). In addition, a 24 hours measurement of heart rate, blood pressure, and urine production was carried out. RESULTS: NEB (0.05 mg/kg) and BRL (2.5 mg/kg) monotherapy proved to have no influence on the cystometric parameters of animals with RA-induced detrusor overactivity. NEB at 0.1 mg/kg resulted in a drop in the detrusor overactivity index, similarly to BRL at 5 mg/kg. Coadministration of NEB and BRL, both at ineffective doses, decreased the detrusor overactivity index and ameliorated the nonvoiding contractions. ß3AR stimulation proved to induce tachycardia and hypertension. NEB at 0.05 mg/kg proved to ameliorate detrusor overactivity and have preventive properties against adverse cardiovascular effects of the ß3AR agonist. CONCLUSIONS: The combined application of the ß3AR agonist and NEB may improve detrusor overactivity without affecting the heart rate, blood pressure, and urine production.

Nebivolol attenuates oxidative stress and inflammation in a guinea pig model of ovalbumin-induced asthma: a possible mechanism for its favorable respiratory effects.

An experimental model of ovalbumin (OVA) induced asthma was used to assess the effects of nebivolol, the third-generation selective ß1-adrenergic receptor blocker, on airway reactivity, lung inflammation, and oxidative stress markers. The asthma induction protocol was done by OVA sensitization and challenge. Guinea pigs were classified into control, asthmatic, or asthmatic receiving nebivolol either 7.5 or 15 mg·kg-1·day-1 orally. At the end of the study respiratory, the anti-inflammatory and antioxidative effects of nebivolol were assessed. The asthmatic group exhibited a significant increase in early and late airway resistance, airway hyperreactivity to histamine, total and absolute leucocytic count, tumor necrosis factor-α, and interleukin-6 in bronchoalveolar lavage fluid and lung lipid peroxidation and a significant decrease in superoxide dismutase and glutathione compared to the control group. Additionally, there was a significant decrease in lung endothelial nitric oxide synthase (eNOS) and a significant increase in inducible nitric oxide synthase (iNOS) mRNA expression compared to the control group. The high dose of nebivolol counteracted the increased airway resistance induced by OVA, whereas it had no effect on airway hyperresponsiveness. Moreover, nebivolol exhibited significant anti-inflammatory and antioxidant effects and restored the altered levels of eNOS and iNOS compared to the asthmatic group. Collectively, these results suggest a beneficial effect of nebivolol in asthma.

Neuroprotective effect of nebivolol against cisplatin-associated depressive-like behavior in rats.

One-third of cancer patients undergoing chemotherapy treatment often display symptoms of depression leading to poor adherence and decreased quality of life. Thus, this study aimed to investigate the possible protective effect of nebivolol against cisplatin-associated depressive symptoms in adult male rats. Nebivolol is a highly cardioselective ß-adrenergic receptor blocker that possesses endothelium-dependent vasodilator properties and antioxidant capacities. Animals were allocated into four groups. Group one was given aqueous solution of carboxymethyl cellulose and served as control, group two was given nebivolol (10 mg/kg p.o., daily), group three was given cisplatin (2 mg/kg i.p. once per week) for 10 consecutive weeks and group four was treated with cisplatin concomitantly with nebivolol as per above schedule. Cisplatin-treated rats showed an increase in both depressive-like behaviors in open-field and forced swimming tests. In addition, histopathological examination revealed cortical encephalomalacia along with hippocampal neuronal degeneration and kidney dysfunction. In parallel, cisplatin administration prominently reduced GABA and elevated glutamate levels in the cortical and hippocampal tissues. Furthermore, it resulted in a significant decline in cortical and hippocampal brain-derived neurotrophic factor and nitric oxide contents concomitantly with a marked decrease in endothelial- and an increase in inducible-nitric oxide synthase genes expression. On the other hand, treatment with nebivolol effectively mitigated the aforementioned cisplatin-associated behavioral, biochemical, and histopathological alterations without changing its antitumor activity as evidenced by sulforhodamine B cell survival assay. Taken together, our results suggest that nebivolol may offer a promising approach for alleviating depressive symptoms associated with the use of cisplatin.

Differential Metabolic Effects of Beta-Blockers: an Updated Systematic Review of Nebivolol.

Blood pressure management in hypertensive patients with metabolic abnormalities is challenging, since many of the antihypertensive drugs adversely affect metabolism. Besides effective control of blood pressure in patients with hypertension, third-generation beta-blockers such as nebivolol offer additional benefits for central hemodynamics and neutral or beneficial effects on metabolism. Emerging clinical data suggest that nebivolol also has similar effects on metabolism in obese hypertensive and hypertensive diabetic patients. The present article will provide a systematic analysis of the pathophysiological links among hypertension, insulin resistance, and metabolic syndrome. We will also summarize the available clinical evidence regarding the metabolic effects of beta-blockers in hypertensive patients, with an emphasis on nebivolol. Nebivolol exerts neutral or beneficial effects on insulin sensitivity and lipid metabolism in hypertensive patients, owing to its nitric oxide-mediated vasodilatory and antioxidative properties. Thus, nebivolol could be a favorable therapeutic option for the treatment of hypertension in patients with impaired glucose and lipid metabolism.

Pretreatment with nebivolol attenuates level and expression of matrix metalloproteinases in a rat model of renal ischaemia-reperfusion injury.

AIM: Matrix metalloproteinases (MMPs) are zinc-containing proteinases that are involved in the degradation of extracellular matrix (ECM) and a number of cell surface proteins in order to maintain tissue homeostasis. They are involved in pathogenesis of several ischaemic organ injuries. In the present study, we aimed to determine the expression and level of MMP-2 and MMP-9 in renal ischaemia-reperfusion injury (IRI) model and the potential beneficial effect of nebivolol, a ß1 -adrenergic receptor blocker, on both MMP-2 and -9 level and expression and tubular injury caused by IRI. METHODS: Twenty Wistar albino rats were divided into three groups: sham-operated , ischaemia-reperfusion, and nebivolol-pretreated. IRI model was induced by bilateral clamping of renal arteries for 45 min followed by 24 h of reperfusion. The analysis of serum creatinine levels, quantity and expression of MMP-2 and MMP-9 were performed after 24 h of IRI. The effects of nebivolol on level and expression of MMP-2 and MMP-9 levels were investigated by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. The pathological examinations were performed to score tubular damage by light microscopy. RESULTS: Creatinine levels increased significantly in the ischaemia-reperfusion group compared to the sham-operated group. Rats in the nebivolol-pretreated group showed significant decrease in expression and quantity of MMP-2 and MMP-9 during IRI. The pathological examinations demonstrated significantly low level of tubular injury score in nebivolol-pretreated group. CONCLUSION: Nebivolol attenuated IRI by decreasing the expression and level of MMP-2 and MMP-9.

Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia.

ß-Blockers are a standard treatment for heart failure and cardiac arrhythmias. There are ∼30 commonly used ß-blockers, representing a diverse class of drugs with different receptor affinities and pleiotropic properties. We reported that among 14 ß-blockers tested previously, only carvedilol effectively suppressed cardiac ryanodine receptor (RyR2)-mediated spontaneous Ca2+ waves during store Ca2+ overload, also known as store overload-induced Ca2+ release (SOICR). Given the critical role of SOICR in arrhythmogenesis, it is of importance to determine whether there are other ß-blockers that suppress SOICR. Here, we assessed the effect of other commonly used ß-blockers on RyR2-mediated SOICR in HEK293 cells, using single-cell Ca2+ imaging. Of the 13 ß-blockers tested, only nebivolol, a ß-1-selective ß-blocker with nitric oxide synthase (NOS)-stimulating action, effectively suppressed SOICR. The NOS inhibitor (N-nitro-l-arginine methyl ester) had no effect on nebivolol's SOICR inhibition, and the NOS activator (histamine or prostaglandin E2) alone did not inhibit SOICR. Hence, nebivolol's SOICR inhibition was independent of NOS stimulation. Like carvedilol, nebivolol reduced the opening of single RyR2 channels and suppressed spontaneous Ca2+ waves in intact hearts and catecholaminergic polymorphic ventricular tachycardia (CPVT) in the mice harboring a RyR2 mutation (R4496C). Interestingly, a non-ß-blocking nebivolol enantiomer, (l)-nebivolol, also suppressed SOICR and CPVT without lowering heart rate. These data indicate that nebivolol, like carvedilol, possesses a RyR2-targeted action that suppresses SOICR and SOICR-evoked VTs. Thus, nebivolol represents a promising agent for Ca2+-triggered arrhythmias.

Heart rate is a useful marker of adherence to beta-blocker treatment in hypertension.

OBJECTIVES: Suboptimal medication adherence is common among patients with hypertension. Measurements of plasma or urinary levels of antihypertensive drugs are useful, but not widely available. The aim of our study was to investigate the relation of patients' heart rates to their serum beta-blocker levels. METHODS: We correlated 220 measurements of serum beta-blocker levels in 106 patients with apparently resistant hypertension to their corresponding office heart rate. A significant proportion, 44.6% of patients, were non-adherent to beta-blocker treatment according to serum level measurement. Non-adherent patients had significantly higher heart rates (80.9 vs. 66.6 bpm, p < .001), systolic (157.4 vs. 147.0 mm Hg, p = .002) and diastolic blood pressure (91.1 vs. 87.2 mm Hg, p = .041) in comparison to adherent patients. RESULTS: Heart rate above 75.5 beats per minute predicted non-adherence to beta-blocker treatment with a sensitivity of 62.5%, specificity 86.8% and AUC ROC 0.802 (p < .001). Higher heart rate cutoff might be applicable for nebivolol but was not determined due to the low number of patients treated with nebivolol. CONCLUSIONS: We concluded that heart rate was shown to be a good predictor of non-adherence to beta-blocker treatment, and might become a quick and easy measure to determine patient adherence in hypertensive patients.

Effect of obstructive sleep apnea on the response to hypertension therapy.

Obstructive sleep apnea (OSA) often precedes cardiovascular disease, partly due to treatment resistant hypertension. The nocturnal apneas of OSA trigger increased sympathetic nervous discharge during both sleep and wakefulness. Apneas also trigger cardiac release of the endogenous diuretic atrial natriuretic peptide. We hypothesized that treatment of the excess sympathetic nervous activity of OSA with a ß1 blocker would lower 24 h blood pressure (BP) more than diuretic therapy. Subjects with OSA associated hypertension received 2 weeks of placebo followed by the ß1 blocker nebivolol or hydrochlorothiazide (HCTZ) for 6 weeks in a blinded crossover study. BP, baroreflex sensitivity (BRS), heart rate variability (HRV), arterial reactivity, and stiffness were measured after placebo and each treatment. The ß1 blocker lowered clinic BP by -11/-8 mmHg, more than the -3/-1 effect of HCTZ (P < 0.01). The ß1 blocker lowered 24 h diastolic blood pressure (DBP) more than HCTZ. Although given at bedtime, neither drug increased BP dipping. Nebivolol increased HRV in the high-frequency band. Nebivolol did not alter BRS while HCTZ significantly diminished BRS compared to nebivolol (P < 0.01). Nebivolol increased flow-mediated brachial artery dilation when compared to HCTZ and slowed pulse wave velocity, indicating a decrease in arterial stiffness. Diuretic therapy failed to lower BP in OSA subjects and this might account for the frequent association of OSA with treatment resistant hypertension. However, blockade of the excess sympathetic nervous activity of OSA with a ß1 blocker lowered both clinic and 24 h DBP.

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.

Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans.

Use of ß-adrenergic receptor (AR) blocker is associated with increased risk of fatigue and exercise intolerance. Nebivolol is a newer generation ß-blocker, which is thought to avoid this side effect via its vasodilating property. However, the effects of nebivolol on skeletal muscle perfusion during exercise have not been determined in hypertensive patients. Accordingly, we performed contrast-enhanced ultrasound perfusion imaging of the forearm muscles in 25 untreated stage I hypertensive patients at rest and during handgrip exercise at baseline or after 12 wk of treatment with nebivolol (5-20 mg/day) or metoprolol succinate (100-300 mg/day), with a subsequent double crossover for 12 wk. Metoprolol and nebivolol each induced a reduction in the resting blood pressure and heart rate (130.9 ± 2.6/81.7 ± 1.8 vs. 131.6 ± 2.7/80.8 ± 1.5 mmHg and 63 ± 2 vs. 64 ± 2 beats/min) compared with baseline (142.1 ± 2.0/88.7 ± 1.4 mmHg and 75 ± 2 beats/min, respectively, both P < 0.01). Metoprolol significantly attenuated the increase in microvascular blood volume (MBV) during handgrip at 12 and 20 repetitions/min by 50% compared with baseline (mixed-model P < 0.05), which was not observed with nebivolol. Neither metoprolol nor nebivolol affected microvascular flow velocity (MFV). Similarly, metoprolol and nebivolol had no effect on the increase in the conduit brachial artery flow as determined by duplex Doppler ultrasound. Thus our study demonstrated a first direct evidence for metoprolol-induced impairment in the recruitment of microvascular units during exercise in hypertensive humans, which was avoided by nebivolol. This selective reduction in MBV without alteration in MFV by metoprolol suggested impaired vasodilation at the precapillary arteriolar level.

Nebivolol has a beneficial effect in monocrotaline-induced pulmonary hypertension.

Pulmonary hypertension is a rare disorder that, without treatment, is progressive and fatal within 3-4 years. Current treatment involves a diverse group of drugs that target the pulmonary vascular bed. In addition, strategies that increase nitric oxide (NO) formation have a beneficial effect in rodents and patients. Nebivolol, a selective ß1 adrenergic receptor-blocking agent reported to increase NO production and stimulate ß3 receptors, has vasodilator properties suggesting that it may be beneficial in the treatment of pulmonary hypertension. The present study was undertaken to determine whether nebivolol has a beneficial effect in monocrotaline-induced (60 mg/kg) pulmonary hypertension in the rat. These results show that nebivolol treatment (10 mg/kg, once or twice daily) attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension. This study demonstrates the presence of ß3 adrenergic receptor immunoreactivity in pulmonary arteries and airways and that nebivolol has pulmonary vasodilator activity. Studies with ß3 receptor agonists (mirabegron, BRL 37344) and antagonists suggest that ß3 receptor-mediated decreases in systemic arterial pressure occur independent of NO release. Our results suggest that nebivolol, a selective vasodilating ß1 receptor antagonist that stimulates ß3 adrenergic receptors and induces vasodilation by increasing NO production, may be beneficial in treating pulmonary hypertensive disorders.

Nebivolol versus Carvedilol or Metoprolol in Patients Presenting with Acute Myocardial Infarction Complicated by Left Ventricular Dysfunction.

OBJECTIVE: The aim of this study was to evaluate the efficacy of nebivolol, carvedilol or metoprolol succinate on the outcome of patients presenting with acute myocardial infarction (AMI) complicated by left ventricular dysfunction. SUBJECTS AND METHODS: Patients (n = 172, aged 28-87 years) with AMI and left ventricular ejection fraction ≤0.45 were randomized to the nebivolol (n = 55), carvedilol (n = 60) and metoprolol succinate (n = 57) groups. Baseline demographic and clinical characteristics and composite event rates of nonfatal MI, cardiovascular mortality, hospitalization due to unstable angina pectoris or heart failure, stroke or revascularization during the 12-month follow-up were compared among the groups using the x03C7;2 test, t test or log-rank test as appropriate. RESULTS: Baseline demographic and clinical characteristics were similar in the three groups. The composite end point during follow-up was lower in the patients treated with nebivolol than those treated with metoprolol (14.5 vs. 31.5%; p = 0.03). However, event rates were similar between the patients treated with carvedilol and those treated with the metoprolol (20.3 vs. 31.5%, p > 0.05) and between the patients treated with nebivolol and carvedilol (14.5 vs. 20.3%, p > 0.05). CONCLUSION: The patients treated with nebivolol experienced 12-month cardiovascular events at a lower rate than those treated with metoprolol succinate. However, event rates were similar between the carvedilol and the metoprolol succinate groups and between the nebivolol and the carvedilol groups.

Effect of nebivolol on renal nitric oxide availability and tubular function in patients with essential hypertension.

AIMS: Nebivolol is a selective ß1 -receptor antagonist with vasodilating properties. In patients with essential hypertension, we tested the hypothesis that nebivolol increases systemic and renal nitric oxide (NO) availability using L-N(G) -monomethyl arginine (L-NMMA) as an inhibitor of NO production. METHODS: In a randomized, placebo-controlled, crossover study, patients with essential hypertension were treated with nebivolol for five days, along with a standardized diet and fluid intake. We examined the acute effects of systemic NO synthase inhibition with L-NMMA on brachial blood pressure (bBP), pulse wave velocity (PWV) and central blood pressure (cBP) estimated by applanation tonometry, glomerular filtration rate (GFR), fractional excretion of sodium (FENa ), urinary excretion of both aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaCγ ), and plasma concentrations of nitrate/nitrite (p-NOx ) and vasoactive hormones after five days' treatment with placebo and nebivolol. RESULTS: Nebivolol significantly reduced PWV, bBP, cBP and plasma renin, angiotensin II and aldosterone concentrations. The renal parameters, p-NOx and plasma arginine vasopressin concentration were not changed by nebivolol. There was no difference between nebivolol and placebo in the response to L-NMMA, with LMMA inducing a similar increase in PWV, bBP and cBP and a similar decrease in GFR, uAQP2 and u-ENaCγ and FENa [mean change -0.62% (95% confidence interval {CI} -0.40 to -0.84) during placebo vs. -0.57% (95% CI -0.46 to -0.68; P = 0.564) during nebivolol treatment]. Vasoactive hormones were changed to a similar extend by L-NMMA during administration of nebivolol and placebo. CONCLUSIONS: Nebivolol did not change p-NOx , and inhibition of NO synthesis induced the same response in blood pressure, GFR, renal tubular function and vasoactive hormones during nebivolol and placebo. Thus, the data did not support the hypothesis that nebivolol changes vascular and renal NO availability in patients with essential hypertension.