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The cardiovascular effects and pharmacokinetics of nebivolol were assessed in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive and normotensive control rats. Male Wistar rats were randomly divided to drink tap water (control) or L-NAME solution for 2 weeks. The effects of nebivolol (3 or 10 mg kg(-1) i.v.) on blood pressure (BP), heart rate and BP variability (BPV) were recorded in awake L-NAME and control rats. Short-term and beat-to-beat BPV was assessed by the s.d. and spectral analysis of the BP recordings. Nebivolol pharmacokinetics was studied by means of traditional blood sampling. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; the clearance and the volume of distribution of l-nebivolol were significantly greater than those of the d-enantiomer. The hypotensive response to nebivolol was significantly enhanced in L-NAME rats (Δmean arterial pressure (MAP): -16.1±1.1%, P<0.05 vs. control rats) compared with normotensive animals (ΔMAP: -1.4±2.1%). An analysis of the beat-to-beat BPV showed a greater reduction in VLF BPV in the L-NAME compare with the control rats. Nebivolol significantly reduced the low-frequency/high-frequency ratio in hypertensive L-NAME animals compared with normotensive rats. Short-term BPV was markedly reduced by nebivolol in both experimental groups, although the attenuation of the s.d. of BP recording was greater in L-NAME rats. In conclusion, the hypotensive efficacy of nebivolol is significantly enhanced in L-NAME rats compared with normotensive animals, which is most likely due to a greater reduction in vascular sympathetic activity. Nebivolol markedly attenuated short-term BPV in both experimental groups, suggesting that β-blockers with additional pharmacological actions provide beneficial cardiovascular effects by controlling high BP and its short-term variability.

Inflammation reduces pharmacological response to β1-blockers by down-regulating the target receptor protein. This may contribute to the sub-optimal response to pharmacotherapy with β-blockers. Nebivolol is a third generation β-adrenoceptor (AR) blocker with high selectivity for blocking β1 and β3-agonistic properties. We studied whether response to nebivolol is also reduced by inflammation. Male Sprague-Dawley rats (Inflamed; Mycobacterium butyricum induced) and Control (healthy) were orally administered single doses of 2 mg/kg nebivolol (n=5) or 25 mg/kg propranolol (positive control, n=7-8); ECG recorded for PR and RR interval measurements; serial blood samples were collected for pharmacokinetic assessment. Subsequently, the myocardial β1, β2 and β3-AR levels were measured in homogenized hearts. For propranolol, inflammation resulted in increased concentration but reduced response and down-regulation of β1- AR. The action and disposition of nebivolol were, however, unaffected by inflammation despite the reduced β1-AR levels. The levels of β2 and β3-AR were unaffected by inflammation. The consistency of response to nebivolol despite inflammation may be due to the predominance of contribution of β2 and β3-AR. The lack of an inhibitory effect of inflammation on the clearance of nebivolol is suggestive of mechanisms other than an efficient hepatic metabolism for its low bioavailability. If extrapolated to human, nebivolol may be a more effective cardiovascular drug when inflammatory conditions are present.

Nebivolol is a third-generation β1-adrenoceptor blocker with β3 agonistic properties (AR). It has a low oral bioavailability that is speculated to be due to its hepatic first-pass metabolism. Inflammation is known to suppress the clearance of drugs with efficient hepatic metabolism. However, inflammation does not influence nebivolol clearance. Therefore, we looked into the mechanism involved in the drug's low bioavailability and stereoselectivity. Single 1 mg/kg i.v. or intraperitoneal (i.p.) or 2 mg/kg oral doses were administered to male Sprague-Dawley rats and the plasma nebivolol concentration was measured using chiral and achiral assays. The passage of nebivolol enantiomers through the gut was also measured using everted rat sacs. The serum protein binding of the enantiomers was studied in vitro using the ultrafiltration method. Plasma nebivolol concentrations were significantly lower after p.o., but not after i.p., compared with i.v. doses suggesting the gut as the site of pre-systemic loss. Approximately 50% of the enantiomers were lost during 90 min incubation in the presence of gut. Only 0.1% of the added drug crossed the gut wall with no evidence of stereoselectivity. Thus stereoselectivity in the pharmacokinetics of nebivolol (+ > -) is likely at the level of plasma protein binding. The low nebivolol bioavailability is due to its loss in the gut as well as its limited permeability through the intestinal wall., (Copyright © 2013 John Wiley & Sons, Ltd.)

In the present work, a rapid, sensitive, specific, precise and accurate liquid chromatography-tandem mass spectrometry method for determination of nebivolol in human plasma was developed and validated with a large calibration curve range (50-5000 pg/mL) which can be used for routine drug analysis and bioequivalence studies. Liquid-liquid extraction method was used to extract the analyte from the human plasma. The separation was achieved using Waters symmetry, C18, 4.6 × 150 mm, 5 μm column with formic acid in water, 0.01%, v/v: Acetonitrile (40:60) as a mobile phase. A flow rate of 0.8 mL/min, no splitting and run time 2.00 min was used for the chromatographic analysis of nebivolol. Sensitivity of this method was found to be 30 pg/mL. The analyte was analyzed by mass spectrometry in the multiple reaction monitoring mode. A Turbo-Ion spray source was interfaced between the HPLC and triple quadrupole mass spectrometer (MDS Sciex API 4000). The precursor-product ion m/z 406.00-151.00 for nebivolol and m/z 410.20-151.00 for nebivolol-D4 were used for quantification of an analyte and its IS. The method was validated in terms of accuracy, precision, selectivity, absolute recovery, freeze-thaw stability, bench-top stability, dry extract stability, short and long term stock solution stability, wet extract stability and re-injection reproducibility. The within- and between-batch accuracy was found to lie within the range of 87.00-100.40% and within- and between-batch precision was obtained within the range 0.33-8.67%. The mean recovery of all three concentration levels for drug was obtained 67.67% where as the mean recovery of IS was 68.74%. The %RSD value at higher concentration and lower concentration in all stability experiments was within 15%. This method is free from ion suppression, ion enhancement and any type of abnormal ionization.

Background: We have demonstrated previously that a high-salt diet (HS) produces myocardial fibrosis, left ventricular (LV) dysfunction, and renal insufficiency in adult spontaneously hypertensive rats (SHR), and that blockade of the renin-angiotensin system prevented those adverse effects of HS., Methods and Results: Eight-week-old male SHR were divided into four groups: controls received regular rat chow (0.6 NaCl); the other three were given HS. The second group was given placebo; the third, nebivolol (2 × 10 mg/kg/day) orally; and, the fourth, the same dose of nebivolol by osmotic minipump. Rats received respective treatments for 8 weeks. The data demonstrated that the HS induced increased cardiac mass (2.85 ± 0.05 vs. 5.36 ± 0.22 mg/g; P < .05 in control and HS groups, respectively); LV fibrosis as indicated by higher hydroxyproline concentration; further increase in arterial pressure (161 ± 7 vs. 184 ± 8 mm Hg; P < .05); myocardial ischemia; and LV diastolic dysfunction. Nebivolol ameliorated the adverse cardiac effects of HS, demonstrated by decreased LV mass and fibrosis and improved coronary hemodynamics and LV function., Conclusions: The effects of nebivolol were independent of arterial pressure. The results of this study provide important laboratory data that support a rationale for nebivolol in the treatment of patients with hypertension having diastolic dysfunction with preserved ejection fraction., (Copyright © 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Cardiovascular effects and pharmacokinetics of nebivolol were assessed in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) animals. Male SH and WKY rats were treated with vehicle or nebivolol 0.3, 3, or 10 mg kg(-1) (i.v.) and effects on blood pressure (BP), heart rate, and blood pressure variability (BPV) were recorded. Plasma pharmacokinetics of d- and l-nebivolol was studied by traditional blood sampling. Short-term and beat-to-beat BPV was assessed by standard deviation and spectral analysis of BP recording, respectively. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; clearance of l-nebivolol was significantly greater than d-enantiomer. Clearance of nebivolol was significantly reduced in SHR with regards to WKY animals. Hypotensive response to nebivolol 3 and 10 mg kg(-1) was significantly enhanced in SHR compared with normotensive animals. Spectral analysis of beat-to-beat BPV showed a greater reduction in low frequency BPV in SHR than in WKY rats. Nebivolol 3 and 10 mg kg(-1) significantly reduced ratio low frequency/high frequency BPV only in SHR. Short-term BPV was markedly reduced by nebivolol 0.3, 3, and 10 mg kg(-1) in WKY and SHR. In conclusion, the hypertensive stage in SHR modifies nebivolol pharmacokinetic properties and enhances its hypotensive response due to a greater attenuation in vascular sympathetic activity and enhancement of endothelial-derived NO activity. Nebivolol markedly attenuates short-term BPV in both experimental groups providing beneficial cardiovascular effects by both controlling high blood pressure and its short-term variability.

PURPOSE. The pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of nebivolol are reviewed. SUMMARY. Nebivolol, a third-generation, highly β(1)-specific β-blocker, is labeled for the treatment of hypertension in the United States. In addition to its β-blocking effects, nebivolol has been shown to increase endothelin-dependent nitric oxide, giving it a unique peripheral vasodilatory action. Nebivolol is extensively metabolized by cytochrome P-450 isoenzyme 2D6. In patients with heart failure, certain β-blockers antagonize excessive adrenergic stimulation and can slow the progression of the disease. Clinical trials have compared nebivolol at target dosages of 5 and 10 mg once daily with placebo and, in small trials, with carvedilol in the treatment of adults with chronic heart failure. Nebivolol appears to have beneficial effects in patients with heart failure, including improvements in left ventricular ejection fraction, left ventricular volumes, and exercise capacity. In addition, the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure showed a reduction in morbidity and mortality after treatment with nebivolol when compared with placebo, though this effect appeared to be less than that of other β-blockers currently recommended for the treatment of heart failure. Nebivolol was well tolerated in all clinical trials, with the most frequently reported adverse events including bradycardia, hypotension, and dizziness. To date, no large clinical trials have compared nebivolol with currently recommended β-blockers in patients with heart failure. CONCLUSION. Nebivolol has beneficial effects in heart failure but cannot be considered equivalent to other currently accepted therapies.

This study sought to determine if metoprolol succinate ER (MET), and nebivolol (NEB), a β1-AR with increased bioavailability of nitric oxide (NO), would have differing effects on plasma asymmetric dimethylarginine concentration in hypertensives. It was hypothesized that NEB, a β1-AR antagonist and β3-AR agonist with NO-releasing properties, and MET, only a β1-AR antagonist, would have different effects on plasma asymmetric dimethylarginine (ADMA) concentration. Forty-one hypertensive subjects randomly received either 50 mg of MET (n = 19) or 5 mg of NEB (n = 22) for 4 weeks followed by 100 mg MET and 10 mg NEB for 4 weeks. ADMA and insulin-like growth factor-1 (IGF-1) were measured by enzyme-linked immunosorbent assay kit; endothelial progenitor cells were estimated using fluorescein-labeled monoclonal antibody to KDR and CD133 receptors; arterial augmentation index was measured by radial tonometry. Baseline systolic/diastolic blood pressure was 155.1 ± 18.7/85.3 ± 12.5 mm Hg for MET subjects and 157.6 ± 20.7/87.1 ± 14.0 mm Hg for NEB subjects. Baseline ADMA was 0.32 ± 0.123 μmol/L in the MET group and 0.4035 ± 0.1378 in the NEB group. ADMA increased 44.78% and 72% in the MET group at weeks 4 and 8 (P < .05 for both), respectively, without increase in the NEB group. At week 8, augmentation index was increased in the MET group (P < .05). IGF-1 and endothelial progenitor cells were unchanged by treatment. Plasma ADMA and augmentation index are increased in a dose-dependent fashion by MET but not with NEB., (Copyright © 2011 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Drug interactions are a significant clinical concern, particularly in patients with conditions such as heart disease and hypertension, in whom coadministration of multiple drugs is common. Nebivolol is a selective β(1)-blocker with vasodilatory properties approved for the treatment of hypertension. Drug-drug interactions were investigated when nebivolol was coadministered to subjects classified as poor CYP2D6 metabolizers and extensive CYP2D6 metabolizers who were receiving other drugs commonly administered to patients with hypertension or compounds metabolized by cytochrome P450 (CYP) 2D6. There were no drug-drug interactions when nebivolol was coadministered with hydrochlorothiazide, furosemide, ramipril, losartan, digoxin, or warfarin. Coadministration with fluoxetine (also metabolized by CYP2D6) in extensive CYP2D6 metabolizers impeded the apparent clearance of nebivolol. The authors conclude that nebivolol is safe and well tolerated regardless of genotype and type of medication coadministered.

Unlabelled: Consistent neurohormonal activation of sympatho-adrenal system in patients with chronic heart failure (CHF) and hyperglycemia contributes to development of oxidative stress--one of the most important pathogenetic mechanisms of endothelial dysfunction., Purpose: To study the impact of nebivolol concerning modification of clinical and hemodynamic indicators and parameters of oxidative stress in patients with CHF and with or without concomitant diabetes mellitus type 2 (DM2)., Material: Nebivolol was used in complex therapy of CHF in 82 patients, suffering from NYHA class I - III CHF (EF < 50%) of ischemic genesis with or without comorbid DM2, average age 63.2 +/- 8.2 years., Results: After 8 months of therapy significant improvement of clinical status was observed in both groups, tolerance to physical activity increased (significant reduction of average class of CHF in the group with DM2 from 2.5 +/- 0.58 to 2.125 +/- 0.71, p = 0.001, and in the second group from 2.3 +/- 0.5 to 1.9 +/- 0.4, p = 0.01). We also noted in both groups increase of plasma oxidative resistance (reduction of intensity of fast flash in lipid peroxidation h from 7 to 6 mm, p = 0.016, and from 8 to 6 mm, p = 0.03, respectively) and increase of antioxidant plasma protection (increase of SH-groups from 154.19 to 182.4 mmol/1, p = 0.00035, and from 176 to 205, p = 0.004, respectively)., Conclusion: Nebivolol is a modern neurohormonal modulator, which contributes to reverse evolution of oxidative changes in patients with CHF and hyperglycemia.

Although its clinical use in Europe dates almost 10 years, nebivolol is a beta-blocker that has been only recently introduced in the U.S. market. Like carvedilol, nebivolol belongs to the third generation of beta-blockers, which possess direct vasodilator properties in addition to their adrenergic blocking characteristics. Nebivolol has the highest beta(1)-receptor affinity among beta-blockers and, most interestingly, it substantially improves endothelial dysfunction via its strong stimulatory effects on the activity of the endothelial nitric oxide synthase and via its antioxidative properties. Because impaired endothelial activity is attributed a major causal role in the pathophysiology of hypertension, coronary artery disease, and congestive heart failure, the endothelium-agonistic properties of nebivolol suggest that this drug might provide additional benefit beyond beta-receptor blockade. Although lesser beta-blocker-related side effects have been reported in patients with chronic obstructive pulmonary disease or impotence taking nebivolol, side effects and contraindications overlap those of other beta-blockers. Clinically, this compound has been proven to have antihypertensive and anti-ischemic effects as well as beneficial effects on hemodynamics and prognosis in patients with chronic congestive heart failure. Further studies are now necessary to compare the benefit of nebivolol with that of other drugs in the same class and, most importantly, its prognostic impact in patients with hypertension.

Beta (beta) blockers are widely used for treatment of cardiovascular and noncardiovascular diseases. Nevertheless, their mechanism of action is not fully understood and differs significantly among agents in this class. Chronic increases in adrenergic activity in heart failure result in desensitization of cardiac beta-adrenergic receptor signal transduction and adverse effects on myocytes. By reducing heart rate and decreasing myocardial workload, the pathologic remodeling of the heart may be reversed with beta-blocking agents. Among beta-blockers, there are clear differences in pharmacodynamic and pharmacokinetic properties. Newer beta-blockers differ from older agents with respect to beta-adrenoceptor affinity and selectivity and partial agonist activity, which may affect their mechanism of action and be important in clinical use.The first beta-antagonist compounds were nonselective; the next generation of beta-blockers was selective for beta1-receptors. The most recent beta-blockers may be nonselective or selective, and they have the additional ancillary property of vasodilation. Nebivolol is among the newer third-generation beta-blockers. It is unique in the class, since apart from its cardioselectivity, it also produces nitric oxide-mediated vasodilation. As a result, its hemodynamic profile is clearly different from those of traditional beta-blockers. This review will evaluate this class of agents and the basis for their differences in clinical use.

Background: The major clinical problem of Marfan syndrome (MFS) is the aortic root aneurysm, with risk of dissection when the root diameter approximates 5 cm. In MFS, a key molecule, transforming growth factor-beta (TGF-beta), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-beta blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-beta effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. beta-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation beta-adrenergic blocker nebivolol retains the beta-adrenergic blocker effects on heart rate and further exerts antistiffness effects, typically increased in MFS., Methods: The open-label phase III study will include 291 patients with MFS and proven FBN1 gene mutations, with aortic root dilation (z-score > or =2.5). The patients will be randomized to nebivolol, losartan and the combination of the two drugs. The primary end point is the comparative evaluation of the effects of losartan, nebivolol and the association of both on the progression of aortic root growth rate. Secondary end points include the pharmacokinetics of the two drugs, comparative evaluation of serum levels of total and active TGF-beta, quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3'), pharmacogenetic bases of drug responsiveness. The quality of life evaluation in the three groups will be assessed. Statistical evaluation includes an interim analysis at month 24 and conclusive analyses at month 48., Conclusion: The present study will add information about pharmacological therapy in MFS, supporting the new application of angiotensin receptor 1 blockers and finding beta-adrenergic blockers that may give more specific effects. Moreover, the study will further deepen understanding of the pathogenetic mechanisms that are active in Marfan syndrome through the pharmacogenomic and transcriptomic mechanisms that may explain MFS phenotype variability.

Background: Nebivolol is a third-generation beta(1)-selective beta-blocker that is approved for the treatment of hypertension., Objective: This article reviews the clinical pharmacology of nebivolol and its efficacy and safety profile in clinical studies of hypertension (the US Food and Drug Administration-approved indication) and heart failure (off-label use)., Methods: Pertinent articles were identified through searches of MEDLINE and Current Contents from 1966 through December 15, 2008, using the terms nebivolol, drug interaction, pharmacokinetics, and pharmacology. The reference lists of the identified publications were reviewed for additional references. Abstracts presented at meetings of the American Heart Association and the American Society of Hypertension from 2006 through 2008 were also reviewed. All human clinical trials were included, regardless of design., Results: Twelve published clinical trials were identified that evaluated the use of nebivolol in the management of hypertension; 1 was placebo controlled, 1 was placebo and active controlled, and 10 involved direct comparisons with other antihypertensive agents. Nebivolol was reported to be as effective in lowering blood pressure (BP) as other beta-blockers (atenolol and bisoprolol), angiotensin-converting enzyme inhibitors (lisinopril and enalapril), the angiotensin-receptor blocker telmisartan, and calcium channel blockers (nifedipine and amlodipine). No published studies were identified that evaluated the effect of nebivolol on long-term cardiovascular outcomes. In data from a study in heart failure, nebivolol was associated with a 14% reduction in all-cause mortality and cardiovascular hospitalization at 12 months (P < 0.05). In comparative clinical studies, nebivolol appeared to be well tolerated relative to the other antihypertensive agents studied. The most commonly reported adverse events with nebivolol were fatigue (4%-79%), headache (2%-24%), paresthesia (7%-13%), bradycardia (6%-11%), rhinitis (1%-7%), and dizziness (2%-5%). Because of differences in its pharmacologic properties, nebivolol may have potential advantages in patients who are unable to tolerate traditional beta-blockers (eg, patients with asthma or chronic obstructive pulmonary disease, or men who experience erectile dysfunction while taking antihypertensive therapy)., Conclusions: Nebivolol is a cardioselective beta-blocker that has been reported to be efficacious and well tolerated for achieving BP control in patients with hypertension. Preliminary evidence suggests a potential for reduced mortality in patients with heart failure.

Purpose: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, safety, economic issues, dosage, and place in therapy of nebivolol are reviewed., Summary: Nebivolol is a novel, highly selective beta(1)-receptor blocker that causes peripheral vasodilation by increasing the production and release of nitric oxide and decreasing nitric oxide degradation. The nitric oxide-mediated effects of nebivolol lead to decreases in systemic vascular resistance and large artery stiffness and possible reversal of endothelial dysfunction. Clinical studies have shown nebivolol to be at least as effective at lowering blood pressure as other antihypertensive drugs, including other beta-blockers. The most frequent adverse events reported in nebivolol clinical trials were transient headache, dizziness, and tiredness. In a large trial in patients with heart failure, nebivolol was shown to reduce the composite endpoint of mortality and hospitalizations. Nebivolol is highly lipophilic and is rapidly absorbed after oral administration. The nebivolol dose most commonly used in clinical trials for hypertension was 5 mg daily; no significant further decreases in blood pressure were shown with higher doses. The average dose in clinical trials for patients with heart failure was 5-10 mg daily. Dosage adjustments are recommended in elderly patients and patients with severe renal impairment., Conclusion: Nebivolol is a unique, highly selective beta-blocker with vasodilatory properties mediated through the nitric oxide pathway; it may be useful in the treatment of uncomplicated mild-to-moderate essential hypertension and in patients with heart failure.

A rapid, sensitive and accurate liquid chromatographic-tandem mass spectrometry method is described for the simultaneous determination of nebivolol and valsartan in human plasma. Nebivolol and valsartan were extracted from plasma using acetonitrile and separated on a C18 column. The mobile phase consisting of a mixture of acetonitrile and 0.05 mM formic acid (50:50 v/v, pH 3.5) was delivered at a flow rate of 0.25 ml/min. Atmospheric pressure ionization (API) source was operated in both positive and negative ion mode for nebivolol and valsartan, respectively. Selected reaction monitoring mode (SRM) using the transitions of m/z 406.1-->m/z 150.9; m/z 434.2-->m/z 179.0 and m/z 409.4-->m/z 228.1 were used to quantify nebivolol, valsartan and internal standard (IS), respectively. The linearity was obtained over the concentration range of 0.01-50.0 ng/ml and 1.0-2000.0 ng/ml and the lower limits of quantitation were 0.01 ng/ml and 1.0 ng/ml for nebivolol and valsartan, respectively. This method was successfully applied to the pharmacokinetic study of fixed dose combination (FDC) of nebivolol and valsartan formulation product after an oral administration to healthy human subjects.

Although their specific mechanisms of action are incompletely understood, beta blockers are most likely lower blood pressure and provide target organ protection by several different mechanisms, including inhibition of renin-angiotensine system by decreasing renin release by the jugstaglomerular cells of the kidney, central inhibition of sympathetic nervous system outflow and slowing of heart rate with a decrease in cardiac output. These agents are widely recommended as important parts of antihypertensive regimens and as well as preferred therapies for patients at high risks of coronary heart disease, and including those with angina pectoris, myocardial infarction or heart failure. The third generation beta blockers are distinguished from the earlier class of beta blockers by their vasodilating activity. Labetalol, carvedilol and bucindolol appear to provide a vasodilation primarily through their blockade of alpha-1 rerceptors. Nebivolol is a lipophilic beta reseptor blocker of third generation with distinct beta-1 with selective and vasodilating properties. A number of experimental and human pharmological studies suggest that the vasodilatation is triggered via increasing vascular NO bioavailabilty which is a consequence of stimulation of NO release and antioxidant properties of this compound. The pharmocological profile is characterised by the significant antihypertensive effect as well as lowering of cardiac pre and after load. Nebivolol is well tolerated and does not appear to significantly influence glucose or plasma lipid metabolism. It is devoid of intrinsic sympathomimetic activity (ISA). This article will review patents, novel composition, pharmacology, haemodynamics, antihypertensive efficiency, metabolic effect and tolerability of nebivolol.

Nebivolol is a highly selective beta1-adrenergic blocker that also enhances nitric oxide bioavailability via the L-arginine-nitric oxide pathway, leading to vasodilation and decreased peripheral vascular resistance. It is marketed in Europe for the treatment of hypertension and heart failure and is currently being reviewed for use in the US by the Food and Drug Administration. Nebivolol appears to be well tolerated with an adverse event profile that is at least similar, if not better, than that of other beta-adrenergic blockers. Studies suggest that long-term therapy with nebivolol improves left ventricular function, exercise capacity, and clinical endpoints of death and cardiovascular hospital admissions in patients with stable heart failure. To date, it is one of the only beta-adrenergic blockers that have been exclusively studied in elderly patients. Additionally, the unique mechanism of action of nebivolol makes it a promising agent for treatment of chronic heart failure in high-risk patient populations, such as African Americans. This article will review the pharmacologic and pharmacokinetic properties of nebivolol as well as clinical studies assessing its efficacy for the treatment of heart failure.

Nebivolol is a beta-blocker under U.S. Food and Drug Administration review for the treatment of hypertension. The unique pharmacologic properties of nebivolol include high specificity for the beta-1 receptor and a nitric oxide-mediated vasodilatory effect. The agent provides significant blood pressure reduction from baseline values as compared with placebo. Clinical trials have demonstrated that nebivolol reduces blood pressure similarly to atenolol, bisoprolol, amlodipine, nifedipine, lisinopril, and hydrochlorothiazide. The tolerability of nebivolol is similar to or better than that of these agents. In elderly patients (> or = 70 years of age) with clinically stable congestive heart failure, the addition of nebivolol to the treatment regimen improved the time to all-cause mortality and cardiovascular hospital admissions over that of placebo. If approved, nebivolol would likely be a viable alternative therapy for hypertension and heart failure; however, additional studies are needed in patients having coronary artery disease.

Objective: To describe the pharmacologic and pharmacokinetic properties of a new beta-adrenergic blocker, nebivolol, and review the literature evaluating its efficacy in the treatment of hypertension and heart failure., Data Sources: Articles were identified through searches of MEDLINE (1996-May 2006) and International Pharmaceutical Abstracts (1970-May 2006), using the key word nebivolol. Additional references were selected from the bibliographies of the articles cited. Searches were not limited by language, time, or human subject., Study Selection and Data Extraction: Preclinical studies evaluating the pharmacologic and pharmacokinetic properties of nebivolol in humans were selected for review. Randomized, controlled, blinded clinical trials assessing the efficacy of nebivolol for the treatment of hypertension and heart failure were also included., Data Synthesis: Preclinical data have established nebivolol as a third-generation beta-adrenergic blocker, as it possesses vasodilatory properties that contribute to its hemodynamic effects beyond those achieved at beta-adrenergic receptors. Short-term, randomized, controlled clinical trials have shown nebivolol to be as effective as other antihypertensive therapies at lowering blood pressure. One long-term trial showed a significant reduction in death and hospital admissions for cardiovascular causes when nebivolol was compared with placebo in patients with heart failure (31.1% vs 65.3%; HR 0.86; 95% CI 0.74 to 0.99)., Conclusions: Nebivolol is a novel beta-adrenergic blocker that possesses unique pharmacologic properties, compared with other agents in its class. Nebivolol appears to be as effective as other antihypertensive agents at lowering blood pressure and possesses benefits for patients with heart failure. Additional studies are needed to address the long-term benefits of nebivolol for hypertension, to compare nebivolol with other beta-adrenergic blockers for heart failure, and to investigate the clinical relevance of nitric oxide-mediated vasodilation.

Background: Nebivolol is a selective beta(1)-adrenergic receptor antagonist that causes a direct vasodilator effect attributed to the action on vascular nitric oxide (NO). This study aimed to investigate whether nebivolol or its metabolites induces NO production and to explore the mechanisms underlying this pharmacologic effect., Methods: Conductance and resistance arteries from Wistar-Kyoto rats (WKY) (n = 33) incubated with the fluorescent probe diaminofluorescein-2 (DAF-2) were stimulated with increasing concentrations of nebivolol or its enantiomers and metabolites, and NO release was histologically evaluated., Results: Nebivolol induced a dose-dependent increase in NO levels in the endothelium of both arteries. Levels of NO were significantly increased at 10(-6)mol/L and reached a plateau state at 10(-5)mol/L. Induction of NO is not a general action of beta-adrenoceptor antagonists, as atenolol had no effects. Nebivolol action on NO release was mainly caused by the D-isomer. Moreover NO production is also maintained after hepatic metabolism, as the three main metabolites of nebivolol were able to induce a significant increase in endothelial NO release. Finally, nebivolol-activated calcium mobilization is crucial to NO production., Conclusion: Our study shows the effects of D-nebivolol and its metabolites on endothelial NO production in both conductance and resistance arteries, and clarifies that this effect is realized through a calcium-dependent mechanism.

Objective: Bisoprolol, carvedilol and nebivolol have been shown to be effective in the treatment of heart failure. However, the beta-blocking effects of these drugs have never been compared directly., Methods: Therefore, we performed a randomized, double-blind, placebo-controlled, cross-over trial in 16 healthy males. Subjects received 10 mg bisoprolol, 50 mg carvedilol, 10 mg nebivolol and placebo on the first morning followed by 5 mg bisoprolol once daily, 25 mg carvedilol twice daily, 5 mg nebivolol once daily and placebo for 1 week. Heart rate and blood pressure were measured at rest and exercise 3 and 24 h following intake of the first dose, and immediately before and 3 hours following intake of the last dose of each drug. In addition, effects of the drugs on nocturnal melatonin release were determined, and quality of life (QOL) was evaluated., Results: Heart rate at exercise was decreased at 3 h following intake of the first single dose of each drug by bisoprolol (-24%), carvedilol (-17%) and nebivolol (-15%), and at 24 h following intake of the respective last dose of each drug following 1 week of chronic administration by bisoprolol (-14%), carvedilol (12 h; -15%) and nebivolol (-13%) (p < 0.05 in all cases). Thus, trough-to-peak-ratios at long-term were as follows: Bisoprolol, 58%; carvedilol (12 h), 85%; nebivolol, 91%. Nocturnal melatonin release was decreased by bisoprolol (-44%, p < 0.05) whereas nebivolol and carvedilol had no effect. QOL with carvedilol was slightly but significantly lower than with the other drugs, whereas bisoprolol and nebivolol did not alter QOL., Conclusions: These data show that peak beta-blocking effects of bisoprolol appear stronger than those of nebivolol and carvedilol. On the other hand, nebivolol exerts the highest trough-to-peak-ratio. However, beta-blocking effects of all the three drugs are similar at trough. Only bisoprolol but neither nebivolol nor carvedilol decreased nocturnal melatonin release, a feature which might cause sleep disturbances. Finally, only carvedilol slightly decreased QOL, whereas nebivolol and bisoprolol did not affect QOL. We conclude that different beta-blockers may exert clinically relevant different effects., (2006 S. Karger AG, Basel)

A simple, sensitive and rapid liquid chromatographic/electrospray ionization tandem mass spectrometric method was developed and validated for the quantitation of nebivolol in human plasma. The method involved a simple single-step liquid-liquid extraction with diethyl ether/dichloromethane (70/30). The analyte was chromatographed on Waters symmetry C18 reversed-phase chromatographic column by isocratic elution with water:acetonitrile:formic acid (30:70:0.03, v/v) and analyzed by mass spectrometry in the multiple reaction monitoring mode. The precursor to product ion transitions of m/z 406.4-151.5 and m/z 409.1-228.1 were used to measure the analyte and the internal standard (I.S.), respectively. The chromatographic runtime was 2 min and the weighted (1/x2) calibration curves were linear over the range 50-10,000 pg/mL. The method was validated in terms of accuracy, precision, absolute recovery, freeze-thaw stability, bench-top stability and re-injection reproducibility. The limit of detection and lower limit of quantification in human plasma were 10 and 50 pg/mL, respectively. The within- and between-batch accuracy and precision were found to be well within acceptable limits (<10%). The analyte was stable after three freeze-thaw cycles (deviation <10%). The average absolute recoveries of nebivolol and tamsulosin, used as an internal standard, from spiked plasma samples were 73.4+/-3.7 and 72.1+/-2.0%, respectively. The assay method described here was applied to study the pharmacokinetics of nebivolol.

Purpose: Nitric oxide may stimulate sympathoinhibitory reflexes. Nebivolol is a beta(1) selective adrenergic receptor antagonist with ancillary vasodilating properties by modulating nitric oxide secretion. We investigated whether nebivolol affects autonomic function differently compared with atenolol, another selective beta(1)-blocker without vasorelaxant actions., Methods: Fourteen healthy volunteers (9 men, 5 women; 25 +/- 3.7 years) received single oral doses of 5 mg nebivolol, 50 mg atenolol, and 100 mg atenolol, each taken for a 2-week period. Heart rate variability (HRV) measurements in time- (SDNN; rMSSD; pNN50) and frequency-domain (low frequency-LF; high frequency-HF; LF/HF ratio) were used to study the autonomic effects of the three regimens on the same patients from serial 24-hour ECGs., Results: Both nebivolol and atenolol, the 50 mg dose as well as the 100 mg dose, produced similar decreases in heart rate compared with baseline throughout the 24-h period (from 82 +/- 9 beats/min to 72 +/- 7 beats/min, 69 +/- 9, and 68 +/- 8 beats/min, respectively, p < 0.001). Overall, the administration of each beta -blocker led to directionally similar increases in the HRV variables, which were most significant following 100 mg atenolol. Nebivolol and the 50 mg dose of atenolol produced similar increases in rMSSD and pNN50 during the entire 24-h period, and in HF power, particularly during the nighttime (p < 0.05). However, the coefficient of HF variance resulted in similar values after either beta -blocker regimen. The LF/HF ratio was most reduced throughout the 24-h period following 100 mg atenolol (p < 0.001), and to a similar extent decreased in the nighttime following nebivolol and atenolol 50 mg (p < 0.01)., Conclusions: Nebivolol 5 mg exerts similar effects on time and frequency domain indexes of HRV as 50 mg atenolol. Nebivolol attenuates sympathetic tone, but does not appear to promote vagal activity more than atenolol.

New evidence from recently completed clinical studies performed with nebivolol, a highly selective beta-1 beta-blocker, endowed with additional vasodilating activity mediated by nitric oxide (NO) endothelial release, confirm previous findings that nebivolol differs from other beta-blocking agents and that the combination of beta-1 blockade and NO-mediated vasodilation not only potentiates the blood pressure lowering activity, but leads to a broader favourable haemodynamic profile, which is clinically relevant to the treatment of hypertensive patients. In particular, six new studies focusing on the vasodilation properties of nebivolol demonstrated that: (i) its blood pressure lowering effect is accompanied by a vasodilating action that is seen after single and chronic administration of the usual antihypertensive oral dose of 5 mg once daily; (ii) the vasodilation can be documented systemically, at various regional vascular beds and skin microcirculation, and is accompanied by increased small arterial distensibility; (iii) the NO-endothelium-dependency of its vasodilating action is shown by the model of forearm or cutaneous vasodilating response to acetylcholine and by the blockade of the nebivolol-induced local vasodilation by a blocker of the arginine-NO cascade, L-NMMA. Two more studies demonstrated the ability of nebivolol to increase NO concentrations through preservation of NO from oxidative degradation, and not only by stimulation of its synthesis. Finally, two studies confirmed the favourable haemodynamic action of nebivolol on both systolic and diastolic function and, in particular, an increase in stroke volume, associated with reduction in vascular resistance, resulting in a maintained cardiac output despite reduced heart rate. These properties consistently differentiate nebivolol from non-vasodilating beta-blockers, such as those used for the active comparative studies, i.e. atenolol, metoprolol or bisoprolol. The observation that nebivolol enhances or restores NO-mediated vasodilation in hypertensive patients has important therapeutic implications in view of the well-established protective role of NO against cardiovascular risk factors, and particularly the development of atherosclerosis. Similarly, the favourable haemodynamic profile of nebivolol, as described by the new investigations (preservation of cardiac output, reduction of peripheral resistance and improved diastolic function) appear to have clinically relevant benefits on the impairment in systolic and/or diastolic function often complicating the hypertension.

Nebivolol (Nobiten, Menarini) is a new beta-blocker recommended for the management of essential hypertension, at a dose of 5 mg once daily. It is administered as a racemic mixture of equal proportions of d- and l-enantiomers. As a lipophilic agent, it is metabolised in the liver and transformed in several active metabolites, essentially via the CYP 2D6, an isoform of cytochrome P450 characterized by a genetic polymorphism. Nebivolol is highly specific for beta-1 adrenergic receptors; it is devoid of intrinsic sympathomimetic or membrane stabilising activity. Interestingly enough, it appears to have nitric oxide-mediated vasodilatory effects which might explain its favourable haemodynamic profile. Several comparative trials demonstrated an antihypertensive activity that was similar or slightly superior to that observed with various other reference antihypertensive agents. Nebivolol has an additive antihypertensive effect in combination with hydrochlorothiazide. All studies reported that the drug has a good clinical and biological tolerance profile. Therefore, nebivolol may be recommended as an alternative first-line treatment option for the management of patients with mild to moderate essential hypertension.

Nebivolol (CAS 99200-09-6) is a novel beta 1-selective adrenoceptor antagonist which possesses vasodilating properties and lowers systemic vascular resistance in dogs and humans, presumably by a nitric oxide-related mechanism. In the present study, clearance techniques were applied to anaesthetized male Sprague Dawley rats, and the effects of nebivolol on renal hemodynamics (glomerular filtration rate and renal plasma flow), on urinary excretion of sodium, chloride and potassium, on renal NO-excretion, and on plasma renin activity were studied. Nebivolol doses ranging from 0.1 to 2 mg/kg i.v. were tested. The results revealed that nebivolol dose-dependently increased glomerular filtration rate, urine flow and urinary excretion of sodium and chloride. Potassium excretion was only inconsistently increased and showed no dose dependency. At a dose of 1 mg/kg, the drug also significantly increased renal plasma flow measured as 3H-PAH (p-aminohippurate) clearance. The effect of nebivolol on the glomerular filtration rate could be abolished by L-NMMA (N6-monomethyl-L-arginine) (1 mg/kg), a non-selective inhibitor of NO-synthase and by iminoethyllysine (1 mg/kg), a relatively selective inhibitor of the inducible NO-synthase, but not by 7-nitroindazole (1 mg/kg), a relatively selective inhibitor of the neuronal NO-synthase isoform. The saluretic effect of nebivolol was diminished by all of the three NO-synthase inhibitors, but could not be completely reversed. At a dose of 2 mg/kg, nebivolol increased renal NO-excretion by 70.7%. This effect could be completely abolished by L-NMMA (1 mg/kg). Plasma renin activity was lowered by nebivolol (2 mg/kg) from 14.6 +/- 1.49 to 6.5 +/- 1.66 ng angiotensin I/ml/h (p < 0.01). The results demonstrate that, in anaesthetized rats, nebivolol exerts significant renal vasodilating effects and increases urinary excretion of fluid and solutes. The actions of nebivolol on renal hemodynamics are assumed to be mediated by a stimulation of the NO-synthase, probably the inducible isoform. Since none of the NO-synthase inhibitors could completely abolish the saluretic effect of nebivolol, an additional mechanism, not related to NO, may be involved in the tubular action of this drug.

Unlabelled: Nebivolol is a lipophilic beta1-blocker. It is devoid of intrinsic sympathomimetic or membrane stabilising activity but appears to have nitric oxide-mediated vasodilatory effects. Nebivolol is administered as a racemic mixture of equal proportions of d- and l-enantiomers. The drug does not significantly influence glucose or plasma lipid metabolism and appears to have a protective effect on left ventricular function. At the recommended dosage (5 mg once daily) nebivolol reduces resting diastolic blood pressure as effectively as standard therapeutic dosages of atenolol, metoprolol, lisinopril and nifedipine, as shown in comparative trials. Nebivolol reduced blood pressure significantly more than enalapril 10 mg daily in the short but not the long term, although the enalapril dose may not have been optimal. Nebivolol has an additive effect in combination with hydrochlorothiazide. Standing blood pressure and/or mean 24-hour ambulatory blood pressure is significantly and similarly reduced with nebivolol, atenolol or nifedipine. Nebivolol tended to prevent increases in early morning blood pressure better than nifedipine. Overall response rates to nebivolol therapy (a decrease in sitting/supine diastolic blood pressure to < or = 90 mm Hg or a 10% or > or = 10 mm Hg fall in diastolic blood pressure) ranged from 58 to 81% after 4 to 52 weeks' treatment. In comparative studies, response rates were greater in nebivolol than in enalapril or metoprolol recipients, but not significantly different from those in atenolol or nifedipine recipients. Nebivolol 5 mg once daily is well tolerated in patients with hypertension. Adverse events are infrequent, transient and mild to moderate. Those reported most often include headache, fatigue, paraesthesias and dizziness. Several studies reported no signs of orthostatic hypotension with nebivolol. Comparative trials revealed no significant differences between the frequency and severity of adverse events in patients receiving nebivolol, atenolol, enalapril or placebo; however, the overall incidence of adverse events was greater with nifedipine or metoprolol. Some atenolol or enalapril, but not nebivolol, recipients reported impotence or decreased libido during therapy., Conclusion: Current evidence indicates that nebivolol 5 mg once daily is a well tolerated beta-blocker, which is as effective as once daily atenolol and other classes of antihypertensive agents. It may therefore be recommended as a useful alternative first-line treatment option for the management of patients with mild to moderate uncomplicated essential hypertension.

Aims: Obesity can modify the pharmacokinetics of lipophilic drugs. As beta-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic beta-adrenoceptor blockers in obese and control subjects., Methods: Nine obese (157 +/- 24% of ideal body weight (IBW) mean +/- s.d.) and nine non-obese healthy volunteers (98 +/- 10% IBW), aged 32 +/- 9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic beta-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of beta-adrenoceptor blockers were assessed., Results: The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five beta-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well-correlated (r2 = 0.90; P < 0.01) with their distribution coefficient at pH 7.4 (log D7.4), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar., Conclusions: Lipophilic beta-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects. Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.

Aims: The study was designed to investigate the effects of the H2-receptor antagonists, cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of nebivolol in healthy volunteers., Methods: Twelve healthy volunteers took part in a randomized placebo-controlled cross-over study. Each subject received on three separate occasions placebo, cimetidine (400 mg twice daily) or ranitidine (150 mg twice daily) for 24 h before and 48 h after a single oral dose of nebivolol (5 mg). Nebivolol and its individual (+) and (-) enantiomers were determined tby h.p.l.c., Results: Ranitidine had no significant effect on nebivolol pharmacokinetics. Cimetidine, however, resulted in a 21-23% increase in Cmax of unchanged nebivolol and of each enantiomer plus its hydroxylated metabolites. Cimetidine significantly (p < 0.05) increased the AUC [mean +/- s.d. (95% C.I. of differences in mean)] for unchanged (+/-)-nebivolol [7.76 +/- 3.07 ng ml-1 h with placebo; 11.50 +/- 5.40 (1.75, 8.76) ng ml-1 h with cimetidine], (+)-nebivolol plus its hydroxylated metabolites [73.0 +/- 18.0 ng ml-1 h with placebo; 91.5 +/- 25.7 (1.0, 23.1) ng ml-1 h with cimetidine] and (-)-nebivolol plus its hydroxylated metabolites [101 +/- 32 ng ml-1 h with placebo; 123 +/- 38 (3.3, 27.0) ng ml-1 h with cimetidine]. Statistical analysis of the resting blood pressure and heart rate and exercise data did not suggest any consistent effects of ranitidine or cimetidine upon the pharmacodynamic effects of nebivolol., Conclusions: There was no interaction between ranitidine and nebivolol. Although cimetidine inhibited nebivolol metabolism, it did not have a significant influence on the pharmacodynamics of the drug.

Objective: The pharmacokinetics of a single i.v. dose of the new racemic beta-adrenoceptor-blocker nebivolol [0.073 mg base.kg-1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test)., Methods: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4-5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately., Results: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (Vss) 673 l; volume corrected by real body weight (Vss.kg-1) 11.2 l.kg-1; total clearance (CL) 51.6 h-1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l.h-1) were significantly higher in obese patients. But Vss.kg-1 (9.4 l.kg-1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15-18 l.h-1) and the t1/2 prolonged (32-34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form., Conclusion: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.

Nebivolol hydrochloride (R067555), is a new antihypertensive drug. Aromatic and alicyclic hydroxylation at the benzopyran ring systems of nebivolol are important metabolic pathways. Generally, NMR is used to unambiguously assign the sites of hydroxylation. Because of the low dose rates and the extensive metabolism of nebivolol in the different species, NMR identification is not always possible, and therefore another spectroscopic technique was searched for to address this problem. UV-chromophore absorption is affected by the kind and arrangement of adjacent atoms and groups (auxochromes). The effect of these auxochromes (e.g. -NH2, -NR2, -SH, -OH, -OR and halogens) can be strongly influenced by the pH. This paper proves that HPLC at high pH combined with on-line diode-array detection is an excellent technique for the location of the hydroxyl functions in hydroxylated metabolites of nebivolol. With this technique it is possible to differentiate between glucuronidation at the automatic and aliphatic or alicyclic hydroxyl functions.

Objective: Nebivolol is a selective beta 1-adrenergic receptor blocker possessing an ancillary vasodilating effect. The objective of the present study was to study the haemodynamic and pharmacokinetic properties of nebivolol 5 mg once daily in a double-blind, placebo-controlled cross-over study., Methods: Fifteen patients, 12 men and 3 women, with essential hypertension were investigated. Blood pressure and peripheral circulation were determined after acute oral nebivolol administration, 5 mg daily, and after 4 weeks treatment., Results: The acute effect on blood pressure upon single-dosing was weak and non-significant. After 4 weeks both systolic blood pressure (152 vs 163 mmHg) and diastolic blood pressure (89 vs 97 mmHg) were significantly reduced after nebivolol treatment as compared to placebo. Following the first dose the venous volume was higher on placebo (5.88 ml.100 ml-1 tissue) as compared to active nebivolol treatment (5.17 ml.100 ml-1 tissue), while there were no statistically significant differences with regard to venous plethysmographic findings after 1 month on placebo (5.53 ml.100 ml-1 tissue) or on active treatment (5.97 ml.100 ml-1 tissue). Calculated peripheral resistance did not differ between active treatment (617 units) or placebo (548 units) after the first dose, whereas it was significantly lowered after 4 weeks of nebivolol treatment (483 units) as compared to placebo (593 units)., Conclusions: Oral nebivolol 5 mg once daily lowered blood pressure and heart rate during steady state compared to placebo. Moreover, venous volume was reduced during acute but not steady-state dosing, while peripheral resistance was unaffected in the acute phase but reduced during steady state. Plasma concentrations of the separate enantiomers plus hydroxylated metabolites after the first and last dose in hypertensive patients were similar to those in healthy subjects.