Document Detail

Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation.
Jump to Full Text
MedLine Citation:
PMID:  17326335     Owner:  NLM     Status:  MEDLINE    
Nebivolol is a novel beta1-blocker with a greater degree of selectivity for beta1-adrenergic receptors than other agents in this class and a nitric oxide (NO)-potentiating, vasodilatory effect that is unique among beta-blockers currently available to clinicians (nebivolol is approved in Europe and is currently under review in the US). A NO-potentiating agent such as nebivolol may have an important role in hypertensive populations with reduced endothelial function such as diabetics, African-Americans and those with vascular disease. Nebivolol is a racemic mixture with beta-blocker activity residing in the d-isomer; in contrast, l-nebivolol is far more potent in facilitating NO release. Nebivolol is unique among beta-blockers in that, at doses < 10 mg, it does not inhibit the increase in heart rate normally seen with exercise. The efficacy ofnebivolol has been tested successfully in clinical trials against other agents including other beta-blockers, angiotensin-converting enzyme-inhibitors and calcium channel antagonists in patients with hypertension, angina, and congestive heart failure. The tolerability of nebivolol has been shown to be superior to that of atenolol and metoprolol. In controlled clinical trials, nebivolol has a side effect profile that is similar to placebo, in particular as it relates to fatigue and sexual dysfunction. This article will review published clinical data regarding this cardioselective beta-blocker.
Robert Weiss
Related Documents :
6256045 - Labetalol: potent antihypertensive agent that blocks both alpha- and beta-adrenergic re...
18413195 - Beta-blockers have a beneficial effect upon endothelial function and microalbuminuria i...
22437215 - Investigation of end-digit preference in blood pressure records of hospitalized chinese...
20141425 - Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high...
18628485 - Effects of different levels of cigarette smoke exposure on prognostic heart rate and ra...
1657775 - Sympathetic reactivity during a yohimbine challenge test in essential hypertension.
Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Vascular health and risk management     Volume:  2     ISSN:  1176-6344     ISO Abbreviation:  Vasc Health Risk Manag     Publication Date:  2006  
Date Detail:
Created Date:  2007-02-28     Completed Date:  2007-03-20     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  101273479     Medline TA:  Vasc Health Risk Manag     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  303-8     Citation Subset:  IM    
Androscoggin Cardiology Associates, 2 Great Falls Plaza Auburn, ME 04210, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Adrenergic beta-Antagonists / administration & dosage,  pharmacology*,  therapeutic use
Benzopyrans / administration & dosage,  pharmacology*,  therapeutic use
Blood Pressure / drug effects
Cardiovascular Diseases / drug therapy
Endothelium, Vascular / drug effects
Ethanolamines / administration & dosage,  pharmacology*,  therapeutic use
Heart Rate / drug effects
Hypertension / drug therapy
Nitric Oxide / therapeutic use
Vasodilation / drug effects*,  physiology
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Benzopyrans; 0/Ethanolamines; 030Y90569U/nebivolol; 10102-43-9/Nitric Oxide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Vasc Health Risk Manag
Journal ID (publisher-id): Vascular Health and Risk Management
ISSN: 1176-6344
ISSN: 1178-2048
Publisher: Dove Medical Press
Article Information
Download PDF
? 2006 Dove Medical Press Limited. All rights reserved
Print publication date: Month: 9 Year: 2006
Electronic publication date: Month: 9 Year: 2006
Volume: 2 Issue: 3
First Page: 303 Last Page: 308
ID: 1993984
PubMed Id: 17326335

Nebivolol: A Novel Beta-Blocker with Nitric Oxide-Induced Vasodilatation
Robert Weiss
Androscoggin Cardiology AssociatesAuburn, ME, USA
Correspondence: Correspondence: Robert Weiss, Androscoggin Cardiology Associates, 2 Great Falls Plaza Auburn, ME 04210 USA Tel +1 207 782 4022 Fax +1 207 784 3537 Email


Goal blood pressure (BP), defined as <140/90 mm Hg in uncomplicated hypertension, is attained by only 34% of hypertensive patients in the US (Chobanian et al 2003), 24% of patients in France (Chamontin et al 1998), and 13% of patients in Canada (Joffres et al 2001). These low rates of achieving goal BP indicate that a more aggressive approach to BP management is required on a global scale. One of the most important classes of antihypertensive agents, beta-blockers play a critical role in reducing cardiovascular risk in hypertensive patients. A meta-analysis including almost 19 000 patients concluded that beta-blocker therapy was associated with a 42% reduction in heart failure, a 29% reduction in stroke risk, and a 7% reduction in coronary heart disease in hypertensive patients (Psaty et al 1997). The specific mechanism of action of beta-blockers that reduces BP is not completely understood, however, likely mechanisms include an effect on heart rate, inhibition of the sympathetic nervous system, and inhibition of the renin-angiotensin system. Nebivolol is a novel, highly selective beta-blocker with nonadrenergic vasodilating properties. It has been approved for the treatment of essential hypertension and congestive heart failure in Europe and is currently under review for the treatment of hypertension in the US.


Nebivolol is a racemic mixture of equal proportions of d- and l-isomers. The beta-blocker activity resides in the d-isomer while the facilitation of nitric oxide (NO) release is found in the l-enantiomer (Van Neuten and De Cree 1998; Mason et al 2005).

Nebivolol is well absorbed after oral administration. Peak plasma concentrations are reached in 0.5?2 hours and steady-state plasma levels are reached in 24 hours (McNeely and Goa 1999). Nebivolol has a superior trough-to-peak efficacy ratio compared with atenolol, allowing for ?true? once daily dosing (Simon and Johnson 1993). Absorption of the drug following oral administration is not affected by food, age, gender or body weight (McNeely and Goa 1999; Cheymol et al 1997). Nebivolol is metabolized by the liver, and undergoes extensive first-pass metabolism to active moieties via the cytochrome (CYP)2D6 enzymatic pathway (Gu et al 2003; Weber 2005). The mean terminal half-life is approximately 10 hours (Cheymol et al 1997). Less than 0.1% of unchanged drug is excreted in urine (Shaw, Liu, Zachwieja, et al 2005). Metabolism of nebivolol is subject to a debrisoquine-type genetic polymorphism (Weber 2005). The small percentage of patients who are deficient in CYP2D6 enzyme activity (7% of Caucasians, 2% of African-Americans, 2% of Asians) are considered poor metabolizers of nebivolol (Relling et al 1991; Evans et al 1993; Mizutani 2003). The absolute oral bioavailability of nebivolol is 12% in extensive metabolizers and 96% in poor metabolizers (Van Peer 1991). However, a safety trial in both extensive and poor metabolizers has shown no safety or efficacy differences between these patient groups (Lacourci?re et al 2000).

No significant difference in efficacy or safety have been found in patients with mild or moderate renal disease; patients with severe renal impairment may need a lower initial dose due to impaired clearance (Shaw, Liu, Zachwieja, et al 2005). Similarly, a lower starting dose may be needed in patients with mild or moderate hepatic impairment due to alteration in the drug's pharmacokinetics in these patients (Shaw, Liu, Tu, et al 2005).

Clinical perspective

Nebivolol has a hemodynamic effect suggestive of direct vasodilatation (Gao et al 1991; Van Rooy et al 1991). Evidence in the literature indicates that the vasodilation associated with nebivolol is due to its effects on the L-arginine/NO pathway in the endothelium of various regional vascular beds (Bowman et al 1994; Cockcroft et al 1995; Dawes et al 1999; Ritter 2001; Tzemos et al 2001). Using the dorsal hand vein dilatation model, researchers found that nebivolol had a venodilator effect on the human hand whereas atenolol did not. Further, this effect was inhibited by L-NMMA (NG-monomethyl L-arginine), an inhibitor of NO synthase, indicating that the increased blood flow was due to activation of the L-arginine/NO pathway (Bowman et al 1994). This finding was confirmed in hypertensive patients who showed signs of vasodilatation in forearm arteries after nebivolol infusion. The fact that this vasodilatation was inhibited by L-NMMA supports that it is due to activation of the L-arginine/NO pathway (Cockcroft et al 1995; Dawes et al 1999). The endothelial-dependent vasoconstrictive response seen with L-NMMA infusion was inhibited by nebivolol and not by atenolol (Ritter 2001; Tzemos et al 2001).

In another study, the effect of nebivolol on small artery distensibility in patients with hypertension was compared with that of atenolol. Both drugs were equivalent in reducing BP, but only nebivolol improved small artery distensibility, a measure of arterial compliance or ?stiffness? (Arosio et al 2002). Arterial stiffness has been shown to be an independent predictor of mortality in patients with essential hypertension. Drugs that reduce stiffness may therefore confer a survival advantage (Laurent et al 2001). In an animal model comparison with atenolol, nebivolol infusion showed a statistically significant reduction in a measure of arterial distensibility, namely pulse wave velocity, with no change in mean arterial pressure (McEniery et al 2004). In contrast, atenolol had no effect on pulse wave velocity despite a small drop in mean arterial pressure. This difference suggests that the release of NO mediated by nebivolol, independent of a beta-adrenoceptor-dependent mechanism, an effect not seen with older beta-blockers such as atenolol, may be of particular benefit in patients with impaired arterial compliance, such as those with isolated systolic hypertension (McEniery et al 2004).

Clinical trials also show that nebivolol has an anti-oxidative effect (de Groot et al 2004; Pasini et al 2005). In a study of 20 hypertensive patients compared with 20 matched healthy subjects, nebivolol reduced the oxidative inactivation of NO, a result not seen with atenolol (Pasini et al 2005). In addition, nebivolol inhibited vascular smooth muscle proliferation in a rat aortic smooth muscle cell model via an apparent NO-dependent mechanism (Ignarro et al 2002). Both of these findings suggest that nebivolol may offer anti-atherosclerotic activity, a particular benefit, if verified, in patients with arterial disease.

Nebivolol comparative efficacy

Clinical trials suggest that on a weight-for-weight basis, nebivolol is ten times more potent than atenolol. In one study, the effect of doses of nebivolol (2.5 mg/day, 5.0 mg/day, and 10.0 mg/day) on exercise-induced increases in heart rate and blood pressure in 25 male hypertensive volunteers was compared with that of atenolol 50 mg/day and 100 mg/day and of placebo using a double-blind, crossover design and a parallel, placebo group (n=7) (Simon and Johnson 1993). At 24 hours after dosing, sitting and standing diastolic and systolic blood pressures and heart rates (at rest and during submaximal exercise) were reduced to the same extent by nebivolol and atenolol.

However, the hemodynamic effect of nebivolol appears to be different from that of atenolol. In a double-blind, randomized, prospective study in patients with essential hypertension, atenolol reduced cardiac output, stroke volume, and heart rate. In contrast, nebivolol reduced peripheral resistance and increased stroke volume, preserving cardiac output (Kamp et al 2003). The effects of nebivolol demonstrated in this study suggest that the drug may be important in treating heart failure, where preservation of cardiac output is critical.

Nebivolol 5 mg/day was compared with metoprolol 100 mg twice daily (BID) in 155 patients with mild-to-moderate essential hypertension (Uhlir et al 1991). Target blood pressure was attained in 79% of nebivolol-treated patients and 66% of those in the metoprolol group. There were fewer adverse events reported by patients in the nebivolol group. In a second study, nebivolol 5 mg/day was compared with metoprolol 100 mg BID in 80 newly diagnosed hypertensive patients (Celik et al 2006). After 6 months of treatment, the researchers found that both drugs significantly reduced BP and heart rate, with a more profound bradycardic effect seen in the metoprolol group. In contrast, only nebivolol significantly reduced oxidative stress, insulin resistance index, and plasma levels of P-selectin, a cell-surface adhesion molecule believed to play a role in the initiation of atherosclerosis (Celik et al 2006).

Nebivolol 5 mg/day was also compared with the angiotensin-converting enzyme (ACE) inhibitor lisinopril 20 mg/day in 68 patients with uncomplicated mild-to-moderate hypertension, treated for 12 weeks. The primary endpoints of the study were response rate, where patients were defined as ?normalized? responders if their blood pressure values were <140/90 mm Hg at study end, or as ?non-normalized? responders if the reduction in blood pressure was ?10 mm Hg compared with baseline; and changes in sitting blood pressure at the end of the study. Patients were randomly assigned to one of the study arms, however, a significant difference in sitting diastolic blood pressure (DBP) was found between the 2 groups at baseline. Analysis of covariance of the raw data including baseline values as covariate suggested that DBP and heart rate were significantly lower in the nebivolol-treated group at week 8. This difference disappeared, however, when an analysis of variance for repeated measures was performed, which indicated a significant reduction in systolic blood pressure (SBP), DBP, and heart rate in both groups. There was a statistically significant difference in favor of the nebivolol group in the distribution of responders and non-responders at week 8. Lisinopril and nebivolol were equally well tolerated (Rosei et al 2003).

Nebivolol 2.5?5 mg/day was compared with the calcium channel antagonist, amlopidine, 5?10 mg/day (Mazza et al 2002) in elderly patients (?65 years). In this double-blind, multicenter, randomized trial, efficacy was similar between the two groups. Both drugs were well tolerated, however, there was a higher incidence of adverse events such as headache and ankle edema in the group treated with amlodipine. In a double-blind study, the efficacy of nebivolol 5 mg/day was compared with that of the sustained-release calcium channel antagonist, nifedipine, 20 mg/BID in 51 patients with mild-to-moderate hypertension over a 12 week-treatment period (Lacourci?re et al 1992). The treatment response rate was 69% for nebivolol and 59% for nifedipine. Both treatment groups showed a significant reduction in BP, with no significant difference in BP reduction between the groups either in clinic BP or in 24-hour ambulatory BP. Nebivolol appeared to be superior to nifedipine in preventing the usual early morning increase in BP. Beta-blockers have usually been found to increase plasma cholesterol (Ames 1986; Lacourci?re et al 1990). However, both agents were associated with a significant decrease in cholesterol after 12 weeks of treatment, 5% and 3%, for nebivolol and nifedipine, respectively.

The largest double-blind study in hypertension included 909 patients with mild-to-moderate hypertension (Weiss et al 2005). Nebivolol in doses of 1.25?40 mg/day were compared with placebo over 12 weeks. Placebo-subtracted reductions in trough sitting BP (SBP/DBP) ranged from 6.6/5.1?11.7/8.3 mm Hg and were dose dependent. Reported adverse events were: headache (7.1 vs 7.4% placebo, fatigue (3.6 vs 2.5% placebo, nasopharyngitis (2.9% vs 7.4% placebo), diarrhea (2.8% vs 2.5% placebo) and dizziness (2.8 vs 3.7% placebo). The incidence of typical beta-blocker adverse effects was very low and no different from placebo including erectile dysfunction (0.2% vs 0.0% placebo), decreased libido (0.1% vs 0.0% placebo), dyspnea (1.0% vs 0.0% placebo) and bradycardia (0.7% vs 0.0% placebo).

Nebivolol tolerability

In controlled clinical trials, nebivolol demonstrates a side effect profile similar to placebo, most notably in regards to side effects commonly associated with beta-blockers, such as fatigue and sexual dysfunction (Weber 2005). Quality of life was evaluated in a double-blind, randomized trial of 314 patients with hypertension who were treated with either nebivolol 5 mg/day or losartan 50 mg/day for 12 weeks (Van Bortel et al 2005). The two agents had an equivalent effect in reducing SBP but the decrease in DBP was slightly greater with nebivolol. Interestingly, the side effect profile of losartan, an angiotensin receptor antagonist known for few side effects, was no different than that of nebivolol. In a separate study, nebivolol (5 mg/day) was compared with atenolol (50 mg/day) and placebo in 364 patients in general practice (Van Nueten et al 1998). There was no significant difference in BP or in sitting heart rate between the treatment groups, and there was no significant difference in the incidence of side effects between the groups, except for significantly more complaints of sexual dysfunction in the atenolol group.

Beta-blockers have been associated in the past with a risk of sexual dysfunction, however recent meta-analysis suggests that the risk of this adverse event is not substantial (Ko et al 2002). A recent clinical trial studied 29 out of 44 hypertensive men who complained of erectile dysfunction while taking atenolol, metoprolol or bisoprolol. The researchers found that after switching to nebivolol therapy, 20 of the 29 noted significant improvement in erectile function without a significant change in BP (Doumas et al 2006). It is reasonable to speculate that this improvement in erectile function may be due to the involvement of NO in erectile dysfunction and its potentiation with nebivolol therapy (Doumas et al 2006).

Nebivolol in other cardiovascular diseases

Nebivolol (5 mg/day) versus placebo has been evaluated in the treatment of angina (Cherchi et al 1991). In a placebo-controlled trial of 16 patients, nebivolol therapy significantly prolonged treadmill time to 1 mm ST depression from 555 ? 37sec to 667.5 ? 49 sec (p<0.05). Anginal threshold was also significantly delayed from 697 ? 51 sec to 767 ? 64 sec (p<0.05). Further testing of nebivolol in a dose ranging, single-blind trial (2.5 mg/day, 5 mg/day, and 10 mg/day) was performed in 10 patients with stable angina; 5 of the patients also had a history of myocardial infarction (Ulvenstam 1991). The doses were titrated in 2 week intervals in this trial. The time to 1 mm ST change increased at all 3 doses of nebivolol compared with placebo.

In a double-blind, placebo-controlled study of maximal and submaximal exercise testing conducted in patients with ischemic left ventricular dysfunction but no overt signs of heart failure, both atenolol and propanolol reduced resting heart rate and improved left ventricular ejection fraction compared with placebo. Only nebivolol produced a parallel, downward shift of the pressure-volume relationship during early diastolic filling and improved the early peak filling rate compared with placebo (Rousseau et al 1996). In addition, compared with baseline, nebivolol therapy increased maximal exercise duration by 44 sec, a statistically significant difference from baseline (p=0.007 vs baseline), whereas the improvements seen with placebo and atenolol, 7 sec and 13 sec respectively, were not statistically significant changes from baseline.

In patients with ischemic left ventricular dysfunction without clinical congestive heart failure (Stoleru et al 1993), maximal exercise function increased more in those treated with nebivolol 5 mg/day than in those treated with atenolol 50 mg/day (p<0.0077). This was associated with an improved pressure-volume relationship during early diastolic filling and improved early peak filling rate. An improvement in left ventricular ejection fraction and cardiac output was found with nebivolol, but not with atenolol.

The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) was a double-blind, randomized, multicenter placebo-controlled trial conducted in Europe. SENIORS was the first randomized, controlled clinical trial with the power to demonstrate efficacy specifically in elderly patients with heart failure. The aim of the study was to assess the effect of nebivolol on mortality and cardiovascular hospital admissions in elderly patients (?70 years) with heart failure, regardless of ejection fraction (Flather et al 2005). The SENIORS researchers note that this age inclusion criterion makes the study population closely resemble the actual population of heart failure patients, where the average age is 76 years; in contrast, the average age of patients enrolled in previous, large heart failure studies was 63 years.

All 2128 patients enrolled in the SENIORS study had a history of chronic heart failure, as evidenced by hospital admission within the past 12 months with a diagnosis of congestive heart failure on discharge or a documented ejection fraction of 35% or less within the previous 6 months. Following randomization, 1067 patients received nebivolol 1.25 mg/day titrated to 10 mg/day; 1061 patients received placebo. The primary outcome of the study was a composite of all-cause mortality or cardiac hospitalization (time to first event) during a 21 month follow up period. At baseline, the mean ejection fraction was 36%, with 35% of patients having an ejection fraction >35%. More than two thirds of patients (68%) had a history of coronary artery disease. The primary outcome occurred in 31.1% (n=332) of nebivolol-treated patients and 35.3% (n=375) of patients receiving placebo (hazard ratio [HR] 0.86; 95% confidence interval [CI]: 0.74?0.99; p=0.039). The all-cause mortality rate was 15.8% (n=169) in the nebivolol group and 18.1% (n=192) in the placebo group (HR 0.88, 95% CI 0.71?1.08; p=0.21) Subgroup analysis by age less than the median age in SENIORS (75.2 years) in patients with an ejection fraction less than 35% allowed comparison with the results of previous trials; the HR for primary outcome was 0.73 (95% CI, 0.56?0.96), the HR for all cause mortality alone was 0.62 (95% CI, 0.43?0.89). These results suggest that the efficacy of nebivolol in this patient subgroup is similar to that seen in previous studies conducted with bisoprolol, metoprolol, and carvedilol (Flather et al 2005).

Nebivolol efficacy in black hypertensive patients

The efficacy and tolerability of nebivolol in black hypertensive patients was assessed in a randomized, placebo-controlled, multicenter trial conducted in Europe and the US that included 509 patients with essential hypertension (Van Neuten et al 1997). Doses of 0.5 mg/day, 1.0 mg/day, 2.5 mg/day, 5 mg/day and 10 mg/day of nebivolol were compared with placebo. Doses of nebivolol at 2.5 mg/day, 5 mg/day, and 10 mg/day were shown to be more effective than placebo in a dose-dependent manner. There was no significant difference in efficacy seen between black (22% of the study population) and white patients, with response rates of 58% and 62%, respectively (response defined as reduction of DBP to <90 mm Hg or by ?10 mm Hg from baseline). The drug was well tolerated.

The efficacy of nebivolol in black patients may in part be due to improved NO levels. The importance of NO in black patients has been shown in the treatment of congestive heart failure where a regimen of hydralazine and nitrates reduced mortality by 43% over a standard regimen including an ACE inhibitor and a beta-blocker (Taylor et al 2004). Nebivolol has been shown to restore NO bioavailability in blacks to the level observed in whites, independent of beta1-selective blockade, by augmenting NO release and reducing nitroxidative stress in the vascular endothelium (Mason et al 2005). These findings suggest that nebivolol may be a more effective antihypertensive in black patients than older beta-blockers.


Beta-blockers are important agents in cardiovascular medicine, proving critically important in the management of hypertension and heart failure and in reducing cardiovascular risk. Nebivolol is a novel highly cardioselective beta-blocker with antihypertensive efficacy similar to that of other beta-blockers, but with tolerability better than older agents in its class, which may permit nebivolol to be used more widely and effectively than other beta-blockers. Nebivolol's vasodilating effect, its anti-atherosclerotic effect, and its positive effects on arterial compliance suggest that it may provide more cardiovascular benefits than traditional beta-blockers, particularly in patients with isolated systolic hypertension, diabetics, black patients, and patients with known vascular disease.

Ames RP. The effects of antihypertensive drugs on serum lipids and lipoproteins. II. Non-diuretic drugsDrugs 1986;32:335–57. [pmid: 2877846]
Arosio E,De Marchi S,Prior M,et al. Effects of nebivolol and atenolol on small arteries and microcirculatory endothelium-dependent dilation in hypertensive patients undergoing isometric stressJ Hypertens 2002;20:1793–7. [pmid: 12195121]
Bowman AJ,Chen CPL,Ford GA. Nitric oxide-mediated venodilator effects of nebivololBr J Clin Pharmacol 1994;38:199–204. [pmid: 7826820]
Celik T,Iyisoy A,Kursaklioglu H,et al. Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patientsJ Hypertens 2006;24:591–6. [pmid: 16467663]
Chamontin B,Poggi L,Lang T,et al. Prevalence, treatment, and control of hypertension in the French population: Data from a survey on high blood pressure in general practiceAm J Hypertens 1998;11:759–62. [pmid: 9657642]
Cherchi A,Lai C,Pirisi R,Onnis E. Antianginal and anti-ischemic activity of nebivolol in stable angina of effortDrug Invest 1991;3(Suppl 1):86–96.
Cheymol G,Woestenborghs R,Snoeck E,et al. Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjectsEur J Clin Pharmacol 1997;51:493–8. [pmid: 9112066]
Chobanian AV,Bakris GL,Black HR,et al. National High Blood Pressure Education Program Coordinating CommitteeThe seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 reportJAMA 2003;289:2560–72. [pmid: 12748199]
Cockcroft JR,Chowienczyk PJ,Brett SE,et al. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanismJ Pharamcol Exp Ther 1995;274:1067–71.
Dawes M,Brett SE,Chowienczyk PJ,et al. The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertensionBr J Clin Pharmacol 1999;48:460–3. [pmid: 10510163]
Groot AA,Mathy MJ,van Zwieten PA,et al. Antioxidant activity of nebivolol in the rat aortaJ Cardiovasc Pharmacol 2004;43:148–53. [pmid: 14668581]
Doumas M,Tsakiris A,Dourna S,et al. Beneficial effects of switching from ?-blockers to nebivolol on the erectile function of hypertensive patientsAsian J Androl 2006;8:177–82. [pmid: 16491268]
Evans WE,Relling MV,Rahman A,et al. Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black AmericansJ Clin Invest 1993;91:2150–4. [pmid: 8098046]
Flather MD,Shibata MC,Coats AJS,et al. the SENIORS InvestigatorsRandomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)Eur Heart J 2005;26:215–25. [pmid: 15642700]
Gao Y,Nagao T,Bond RA,et al. Nebivolol induces endotheliumdependent relaxations of canine coronary arteriesJ Cardiovasc Pharmacol 1991;17:964–9. [pmid: 1714022]
Gu Z-M,Robinson RA,Cai L,et al. Metabolism Study Of 14C-Nebivolol In Humans With Different CYP2D6 Genotypes [online] [abstract]AAPS PharmSci 2003;5(4):T3362. Accessed 11 January 2006. URL:
Ignarro LJ,Sisodia M,Trinh K,et al. Nebivolol inhibits vascular smooth muscle cell proliferation by mechanisms involving nitric oxide but not cyclic GMPNitric Oxide 2002;7:83–90. [pmid: 12223177]
Joffres MR,Hamet P,MacLean DR,et al. Distribution of blood pressure and hypertension in Canada and the United StatesAm J Hypertens 2001;14:1099–105. [pmid: 11724207]
Kamp O,Sieswerda GT,Visser CA. Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertensionAm J Cardiol 2003;92:344–8. [pmid: 12888152]
Ko DT,Hebert PR,Coggey CS,et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunctionJAMA 2002;288:351–7. [pmid: 12117400]
Lacourci?re Y,Poirier I,Boucher S,Spendar J. Comparative effects of diltiazem sustained-release formulation and metoprolol on ambulatory blood pressure and plasma lipoproteinsClin Pharmacol Ther 1990;48:318–24. [pmid: 2401129]
Lacourci?re Y,Poirer L,Lefebvre J,et al. Comparative effects of a new cardioselective beta-blocker nebivolol and nifedipine sustained-release on 24-hour ambulatory blood pressure and plasma lipoproteinsJ Clin Pharmacol 1992;32:660–6. [pmid: 1353507]
Lacourci?re Y,van Neuten L,Binder C,et al. Evaluation of the safety of nebivolol 5 mgo, d. in mild to moderate hypertensive subjects characterized as poor metabolizers for debrisoquine, in comparison to extensive metabolizersJanssen Research Foundation Clinical Research Report. 2000
Laurent S,Boutouyrie P,Asmar R,et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patientsHypertension 2001;37:1236–41. [pmid: 11358934]
Mason RP,Kalinowski L,Jacob RF,et al. Nebivolol reduces nitroxidative stress and restores nitric oxide bioavailability in endothelium of black AmericansCirculation 2005;12:3795–801. [pmid: 16330685]
Mazza A,Gil-Extremera B,Maldonato A,et al. Nebivolol vs amlodipine as first-line treatment of essential arterial hypertension in the elderlyBlood Press 2002;11:182–8. [pmid: 12126265]
McEniery CM,Schmitt M,Qasem A,et al. Nebivolol increases arterial distensibility in vivoHypertension 2004;44:305–10. [pmid: 15262912]
McNeely W,Goa KL. Nebivolol in the management of essential hypertension: a reviewDrugs 1999;57:644–51.
Mizutani T. PM frequencies of major CYPs in Asians and CaucasiansDrug Metab Rev 2003;35:99–106. [pmid: 12959412]
Pasini AF,Garbin U,Nava MC,et al. Nebivolol decreases oxidative stress in essential hypertensive patients and increases nitric oxide by reducing its oxidative inactivationJ Hypertens 2005;23:589–96. [pmid: 15716701]
Psaty BN,Smith NL,Siscovick DS,et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysisJAMA 1997;277:139–745.
Relling MV,Cherrie J,Schell MJ,et al. Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjectsClin Pharmacol Ther 1991;50:308–13. [pmid: 1680593]
Ritter JM. Nebivolol: endothelium-mediated vasodilating effectJ Cardiovasc Pharmacol 2001;38(Suppl 3):S13–16. [pmid: 11811387]
Rosei EA,Rizzoni D,Comini S,et al. the Nebivolol-Lisinopril Study GroupEvaluation of the efficacy and tolerability of nebivolol versus lisinopril in the treatment of essential arterial hypertension: A randomized, multicenter, double blind studyBlood Press 2003;12(suppl 1):30–5.
Rousseau MF,Chapelle F,van Eyll C,et al. Medium-term effects of beta-blockade on left ventricular mechanics: a double-blind, placebocontrolled comparison of nebivolol and atenolol in patients with ischemic left ventricular dysfunctionJ Cardiac Failure 1996;2:15–23.
Shaw AA,Liu S,Zachwieja LF,et al. Effects of varying degrees of renal impairment on the pharmacokinetic disposition of nebivololClin Pharmacol Ther 2005;77:P38.
Shaw AA,Liu S,Tu HC,et al. Effects of hepatic impairment on the pharmacokinetic disposition of nebivolol: A dual acting nitric oxide modulating/cardioselective beta1-antagonistClin Pharmacol Ther 2005;77:P41.
Simon G,Johnson ML. Comparison of antihypertensive and B1-adrenoreceptor antagonist effect of nebivolol and atenolol in essential hypertensionClin Exper Hypertens 1993;15:501–9. [pmid: 8098243]
Stoleru L,Wijns W,van Eyll C,et al. Effects of d-nebivolol and lnebivolol on left ventricular systolic and diastolic function: comparison with d-l-nebivolol and atenololJ Cardiovasc Pharmacol 1993;22:183–90. [pmid: 7692155]
Taylor AL,Ziesche S,Yancy C,et al. the African-American Heart Failure Trial InvestigatorsCombination of isosorbide dinitrate and hydralazine in blacks with heart failureN Engl J Med 2004;351:2049–57. [pmid: 15533851]
Tzemos N,Lim PO,MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension. A randomized, double-blind, crossover studyCirculation 2001;104:511–14. [pmid: 11479245]
Uhlir O,Fejfusa M,Havranek K,et al. Nebivolol versus metoprolol in the treatment of hypertensionDrug Invest 1991;3(Suppl 1):107–10.
Ulvenstam G. A single-blind dose-ranging study of the effect of nebivolol in patients with angina pectorisDrug Invest 1991;3(Suppl 1):199–200.
Van Bortel LM,Bulpitt C,Fici F. Quality of life and antihypertensive effect with nebivolol and losartanAm J Hypertens 2005;18:1060–6. [pmid: 16296572]
Van Nueten L,Dupont AG,Vertommen C,et al. A dose-response trial of nebivolol in essential hypertensionJ Human Hypertens 1997;11:139–44. [pmid: 9140802]
Van Nueten L,De Cree J. Nebivolol: Comparison of the effects of dl-nebivolol, d-nebivolol, l-nebivolol, atenolol, and placebo on exercise-induced increases in heart rate and systolic blood pressureCardiovasc Drugs Therapy 1998;12:339–44.
Van Nueten L,Taylor FR,Robertson JI. Nebivolol vs atenolol and placebo in essential hypertension: a double-blind randomized trialJ Human Hypertens 1998;12:135–40. [pmid: 9504355]
Van Peer A,Snoeck E,Woestenborghs R,et al. Clinical pharmacokinetics of nebivolol: a reviewDrug Invest 1991;3(Suppl 1):25–30.
Van Rooy P,Van Nueten L,De Cree J. Nebivolol blood pressure reduction in relation to beta blockade in healthy volunteersDrug Invest 1991;3(Suppl 1):174–76.
Weber MA. The role of new ?-blockers in treating cardiovascular diseaseAm J Hypertens 2005;18:169S–175S. [pmid: 16373195]
Weiss RJ,Weber MA,Carr AA,et al. Nebivolol in the treatment of patients with stage 1 and stage 2 hypertension: Results of a randomized, double-blind, placebo-controlled studyAm J Hypertension 2005;18:A96.

Article Categories:
  • Review

Keywords: nebivolol, hypertension, beta-blocker.

Previous Document:  Metabolic syndrome: the danger signal in atherosclerosis.
Next Document:  Methodological issues in cardiovascular epidemiology: the risk of determining absolute risk through ...