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PubMed1998

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 pressure.

The effects of racemic nebivolol, 2.5, 5.0, and 10.0 mg; d-nebivolol, 2.5 mg; l-nebivolol, 2.5 mg; atenolol, 50 mg; and placebo, each given once daily for 7 days, on exercise-induced increases in heart rate and systolic blood pressure were compared in a seven-way double-blind randomized crossover trial in 14 healthy male volunteers. Observations on these variables were made 3 and 24 hours after dosing on the first and last days of therapy. Similar effects on both exercise-induced tachycardia and increases in systolic blood pressure were seen with nebivolol 5.0 mg and with d-nebivolol 2.5 mg; l-nebivolol 2.5 mg was no different from placebo. These data show that the beta-blocking effects of nebivolol reside in the d-isomer. A dose-related response was evident with racemic nebivolol in inhibiting exercise-induced tachycardia over the range of doses studied. Whereas the effects of atenolol on both exercise-induced tachycardia and increases in systolic blood pressure were fully evident on the first day of treatment, those of nebivolol, especially with regard to heart rate, and, to a lesser degree, systolic pressure, were greater on the final than on the first day. Nebivolol had a clearly superior trough-to-peak efficacy ratio than atenolol.

Adrenergic beta-Antagonists↗

PubMed1993

Effects of D-nebivolol and L-nebivolol on left ventricular systolic and diastolic function: comparison with D-L-nebivolol and atenolol.

(D-L) Nebivolol is a new beta 1-selective adrenoceptor blocker which in normal individuals preserves rest and exercise hemodynamics. We assessed the effects of the enantiomers (L- and D-nebivolol) on left ventricular (LV) systolic and diastolic function and compared their effects with those of the racemic mixture. LV angiography (+Millar) was performed before and after intravenous (i.v.) infusion of either D- or L-nebivolol (1.25-2.5 mg, n = 22) in patients with ischemic heart disease and previous myocardial infarction. Neither L- nor D-nebivolol produced significant changes in heart rate (HR), peak (+) dP/dt, (dP/dt) DP40, cardiac index (CI) or ejection fraction (EF). Diastolic distensibility, evaluated from the shift of the pressure-volume data at the time of mitral valve opening, did not improve after D- or L-enantiomers administration. In contrast, both D-L-nebivolol 2.5 mg (n = 9) and atenolol 15 mg (n = 9) significantly reduced HR and peak (+) dP/dt, but in comparison to atenolol D-L nebivolol improved EF (+4% after D-L nebivolol vs. -4% after atenolol; p < 0.05 D-L nebivolol vs. atenolol) and maintained cardiac output CO, (+2% vs. -21%; p < 0.05 between groups). Moreover, unlike any of the other drugs in the study, the racemate shifted the diastolic pressure-volume data downward, suggesting improved LV distensibility. The beneficial effects of nebivolol on LV systolic and diastolic function appears to require the presence of both D- and L-enantiomers.

Adrenergic beta-Antagonists↗

PubMed2003

Lack of inverse agonistic activity of nebivolol, its D- and L-enantiomers and of in vivo metabolized nebivolol in human myocardium.

The pharmacological profile of nebivolol may be mediated by its enantiomers and/or its hydroxylated metabolites. Therefore, the cardiac effects of the nebivolol enantiomers as well as of serum specimens containing hydroxylated nebivolol metabolites were studied in human myocardium. For control, the beta1-adrenoceptor selective antagonist metoprolol was used. After pre-stimulation of force of contraction with forskolin (0.3 microM) or isoprenaline (0.01 microM), force developement was decreased only at high concentrations (> or =300 nM) of nebivolol or its enantiomers in isolated trabeculae. Nebivolol and its enantiomers, in contrast to metoprolol (0.4 microM: -72% basal force), produced only minor negative intropic effects in isolated trabeculae under basal conditions. Basal force of contraction was not decreased by in vivo metabolized nebivolol in pharmacological concentrations. Neither D- nor L-nebivolol (30 microM) influenced myofibrillar Ca2+ responsiveness. Nebivolol and the D-enantiomer, but not the L-enantiomer (all 0.5 microM), improved the frequency-dependent force generation. D-Nebivolol, in contrast to L-nebivolol, was a beta1-adrenoceptor selective compound in membrane preparations from non-failing donor hearts. In conclusion, nebivolol and its enantiomers as well as in vivo metabolized nebivolol produce only minor negative inotropic effects. This and the finding that nebivolol and its D-enantiomer improve the frequency-dependent force generation may be of particular advantage when treating patients with already compromised cardiac function.

Adenylyl Cyclases↗

PubMed2003

Comparison of the new cardioselective beta-blocker nebivolol with bisoprolol in hypertension: the Nebivolol, Bisoprolol Multicenter Study (NEBIS).

OBJECTIVES: The aim of the present study was to evaluate the antihypertensive efficacy of the highly beta(1)-selective adrenergic antagonist nebivolol in comparison with bisoprolol in the treatment of mild to moderate essential hypertension. METHODS: This multicenter, single-blind, randomized, parallel-group 16-week study involved a 4-week placebo run-in, followed by a 12-week treatment period (5 mg nebivolol or 5 mg bisoprolol). Patients (n = 273) eligible for the study had a sitting diastolic blood pressure (DBP) between 95 and 110 mm Hg and a systolic blood pressure (SBP) </=180 mm Hg at the end of the placebo run-in period. The primary endpoint of the study was the percentage of responders achieving DBP normalization (</=90 mm Hg) or a DBP reduction of at least 10 mm Hg. RESULTS: The baseline SBP and DBP were similar in the two groups. Both SBP and DBP decreased gradually and significantly upon treatment. The two treatments had similar effects on the mean change from the baseline for both DBP (nebivolol -15.7 +/- 6.4 mm Hg vs. bisoprolol -16.0 +/- 6.8 mm Hg) and SBP. A high proportion of responders was noted in both groups (nebivolol 92.0% vs. bisoprolol 89.6%) and there was no significant difference between the treatments. The overall number and incidence of spontaneously reported adverse events were slightly, but not significantly lower for nebivolol (8 events; 5.8%) than for bisoprolol (12 events; 8.9%). CONCLUSIONS: The findings of the present trial indicate that 5 mg nebivolol once daily is an effective antihypertensive agent. It can therefore be recommended as a useful alternative first-line treatment option for the management of patients with mild to moderate essential hypertension.

Adrenergic beta-Antagonists↗

PubMed1995

Comparative assessment of antihypertensive efficacy of DL-nebivolol and D-nebivolol in patients with confirmed mild to moderate hypertension.

We compared the antihypertensive activity of DL- and D-nebivolol in patients with essential hypertension on clinic and 24-h ambulatory blood pressure (BP) and during dynamic exercise as well. After a 4-week placebo run-in period, 30 patients (mean age 48 years) were randomly allocated to double-blind treatment with either DL-nebivolol 5 mg or D-nebivolol 2.5 mg once daily for 4 weeks. After an interim single-blind placebo washout of 2-4 weeks, all patients crossed over double-blind to the alternative DL- or D-nebivolol treatment for 4 weeks. The results show that DL- and D-nebivolol produced similar reductions in clinic trough (delta systolic/delta diastolic BP (delta SBP/delta DBP): -10/-8 and -13/-9 mm Hg, respectively, all p < 0.0001 vs. placebo), 24-h ambulatory (-12/-11 and -13/-11 mm Hg, respectively, all p < 0.0001), and peak exercise BP (-13/-6, both p < 0.01; and -13/-7 mm Hg, both p < 0.0001, respectively) as compared with placebo (SBP/DBP clinic 147/99, ambulatory 147/94, exercise 211/103 mm Hg). Our results showing superimposable clinic and ambulatory BP profiles as well as exercise BP responses with DL- and D-nebivolol treatment do not confirm results of animal pharmacologic experiments in which the L-isomer potentiated the antihypertensive effect of the D-isomer.

Adolescent↗

PubMed2004

Pharmacological mechanisms of clinically favorable properties of a selective beta1-adrenoceptor antagonist, nebivolol.

Nebivolol is a racemic mixture of d- and l-enantiomers. The drug is characterized by beta(1)-adrenoceptor selectivity and long-acting beta-blockade exerted predominantly by d-enantiomer. Nebivolol is devoid of intrinsic sympathomimetic activity and has no relevant membrane stabilizing action. Antiproliferative properties of nebivolol were demonstrated in endothelial and smooth muscle cell cultures. Infusion of nebivolol causes a vasodilation in all vascular beds by endothelial-dependent mechanism involving stimulation of beta(3)-adrenoceptors as well as by endothelial-independent mechanism. Nebivolol possesses not only direct vasodilator properties but also augments the action of endothelium-dependent vasodilators. The antioxidant property of nebivolol can at least in part explain why treatment with this drug enhances eNOS activity and minimizes the reperfusion-induced myocardial injury. The systemic effects of nebivolol in humans have an unusual hemodynamic profile. In contrast to traditional beta-adrenoceptor antagonists, nebivolol reduces preload and afterload due to systemic vasodilation and improves arterial distensibility. At 5 mg daily nebivolol effectively reduces systolic and diastolic blood pressure over a 24-h period. During treatment with nebivolol arterial pressure follows the natural circadian rhythm. Trough-to-peak ratio for nebivolol is 0.9. It has been demonstrated in numerous placebo-controlled studies that exercise tolerance is not reduced during nebivolol therapy. By chronic administration to patients with left ventricular dysfunction nebivolol increases myocardial contractility. Nebivolol produced no significant changes in lipid levels, insulin sensitivity or glucose tolerance. These findings make nebivolol a promising therapeutic tool for the treatment of arterial hypertension and chronic heart failure.

Adrenergic beta-1 Receptor Antagonists↗

PubMed2006

The influence of CYP2D6 phenotype on the clinical response of nebivolol in patients with essential hypertension.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * The variability in drug metabolism has been recognized as an important factor in the occurrence of adverse effects or lack of therapeutic efficacy. * The metabolism of the third-generation beta(1)-receptor antagonist nebivolol has been shown to be highly dependent on cytochrome P450 2D6 enzymatic activity in preclinical studies. WHAT THIS STUDY ADDS: * This paper assesses the role of a cytochrome P450 2D6 gene defect on the antihypertensive response to nebivolol in a clinical setting. * Despite significant differences in drug disposition, the chronic administration of nebivolol produced similar efficacy and tolerability in hypertensive patients either characterized as poor or extensive metabolizers of the drug. * The study offers insight into the relative contribution of nebivolol enantiomers in systemic blood pressure control. AIMS: Nebivolol is a beta(1)-adrenergic receptor antagonist with vasodilating properties used in the treatment of hypertension. It is administered as a racemic mixture (D- and L-nebivolol) and is highly metabolized by the cytochrome P-450 2D6 (CYP2D6). The purpose of this study was to determine the role of CYP2D6 phenotypes on the efficacy and tolerability of nebivolol during chronic administration to patients with essential hypertension. METHODS: Two hundred and eighteen patients were genotyped and phenotyped for CYP2D6 activity, allowing to find and match 14 poor metabolizers (PMs) with 23 extensive metabolizers (EMs). Patients took rac-nebivolol 5 mg daily for 12 weeks. Blood pressure (BP), heart rate, adverse events, plasma levels of the two enantiomers D- and L-nebivolol and their corresponding hydroxymetabolites were assessed. RESULTS: The metabolic disposition of nebivolol was enantioselective and highly influenced by CYP2D6 phenotypes. Mean steady-state plasma concentrations of D- and L-nebivolol were 10- and 15-fold greater in PMs than in EMs, respectively (P < 0.0001). Despite these differences in the pharmacokinetics of nebivolol, EMs and PMs displayed similar BP responses. Mean reductions in sitting systolic and diastolic BPs were -11/-10 +/- 9/4 mmHg in EMs and -11/-9 +/- 10/5 mmHg in PMs. Side-effects were mild to moderate and not different between groups. CONCLUSION: Polymorphisms in the gene encoding CYP2D6 significantly influenced the metabolism of nebivolol, but not its antihypertensive efficacy and tolerability. The similar clinical response between EMs and PMs could be explained by the contribution of active hydroxylated metabolites of nebivolol to its antihypertensive actions in EMs.

Adult↗

PubMed1999

Nebivolol in the management of essential hypertension: a review.

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.

Animals↗

PubMed1997

Pharmacological properties of nebivolol in man.

OBJECTIVES: The aims of the present study were to determine (1) the beta 1-blocking potency and (2) the beta 1-adrenoceptor selectivity of nebivolol in man after repeated dosing (7 days) compared with that after a single oral intake and with that after atenolol for 7 days. In addition, it was investigated whether (3) nebivolol has alpha 1-blocking properties which might at least in part explain the vasodilating property of the compound. METHODS: Twelve healthy subjects were randomized in an open, two-way cross-over study. beta 1-Blocking potency and beta 1-adrenoceptor selectivity of nebivolol 5 mg once daily (o.d.) were compared with those of atenolol at three doses (25, 50 and 100 mg) o.d. Measurements were performed after 1 and 7 days of drug intake. beta 1-Adrenoceptor potency was assessed by the percentage decrease in exercise-induced tachycardia (delta EIT) during beta-blockade. beta 1-Selectivity of nebivolol and atenolol were investigated using the heart rate response to isoprenaline at equipotent beta 1-blocking dosages of both drugs. alpha 1-Blockade of nebivolol was measured using the phenylephrine dose-response test. RESULTS: delta EIT after a single oral dose of nebivolol 5 mg (10%) was significantly smaller than after nebivolol 5 mg o.d. for 7 days (15%). After 1 week of treatment no difference was seen in delta EIT between nebivolol 5 mg o.d. and atenolol 25 mg o.d. (16%). At these dosages the suppression in isoprenaline-induced tachycardia by both drugs did not differ (CD20 ratio 1.7). In contrast to atenolol 25 mg, after 1 week of nebivolol 5 mg o.d., blood pressure decreased. This decrease averaged 10% and-like in a study with hypertensive patients-was similar with that after atenolol 100 mg o.d. None of the phenylephrine test parameters changed from pre-study values after nebivolol. CONCLUSIONS: beta 1-Blockade of nebivolol 5 mg is larger after repeated dosing than after a single oral intake. After once daily repeated dosing nebivolol 5 mg and atenolol 25 mg are equipotent in beta 1-antagonism. No difference in beta 1-selectivity is observed between the two drugs. Nebivolol has no additional alpha 1-blocking property, which may at least in part explain its vasodilating effect.

Adrenergic beta-Antagonists↗

PubMed2001

Nebivolol: endothelium-mediated vasodilating effect.

Nebivolol, a racemic mixture of (S,R,R,R) and (R,S,S,S) enantiomers, is the most beta1-selective adrenoceptor antagonist currently available for clinical use. However, its haemodynamic effects differ from those of classical beta-adrenoceptor antagonists as a result of a vasodilating action. Nebivolol is devoid of alpha-adrenergic antagonist actions, and the detailed mechanism of its vasodilator action is unknown. Nebivolol relaxes precontracted strips of canine coronary and carotid artery only if the endothelium is intact, and such relaxation is antagonized by inhibition of nitric oxide (NO) synthase, implicating the endothelial L-arginine/NO mechanism. Nebivolol and atenolol have been compared in phenylephrine preconstricted dorsal hand veins of 11 healthy men. Nebivolol caused venodilation, which was antagonized by N(G)-monomethyl-L-arginine (LNMMA), whereas atenolol did not, suggesting that such a mechanism could also operate in human veins. Venodilation could be functionally important in reducing cardiac pre-load. Beta2-adrenoceptor stimulation increases forearm blood flow (FBF) by activating the L-arginine/NO pathway but nebivolol lacks direct beta2-adrenoceptor agonist activity. Resistance vessel function has been studied by measuring FBF by venous occlusion plethysmography in healthy men during brachial artery infusions of racemic nebivolol and its enantiomers, atenolol, carbachol (a stable analogue of acetylcholine that vasodilates this vascular bed, in part by activating the L-arginine/NO pathway), nitroprusside (a NO donor that causes non-endothelium-dependent vasodilation through the same effector mechanism as endothelium-dependent agonists) and LNMMA. Nebivolol (354 microg/min) increased FBF by 91 +/- 18% (mean +/- SE, n = 8; p < 0.01), whereas an equimolar dose of atenolol had no significant effect. LNMMA inhibited responses to nebivolol and carbachol to a significantly greater extent than it reduced responses to nitroprusside. Antagonism of nebivolol by LNMMA was abolished by L-arginine. The (S,R,R,R) and (R,S,S,S) enantiomers caused similar increases of FBF. To determine whether brachial artery infusion of nebivolol causes vasodilation in the forearm resistance vasculature of patients with essential hypertension and to investigate the possible involvement of the L-arginine/NO pathway, we studied otherwise healthy volunteers with uncomplicated essential hypertension. Nebivolol (88.5, 177 and 354 microg/min, each dose for 6 min) caused similar vasodilatation as in normotensive subjects, and these responses were sensitive to inhibition by LNMMA. If acute effects of nebivolol on the L-arginine/NO pathway persist during chronic treatment of patients with hypertension or heart failure, this could reduce cardiac after-load as well as pre-load, improve organ perfusion and reduce atherogenesis and thrombosis.

Adrenergic beta-1 Receptor Antagonists↗

PubMed1990

The l-enantiomer of nebivolol potentiates the blood pressure lowering effect of the d-enantiomer.

In this study the effect of l-nebivolol on the blood pressure lowering action of d-nebivolol was investigated after intraperitoneal administration of the drugs to spontaneously hypertensive rats. Doses of l-nebivolol which did not affect blood pressure when given alone potentiated the decrease in systolic and diastolic blood pressure induced by 1.25 mg.kg-1 d-nebivolol. The potentiating effect of l-nebivolol was seen at doses higher than 0.16 mg.kg-1. At 1.25 mg.kg-1 d-nebivolol significantly reduced the heart rate, an effect which was not potentiated by l-nebivolol in doses up to 1.25 mg.kg-1. Higher doses of l-nebivolol (2.5 and 5.0 mg.kg-1) in combination with 1.25 mg.kg-1 d-nebivolol not only lowered the blood pressure further, but also significantly reduced the heart rate; thus at these doses the enantiomers together exerted more pronounced beta 1-adrenoceptor blocking properties. This is probably disadvantageous, because d,l-nebivolol has been shown to decrease arterial blood pressure in hypertensive patients and animals before it reaches its maximal beta 1-adrenoceptor blocking effect. Therefore, the racemic mixture of 50% d-nebivolol and 50% l-nebivolol seems to contain the two compounds in near optimal proportions for an antihypertensive effect.

Adrenergic beta-Antagonists↗

PubMed2006

Comparing beta-blocking effects of bisoprolol, carvedilol and nebivolol.

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.

Adrenergic beta-Antagonists↗

PubMed1992

Exercise tolerance with nebivolol and atenolol.

Patients treated with beta-blocking agents often complain of fatigue during exercise. Exercise capacity is decreased under this condition. Nebivolol is a new beta 1-adrenoceptor antagonist with a particular hemodynamic profile, which might be due to an ancillary property. Five milligrams once daily seems the optimal dose for antihypertensive treatment. In a double-blind, placebo-controlled crossover study, the effects of nebivolol on maximal and endurance exercise capacity are compared with those of atenolol in healthy volunteers. The hemodynamic and metabolic effects during exercise are also studied. Nebivolol 5 mg once daily and atenolol 100 mg once daily decrease blood pressure at rest similarly. At these dosages nebivolol shows a smaller decrease in heart rate than atenolol. During exercise, the rise in systolic blood pressure and heart rate is less depressed with nebivolol than with atenolol. In contrast to atenolol, nebivolol does not decrease maximal and endurance exercise capacity, and does not increase perceived exertion significantly. Changes in hemodynamics influence maximal exercise capacity. Since nebivolol has less effect on exercise hemodynamics than atenolol, this might explain why maximal work capacity is not changed during nebivolol. During endurance exercise metabolic effects are thought to be more important. Under nebivolol glycerol and NEFA production is less depressed during exercise and might explain the preserved endurance capacity. These data suggest less beta blockade during nebivolol than during atenolol at the dosages used in this study. In conclusion, at a dose known to be antihypertensive, nebivolol does not alter exercise capacity significantly in healthy volunteers.

Adrenergic beta-Antagonists↗

PubMed1997

A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine.

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.

Adult↗

PubMed2000

Effect of nebivolol, a novel beta 1-selective adrenoceptor antagonist with vasodilating properties, on kidney function.

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.

Adrenergic beta-1 Receptor Antagonists↗

PubMed2004

Estrogen receptor-mediated vascular responsiveness to nebivolol: a novel endothelium-related mechanism of therapeutic vasorelaxation.

Nebivolol is a highly selective and lipophilic beta1-adrenergic receptor antagonist with vasodilating characteristics attributed mainly to endothelial generation of nitric oxide (NO). Coincidently, rapid vascular vasodilating effects of estradiol are also widely reported and membrane-initiated signaling by estrogen receptor (ER), leading to generation of NO, parallels the vasodilating effects observed for nebivolol. Thus, we hypothesized that the NO-dependent vasodilating effect attributed to nebivolol may be partially mediated through its interaction with the membrane-associated form of ER. The objective of this study was to examine the ER-mediated/endothelium-dependent vascular responses to nebivolol and the specific binding properties of nebivolol to ER. In isolated rat aortic rings, the endothelium-dependent vasodilating effect of nebivolol was significantly blocked by the use of the potent ER antagonist, ICI 182,780. In contrast, in the absence of intact endothelium, nebivolol-induced vasorelaxation was not blocked by ICI 182,780, strongly suggesting that nebivolol-elicited vasorelaxation is partially dependent on ER-mediated pathways. Further, we examined the binding of nebivolol to ER (MCF-7 cells) by radioligand binding assay and revealed specific binding kinetics with an estimated DC50 of 5 x 10 M, coinciding with the approximate EC50 of nebivolol as a vasorelaxant. In conclusion, the endothelium-dependent vascular response to nebivolol is attributed partially to its interaction with ER.

Animals↗

PubMed2006

Nebivolol: a third-generation beta-adrenergic blocker.

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.

Adrenergic beta-Antagonists↗

PubMed2002

Nebivolol inhibits vascular smooth muscle cell proliferation by mechanisms involving nitric oxide but not cyclic GMP.

The objective of this study was to elucidate the mechanisms by which nebivolol, a cardio-selective beta-adrenergic receptor antagonist, inhibits rat aortic smooth muscle cell (RASMC) proliferation. Nebivolol was compared with DETA-NO and S-nitroso-N-acetylpenicillamine (SNAP), two nitric oxide (NO) donor agents, and alpha-difluoromethylornithine (DFMO), a known inhibitor of ornithine decarboxylase (ODC). All four test agents inhibited RASMC proliferation in a concentration-dependent manner, with nebivolol being the most potent (IC(50) = 4.5 microM), whereas atenolol, another relatively selective beta(1)-blocker, was inactive. DFMO, nebivolol, and DETA-NO interfered with cell proliferation in a cell-density-dependent manner, the lower the cell density the greater the inhibition of cell proliferation. The cytostatic effects of nebivolol and DETA-NO were completely independent of cyclic GMP, as neither ODQ (cytosolic guanylyl cyclase inhibitor) nor zaprinast (cyclic GMP phosphodiesterase inhibitor) affected the antiproliferative action of nebivolol or DETA-NO. The cytostatic effects of nebivolol, SNAP, and DFMO were largely prevented by the addition of excess putrescine, but not ornithine, to cell cultures. Moreover, nebivolol caused a marked reduction in the intracellular levels of putrescine, spermidine, and spermine. Like DFMO, nebivolol and DETA-NO interfered with the G(1)-phase to S-phase cell cycle transition in RASMC. These observations confirm previous findings that DFMO and NO interfere with RASMC proliferation by inhibiting ODC and polyamine production and provide evidence that nebivolol works by the same mechanism.

Animals↗