Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nebivolol is a highly selective beta(1)-adrenoceptor blocker with additional vasodilatory properties, which may be due to an endothelial-dependent beta(3)-adrenergic activation of the endothelial nitric oxide synthase (eNOS). beta(3)-adrenergic eNOS activation has been described in human myocardium and is increased in human heart failure. Therefore, this study investigated whether nebivolol may induce an eNOS activation in cardiac tissue. Immunohistochemical stainings were performed using specific antibodies against eNOS translocation and eNOS serine(1177) phosphorylation in rat isolated cardiomyocytes, human right atrial tissue (coronary bypass-operation), left ventricular non-failing (donor hearts) and failing myocardium after application of the beta-adrenoceptor blockers nebivolol, metoprolol and carvedilol, as well as after application of BRL 37344, a specific beta(3)-adrenoceptor agonist. BRL 37344 (10 microM) significantly increased eNOS activity in all investigated tissues (either via translocation or phosphorylation or both). None of the beta-blockers (each 10 microM), including nebivolol, increased either translocation or phosphorylation in any of the investigated tissues. In human failing myocardium, nebivolol (10 microM) decreased eNOS activity. In conclusion, nebivolol shows a tissue-specific eNOS activation. Nebivolol does not activate the endothelial eNOS in end-stage human heart failure and may thus reduce inhibitory effects of NO on myocardial contractility and on oxidative stress formation. This mode of action may be of advantage when treating heart failure patients.
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PMID:ENOS is not activated by nebivolol in human failing myocardium. 1671 62

Nebivolol is a third-generation beta-adrenoceptor antagonist. It differs from other beta-adrenoceptor antagonists as it combines highly selective beta(1)-adrenoceptor antagonist properties with nitric oxide-mediated vasodilatory actions and beneficial effects on endothelial function. Nebivolol is approved in Europe and several other countries for the treatment of essential hypertension and in Europe for the treatment of stable mild or moderate chronic heart failure (CHF) in addition to standard therapies in elderly patients aged >or=70 years. Nebivolol is an effective antihypertensive agent and is well tolerated in patients with hypertension. The drug also effectively decreased the composite endpoint of mortality and cardiovascular hospital admission in elderly patients with CHF and was generally well tolerated in this population. Nebivolol should be considered as an alternative first-line treatment option for patients with uncomplicated mild to moderate essential hypertension and in elderly patients with CHF.
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PMID:Nebivolol: a review of its use in the management of hypertension and chronic heart failure. 1690 72

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.
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PMID:Nebivolol: new therapy update. 1692 66

Nebivolol is a cardioselective lipophilic beta-blocker devoid of intrinsic sympathomimetic and membrane-stabilizing actions. The pharmacological profile differs from that of conventional cardioselective beta3-blockers in that it displays nitric oxide- (NO) mediated vasodilator activity. The net hemodynamic effect of nebivolol is the result of a balance between the depressant effects of beta3-blockade and an action that tends to maintain cardiac output, presumably connected with its afterload reducing vasodilator effect. Recent studies suggest that nebivolol may also restore endothelial dysfunction. Long-term follow-up studies indicate that the compound is efficacious and safe both in patients with mild hypertension and those with stable angina. An interesting effect of chronic nebivolol therapy in elderly patients with mild hypertension is the reversal of a depressor effect into a pressor effect on standing. This action indicates that nebivolol has advantages over other antihypertensive drugs and that it may protect elderly hypertensive patients from orthostatic complaints. The observation that nebivolol improves exercise capacity in non-claudicant hypertensives is also of clinical interest. Nebivolol resembles serotonin reuptake inhibitors in that it is metabolized by CYP450 2D6 and, therefore, concomitant treatment with serotonin uptake inhibitors may lead to overdosing. Nebivolol compared to placebo does not significantly reduce the mortality risk in elderly subjects. The effects of biological age and comorbidities may be responsible for this finding. In conclusion, clinical studies suggest that nebivolol is effective and safe in patients with hypertension, angina pectoris and heart failure. The beneficial effects on endothelial function, autonomic control and exercise capacity are of considerable clinical interest.
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PMID:Nebivolol: a review of its clinical and pharmacological characteristics. 1696 Nov 65

Beta-blockers exert their effects through blockade of beta-adrenoceptors. First-generation beta-blockers non-selectively block beta1- and beta2-adrenoceptors, while second-generation beta-blockers predominantly block beta1-adrenoceptors. Third-generation beta-blockers possess additional vasodilator properties. Nebivolol is a highly selective b1-blocker with additional vasodilator effects which are mediated by the endothelial L-arginine/nitric oxide system. The hemodynamic action of nebivolol differs from those of first and second-generation beta-blockers: it acutely decreases peripheral resistance (while first and second-generation beta-blockers cause an initial transient increase in peripheral resistance) and decreases in heart rate that are less pronounced than those evoked by first and second-generation beta-blockers. Beta-blockers are frequently used in the treatment of hypertension, coronary artery disease and chronic heart failure. Nebivolol should thus be a suitable drug for treating these diseases, especially since nitric oxide has vasodilator and anti-atherogenic effects. One long-term trial (the SENIORS study) has shown that nebivolol, compared with a placebo, reduced death and hospital admission in elderly patients with chronic heart failure. Additional studies are needed to investigate the clinical relevance of nitric oxide-mediated vasodilatation and to show if nebivolol is as efficacious as the other beta-blockers--metoprolol, bisoprolol and carvedilol--in the treatment of chronic heart failure.
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PMID:[Role of the L-arginine/nitric oxide system in the action of nebivolol]. 1709 42

Recent analyses in the temporal trends of mortality and hospitalization in patients with chronic heart failure showed marginal changes in the last 20 years, particularly in the elderly. According to the Euro Heart Survey program and other observational reports, only 37-50% of patients with heart failure are treated with beta-blockers, with a dosage that is approximately half the target dose of clinical trials. The most frequent reason for the limited use of beta-blockers and the suboptimal doses prescribed, is age greater than 70 years. Only two multicenter, double-blind, randomized, placebo-controlled, parallel group trials; the Effects of Nebivolol on Left Ventricular Function in Elderly Patients with Chronic Heart Failure (ENECA) and the Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization Seniors with Heart Failure (SENIORS), both with nebivolol, have been specifically aimed to assess the efficacy of beta-blockade in elderly heart failure patients. The results of such trials demonstrated that the drug is well tolerated and effective in reducing mortality and morbidity, and that the beneficial clinical effect is independent of the baseline ejection fraction.
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PMID:Nebivolol for heart failure in the elderly. 1748 67

Nebivolol is a third generation beta-blocker. It is highly selective for the beta1-adrenoceptor, and has additional nitric oxide-mediated vasodilating and antioxidant properties, along with a favourable metabolic profile. Nebivolol is well tolerated by patients with hypertension and heart failure. Although several smaller studies were conducted with nebivolol in hypertensive patients, no large randomised clinical trials have been performed to prove efficacy on hard clinical end points. In patients with heart failure, a large mortality/morbidity trial was conducted, and nebivolol was shown to reduce the composite end point of mortality and hospitalisations. Nebivolol is registered, in Europe, for mild-to-moderate, uncomplicated hypertension and mild-to-moderate heart failure; and outside Europe, for hypertension. This review describes experimental and clinical data regarding this selective beta-blocker with vasodilating and antioxidant effects.
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PMID:Nebivolol: third-generation beta-blockade. 1766 35

Nebivolol is a beta1-adrenergic receptor antagonist that also reduces blood pressure by evoking endothelial NO production and vasodilation. We aimed at assessing whether nebivolol induces NO production also in the heart and delineating the molecular mechanisms involved. Using the fluorescent probe diaminofluorescein, we found that nebivolol induces a dose-dependent NO production in the heart, statistically significant already at 10(-7) mol/L. It is not an effect because of the blockade of beta1-adrenergic receptor, because this effect is not shared by another drug of the same class, atenolol. Because nebivolol has been reported to act as an agonist on other beta-adrenergic receptors, we tested NO production in the presence of receptor antagonists. Nebivolol was not able to induce NO production in presence of the beta3-antagonist SR59230A, indicating a fundamental role for beta3-adrenergic receptors in cardiac NO production by nebivolol. Moreover, inducible NO synthase inhibition abolishes NO release in the heart, indicating that nebivolol induces NO production by acting on the inducible isoform of the enzyme. The action of nebivolol on inducible NO synthase was confirmed by real-time PCR experiments, showing cardiac overexpression of inducible NO synthase but not neuronal NO synthase or endothelial NO synthase, after 5 hours of treatment with nebivolol. In conclusion, our study demonstrates that nebivolol also stimulates NO production in the heart. This action of nebivolol is exerted via a signaling pathway starting from the activation of beta3-adrenergic receptors and leading to overexpression of inducible NO synthase. Cardiac NO production by nebivolol could participate in the cardiovascular effects of nebivolol treatment in patients affected by hypertension and heart failure.
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PMID:Nebivolol induces nitric oxide release in the heart through inducible nitric oxide synthase activation. 1766 92

Heart failure (HF) is a major public health problem among the elderly. The syndrome of HF may arise in the presence of either a depressed or apparently normal left-ventricular ejection fraction (LVEF). The latter entity is more common in the elderly. In elderly patients with HF, prescription of a beta-adrenoceptor antagonist may raise concerns regarding efficacy and tolerability. Because of these concerns, but also as a result of a paucity of published data, beta-adrenoceptor antagonists are under-prescribed to elderly patients with HF in general practice. We review the evidence regarding the efficacy and tolerability of beta-adrenoceptor antagonist therapy in elderly patients with HF. We found three major sources of evidence: one prospective, randomised controlled trial (RCT), SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure); a subgroup meta-analysis of elderly patients included in systolic HF trials; and a large number of observational studies. SENIORS showed that the third-generation beta-adrenoceptor antagonist nebivolol reduces the risk of all-cause mortality or cardiovascular admission in elderly patients (aged > or =70 years) with HF and a broad range of LVEF. The subgroup meta-analysis of RCTs showed that beta-adrenoceptor antagonists reduce mortality in elderly patients (aged 60-80 years) with systolic HF, and that the benefit is similar to that observed in non-elderly patients (aged <60 years). The observational studies showed a beneficial effect of beta-adrenoceptor antagonists in elderly populations in daily practice, including those with depressed and preserved LVEF. However, the effect of beta-adrenoceptor antagonists on all-cause mortality may be lower in very elderly patients (aged >75 years). Approximately two-thirds of elderly patients with HF tolerate a beta-adrenoceptor antagonist, but only 40-70% of the target doses recommended in RCTs are achieved. Some clinical variables may predict low beta-adrenoceptor antagonist tolerability, such as low systolic blood pressure, higher New York Heart Association HF severity class, advanced age and ischaemic cause of HF. Furthermore, prescription of a high diuretic dose and calcium channel antagonists may also decrease beta-adrenoceptor antagonist tolerability. However, it is difficult to identify on clinical grounds patients intolerant to any beta-adrenoceptor antagonist dose. Low-dose therapy (<50% target dose) may be effective in an elderly population with HF, but prescription of at least a medium dose (> or =50% target dose) may achieve a higher benefit. In conclusion, although elderly patients with HF take lower doses of beta-adrenoceptor antagonists, these agents are still effective and overall well tolerated in this population. Elderly patients with HF should therefore not be denied beta-adrenoceptor antagonist therapy. The dilemma relies on dose-benefit balance, as higher doses would be more effective but may raise tolerability concerns. The beneficial effects of use of beta-adrenoceptor antagonists in elderly patients with HF and preserved LVEF need to be further confirmed in large RCTs.
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PMID:beta-Adrenoceptor antagonists in elderly patients with heart failure: a critical review of their efficacy and tolerability. 1802 May 35

Chronic heart failure (CHF) is a common and disabling condition with morbidity and mortality that increase dramatically with advancing age. There is some evidence available about beta-blocker therapy in the elderly. The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) and retrospective subgroup (elderly) analyses of landmark clinical trials in stable systolic heart failure have provided data supporting the use of beta-blocker as baseline therapy in heart failure in the elderly. However, beta-blocker is still less frequently used in elderly compared to younger patients. There are many reasons, one of which is that available data on elderly patients are not as convincing as those pertaining to their younger counterparts. There is uncertainty or disagreement about whether beta-blockers are equally beneficial and well tolerated in elderly heart failure patients as in younger ones. In other words, the level of evidence regarding beta-blocker therapy in the elderly is not regarded as high as that in younger patients. Indeed, the senior heart failure population, which in fact comprises the majority of all heart failure patients, is in general less well studied, both experimentally and clinically, than younger populations. Both clinical studies and experience indicate good tolerability in the use of beta-blocker in the elderly. Although beta-blockers are well tolerated by the elderly, target doses (based on previous clinical trials) may be difficult to achieve. The question is whether we should use the same target dose in the elderly as that in younger patients. Theoretically, the most effective dose is the highest dose tolerated, which may differ across different age groups. Is it time to abandon the "target dose" for the "highest dose tolerated"? The time has come to carry out active research to achieve better documentation of evidence based heart failure management in the elderly for the benefit of a large number of elderly patients with heart failure. We need clinical trial data that show definite improvement in outcomes as well as a clear-cut, favourable benefit-risk analysis involving beta-blockers in typical older heart failure patients irrespective of comorbidity and polypharmacy. Until the above is available, it may be wiser to adhere to beta-blocker therapy, which at present is better documented than other heart failure therapies in the elderly.
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PMID:Beta-blocker therapy in heart failure in the elderly. 1802 98


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