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 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.
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PMID:Pharmacological mechanisms of clinically favorable properties of a selective beta1-adrenoceptor antagonist, nebivolol. 1549 65

beta-Adrenoceptor antagonists (beta-blockers) provide multiple benefits to patients with coronary artery disease. The 2001 American Heart Association and American College of Cardiology (AHA/ACC) guidelines for secondary prevention of myocardial infarction (MI) recommend initiating beta-adrenoceptor blockade in all post-MI patients and continuing therapy indefinitely. Atenolol and metoprolol have been shown to decrease vascular mortality in the acute-MI period. In the post-MI period timolol provided a 39% reduction in mortality in the Norwegian Multicenter Study group and propranolol was associated with a 26% reduction in mortality in BHAT (Beta-blocker Heart Attack Trial). beta-Adrenoceptor antagonist therapy results in reduction of myocardial oxygen demand and is therefore also effective for the treatment of angina pectoris. In CAST (Cardiac Arrhythmia Suppression Trial) beta-adrenoceptor antagonist therapy was associated with a significant reduction in arrhythmic death or cardiac arrest. In the post-MI amiodarone trials EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) there was a mortality benefit and decreased arrhythmic death in patients who received both amiodarone and beta-adrenoceptor antagonist therapy, compared with patients receiving amiodarone therapy alone. In the post-MI defibrillator (implantable cardioverter defibrillator [ICD]) trials, AVID (Antiarrhythmic Versus Implantable Defibrillator) and MUSTT (Multicenter Unsustained Tachycardia Trial), beta-adrenoceptor antagonist therapy was independently associated with improved overall survival. The exception was the ICD patients in MUSTT, and the benefit was attenuated in the amiodarone and ICD patients in AVID.AHA/ACC guidelines recommend the use of beta-adrenoceptor antagonists in all patients with symptomatic left ventricular dysfunction, based on several large, controlled heart failure trials. Extended-release metoprolol succinate reduced all-cause mortality by 34% in MERIT-HF (Metoprolol Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure). Bisoprolol was associated with a 34% mortality benefit in CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and carvedilol was associated with a 35% mortality reduction in the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) trial. beta-Adrenoceptor antagonists reduce perioperative mortality in patients undergoing cardiac as well as non-cardiac surgery; however, they remain underutilised. Contraindications to beta-adrenoceptor antagonist therapy include severe bradycardia, high-grade atrioventricular block, marked sinus node dysfunction and acute exacerbations of heart failure. Many of the perceived adverse effects of beta-adrenoceptor antagonists have not been substantiated by large clinical trials.beta-Adrenoceptor antagonists differ with regard to receptor selectivity, receptor affinity, lipophilicity and intrinsic sympathomimetic activity. Beneficial properties of beta-adrenoceptor antagonists may not always be extrapolated as a class effect, and patient selection and drug preparations should follow trial guidelines. The beneficial effects of beta-adrenoceptor antagonists are clearly proven in cardiac patients and those at risk for cardiac disease. They are indicated for heart failure and proven beneficial in patients undergoing cardiac and non-cardiac surgery. These benefits appear to be consistent across most patient subgroups. beta-Adrenoceptor antagonists are generally well tolerated, yet significant morbidity and mortality result from their continued underutilisation.
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PMID:Optimising the use of beta-adrenoceptor antagonists in coronary artery disease. 1581 91

Adrenergic receptors (ARs) are the cellular membrane binding sites through which natural catecholamines and sympathomimetic drugs exert their physiological and pharmacological effects. In recent decades, studies to clarify the distribution and function of ARs have been performed mostly on cultured cells, laboratory animals and human target tissues, but little is known about these aspects in domestic animals. This review focuses on AR structure, classification and signalling pathways and on AR subtype distribution in target tissues of some domestic animals, namely dogs, horses and bovines. In these species, different alpha- and beta-AR subtypes have been characterized and the functions controlled by the adrenergic systems have been studied. In the dog, the role played by the adrenergic system in the pathogenesis of cardiovascular disorders and in the modulation of canine aggression has roused particular interest. In dogs affected by dilated cardiomyopathy a significant down-regulation of beta-ARs has been observed both in the heart and circulating lymphocytes. This finding confirms the involvement of the adrenergic system in the pathogenesis and progression of the disorder and suggests new therapeutic strategies. In the horse, AR distribution has been studied in the cardiac, respiratory and gastrointestinal systems as well as in digital veins and arteries. The cardiac beta-ARs in healthy horses seem to be predominantly represented by the beta(1) subtype. In this species, heart failure may increase the expression of the beta(2) subtype, rather than causing AR down-regulation. Different beta- and alpha-AR subtypes have been characterized in the smooth muscle of equine ileum. The sympathetic relaxation of equine ileum smooth muscle seems to depend mainly on beta(3)-AR subtype activation, with minor involvement of the beta(2) subtype. In the respiratory tract, regional differences have been evidenced in the functionality of beta-AR subtype. The beta(2) subtype predominates in all segments but the beta(2) subtype-mediated adenyl cyclase response is tissue-dependent, with higher activity in tracheal membranes than bronchial or pulmonary ones. Both alpha- and beta-AR subtypes are present in the genital tract of cows. Bovine ovarian and myometrial cell membranes express higher concentrations of beta(2)-ARs than the beta(1) subtype, whereas as far as alpha-ARs are concerned, a single class of alpha(1)-ARs and two distinct classes of alpha(2)-AR binding sites have been discriminated. Interestingly, it has been observed that the activation of the sympathetic system could play an important role in the pathogenesis of bovine ovarian cysts as suggested by the modifications in beta-AR levels in the hypophysis and ovary of cows affected by ovarian cysts. In this species, the phenomenon of down-regulation has been well studied in different organs of veal calves treated with clenbuterol as a "partitioning agent". Since differences exist in AR distribution among species, data obtained in laboratory animals or in human beings cannot be extrapolated to domestic animals and further investigation on AR subtypes in domestic animal tissues is necessary.
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PMID:Are so many adrenergic receptor subtypes really present in domestic animal tissues? A pharmacological perspective. 1612 37

The beta-adrenergic receptor blockers play an important role in the management of cardiovascular disease, including hypertension and chronic heart failure. However, concerns regarding safety and tolerability with currently available agents can limit their use. The beta-blockers vary with regard to several pharmacologic properties, including beta1/beta2 selectivity, intrinsic sympathomimetic activity, and, with the newest beta-blockers, vasodilation. These pharmacologic differences may result in clinically important differences in tolerability and hemodynamic properties. Nebivolol is a novel beta-blocker with both a greater degree of selectivity for beta1-adrenergic receptors than other agents in this class and an ability to stimulate endothelial nitric oxide production, leading to vasodilation and other potential clinical effects. Published randomized, controlled, multicenter studies with nebivolol have shown that once-daily treatment significantly reduces systolic and diastolic blood pressure in patients with mild-to-moderate hypertension, compared with placebo, in a dose-dependent manner, and is well tolerated, with an adverse event profile similar to that of placebo. When compared with other beta-blockers as well as with other antihypertensive classes of agents in head-to-head trials, nebivolol demonstrated similar antihypertensive efficacy and a lower incidence of adverse events. Nebivolol has also been shown to significantly reduce morbidity and mortality in a large population of elderly patients with chronic heart failure, independent of left ventricular ejection fraction. Nebivolol is currently available in Europe for the management of hypertension and is expected to be available soon in the United States.
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PMID:The role of the new beta-blockers in treating cardiovascular disease. 1637 95

Cardiac matrix metalloproteinases (MMPs) stimulated by the sympathomimetic action of angiotensin II (AII) exacerbate chamber diastolic stiffening in models of subacute heart failure. Here we tested the hypothesis that MMP inhibition prevents such stiffening by favorably modulating high-energy phosphate (HEP) stores more than by effects on matrix remodeling. Dogs were administered AII i.v. for 1 week with tachypacing superimposed in the last two days (AII+P; n = 8). A second group (n = 9) underwent the same AII+P protocol but was preceded by oral treatment with an MMP inhibitor PD166793 [(S)-2-(4-bromo-biphenyl-4-sulfonylamino-3-methyl butyric acid] 1 week before and during the AII+P period. Pressure-volume analysis was performed in conscious animals, and myocardial tissue was subjected to in vitro and in situ zymography, collagen content, and HEP analysis (high-performance liquid chromatography). As reported previously, AII+P activated MMP9 and MMP2 and specifically exacerbated diastolic stiffening (+130% in chamber stiffness). PD166793 cotreatment prevented these changes, although myocardial collagen content, subtype, and cross-linking were unaltered. AII+P also reduced ATP, free energy of ATP hydrolysis (DeltaG(ATP)), and phosphocreatine while increasing free [ADP], AMP catabolites (nucleoside-total purines), and lactate. PD166793 reversed most of these changes, in part due to its inhibition of AMP deaminase. MMP activation may influence cardiac diastolic function by mechanisms beyond modulation of extracellular matrix. Interaction between MMP activation and HEP metabolism may play an important role in mediating diastolic dysfunction. Furthermore, these data highlight a potential major role for increased AMP deaminase activity in diastolic dysfunction.
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PMID:Metalloproteinase inhibitor counters high-energy phosphate depletion and AMP deaminase activity enhancing ventricular diastolic compliance in subacute heart failure. 1643 97

Blockers of adrenergic beta-receptors (beta-blockers) are commonly administered in cardiology for coronary heart disease, arrhythmias, hypertension and some cardiopathic treatment. They have been also approved as a therapy of chronic heart failure recently. From pharmacological point of view, cardioselective and non selective beta-blockers (with or without intrinsic sympathomimetic activity) are distinguished. New drugs like celiprolol, carvedilol or sotalol have been developed and so the range of the group still continues to widen out. In toxicological routine practice we meet beta-blockers either in acute intoxication cases or in a control of patient's adherence to prescribed therapy. Dizziness, nausea, weakness, vasoconstriction and bradycardia are their usual undesirable effects, whilst in grave cases of a drug overdose bronchoconstriction, coronary spasms, hypotension and even cardiac insufficiency may occur. The article deals with the possibility of detection and identification of beta-blockers and their metabolites in urine by thin layer chromatography.
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PMID:[Identification of blockers of adrenergic beta-receptors by thin layer chromatography]. 1650 5

Lipophilic inhibitors of angiotensin-converting enzyme increased 6-month survival and/or lifetime of rats with experimental chronic heart failure. These drugs had no effect on the mortality rate of animals with acute decompensation of the disease. beta-Adrenoceptor blockers without intrinsic sympathomimetic activity not only prolonged 6-month survival and lifetime, but also decreased the mortality rate of rats with decompensation of chronic heart failure.
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PMID:Survival of rats with experimental chronic heart failure depending on pharmacodynamic and pharmacokinetic parameters of angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers. 1692 60

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

Inotropic agents are indispensable for the improvement of cardiac contractile dysfunction in acute or decompensated heart failure. Clinically available agents, including sympathomimetic amines (dopamine, dobutamine, noradrenaline) and selective phosphodiesterase-3 inhibitors (amrinone, milrinone, olprinone and enoximone) act via cAMP/protein kinase A (PKA)-mediated facilitation of intracellular Ca2+ mobilisation. Phosphodiesterase-3 inhibitors also have a vasodilatory action, which plays a role in improving haemodynamic parameters in certain patients, and are termed inodilators. The available inotropic agents suffer from risks of Ca2+ overload leading to arrhythmias, myocardial cell injury and ultimately, cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and cellular metabolism. Furthermore, they lose their effectiveness under pathophysiological conditions, such as acidosis, stunned myocardium and heart failure. Pimobendan and levosimendan (that act by a combination of an increase in Ca2+ sensitivity and phosphodiesterase-3 inhibition) appear to be more beneficial among existing agents. Novel Ca2+ sensitisers that are under basic research warrant clinical trials to replace available inotropic agents.
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PMID:Acute heart failure: inotropic agents and their clinical uses. 1705 76

In myocardial ischaemia and heart failure, beta-blockers with intrinsic sympathomimetic activity (ISA) e.g. pindolol, xamoterol, bucindolol, nebivolol, have performed poorly in reducing morbidity and mortality. In both indications beta-1 blockade is the vital active ingredient. Beta-1 blockade (bisoprolol) is now an alternative first-line choice to Ace-inhibition in the treatment of heart failure. The therapeutic role of beta-blockers in hypertension is less well understood, particularly since the new recommendations in the UK from the NICE committee stating that: 1. beta-blockers are no longer preferred as a routine initial therapy, 2. the combination with diuretics is discouraged due to the risk of induced diabetes, and 3. in younger patients first-choice initial therapy should be an ACE-inhibitor. Recent data from the Framingham Heart Study and other epidemiological studies have indicated that the development of diastolic hypertension in younger subjects is closely linked to weight-increase and an increase in peripheral resistance; such subjects have a high adrenergic drive and cardiac output. In contrast, elderly systolic hypertension mostly arises de novo via poor vascular compliance. Thus in younger, probably overweight, hypertensives (including diabetics) first-line beta-blockade has performed well in preventing myocardial infarction (a fact hidden by meta-analyses that do not take age into account). Conversely, in elderly hypertensives first-line beta-blockade (atenolol) has performed poorly in reducing cardiovascular risk (due to partial beta-2 blockade atenolol evokes metabolic disturbance and does not improve vascular compliance, or effectively lower central aortic pressure or reverse left ventricular hypertrophy). Thus beta-blockers like atenolol are ill-equipped for first-line therapy in elderly hypertension. Some beta-blockers, e.g. bisoprolol (up to 10 mg/day is highly beta-1 selective) and nebivolol (beta-2/3 intrinsic sympathomimetic activity), do improve vascular compliance and cause no metabolic disturbance. Beta-blockers as second-line to low-dose diuretics (which, by improving vascular compliance and increasing sympathetic nerve activity, create an optimal environment for beta-blockade) in elderly hypertension (including diabetics) have performed well in reducing cardiovascular events (this combination has the added bonus of reducing the risk of bone fracture by about 30%). Meta-analyses which include studies where it is unclear whether a diuretic or beta-blocker was a first-line therapy will dilute the benefit stemming from first-line diuretic/second-line beta-blockade. Hypertensives (of all ages) with ischaemia are well suited to beta-blockade.
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PMID:Are we misunderstanding beta-blockers. 1743 71


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