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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reports in the literature have suggested that a complex alteration in beta-receptor pathway takes place in failing human myocardium. The purpose of our study was to evaluate the beta-adrenergic receptor system in an experimental model of heart failure induced by monocrotaline in rats. Monocrotaline, administered with a single intraperitoneal injection (50 mg/Kg), causes pulmonary hypertension and right ventricular hypertrophy, associated with congestive heart failure. beta 1 and beta 2-receptors were characterized in the right ventricle by direct radioligand binding utilizing [125I] Iodocyanopindolol and selective beta 1-(CGP 20712A) and beta 2-(ICI 118551) antagonists. Adenylate cyclase was measured in basal condition and in the presence of different stimulators as isoproterenol with ICI 118551 (beta 1-receptor-stimulated activity), isoproterenol with CGP 20712A (beta 2-receptor-stimulated activity), Gpp(NH)p, NaF and forskolin. In the right ventricle of the failing hearts the beta 1-receptor density decreased selectively (-55.8%) while the beta 2-receptor density was unchanged. Modifications in the adenylate cyclase system were demonstrated: a reduction in the basal and beta 1- and beta 2-stimulated adenylate cyclase activity; a decrease in adenylate cyclase activation elicited by Gpp(NH)p, but not by forskolin and NaF. In conclusion, these data suggest that in monocrotaline-induced heart failure in the rat there is a selective beta 1-receptor down-regulation and an impaired coupling efficiency of G proteins. These results are in line with biochemical changes found in patients with heart failure.
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PMID:[The adrenergic beta system in an experimental model of heart failure]. 196 56

Acute intravenous administration of the new beta 1-adrenergic receptor partial agonist xamoterol lowers left ventricular end-diastolic pressure and improves the isovolumic indexes of inotropic state and relaxation. To determine if these hemodynamic changes were maintained after prolonged administration, the dose-response relation to cumulative doses of xamoterol was determined in a group of 14 patients with mild (n = 6)-to-serve (n = 8) ischemic left ventricular dysfunction. These patients had been treated with xamoterol (200 mg, b.i.d.) for a mean of 51 +/- 17 months, and the drug had been stopped for 72 hours before testing the responsiveness to xamoterol. In these patients, xamoterol administration still induced dose-dependent decreases in left ventricular end-diastolic pressure from 21.4 +/- 8.2 to 15.8 +/- 7.7 mm Hg (p less than 0.01, vs. baseline and vs. the control data 51 +/- 17 months before). Peak positive dP/dt and dP/dt normalized to a developed pressure of 40 mm Hg [( dP/dt]/DP40) increased by 14% and 23%, respectively (p less than 0.01), whereas the rate of isovolumic pressure decrease improved by 12% (p less than 0.01). It is concluded that the myocardial response to xamoterol is maintained after years of continuous therapy, and that in patients with heart failure, this response was expressed mainly as a reduction in left ventricular end-diastolic pressure.
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PMID:Effects of the beta 1-adrenergic receptor partial agonist xamoterol on left ventricular diastolic function. An evaluation after 1-6 years of oral therapy. 196 60

The sympathetic nervous system becomes activated in heart failure, and while this is initially beneficial, the consequences of prolonged raised levels of catecholamines can be counterproductive. Xamoterol, a partial agonist that acts on the cardiac beta 1-adrenergic receptor, modifies the response of the heart to variations in sympathetic activity. At rest, it produces modest improvements in cardiac contractility, relaxation, and filling without increase in myocardial oxygen demand. The improvements are maintained during exercise although the attendant tachycardia is attenuated. The beneficial effects of xamoterol on both systolic and diastolic function suggested that it would be effective in patients with mild-to-moderate heart failure, and this was demonstrated in small placebo-controlled studies where effort tolerance and symptoms were improved. A large multicenter study program comprised of four studies demonstrated that patients with mild-to-moderate heart failure randomized to xamoterol (n = 617) 200 mg b.i.d. for 3 months significantly (p less than 0.0001) improved exercise capacity by 37% as compared with the placebo group (n = 300) with an increase of 18%. The xamoterol group also showed significant improvements in symptoms of breathlessness, fatigue, and life values as compared with the placebo group. In one of the multicenter studies in which 433 patients were randomized to xamoterol (n = 220), placebo (n = 109), and a positive control, digoxin 0.125 mg b.i.d. (n = 104), the percentages of improvement in exercise work were 33%, 5%, and 17%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Review of clinical experience with xamoterol. Effects on exercise capacity and symptoms in heart failure. 196 61

A new cardioselective beta 1-adrenergic receptor agonist xamoterol (Corwin) has been developed for the treatment of heart failure. To study the acute hemodynamic effects of xamoterol, 24 patients, 39-70 years old, with mild-to-moderate postinfarction left ventricular dysfunction entered a double-blind, between-patient comparison of a single 5-minute intravenous infusion of xamoterol (0.2 mg/kg) and placebo. The acute hemodynamic effects of xamoterol were measured at rest and during two multistaged symptom-limited supine bicycle exercise tests (Ex-T), a control Ex-T followed by an Ex-T with either xamoterol or placebo. Compared with placebo, xamoterol significantly increased left ventricular contractility (Vmax and positive [+] dP/dt) and enhanced relaxation (dP/dt- and time constant relaxation) at rest and at the 25% and 50% levels of maximum exercise. The heart rate, the frequency and time to onset of anginal symptoms, the magnitude of exercise-induced ST segment depression, the left ventricular end-diastolic and peak systolic pressures, the mean pulmonary artery pressures, the cardiac index, the left ventricular stroke-work index, and the epinephrine and norepinephrine plasma levels at rest and during exercise did not differ significantly between placebo xamoterol groups. Thus, xamoterol can be a useful addition for the treatment of left ventricular dysfunction because of long-term ischemic heart disease.
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PMID:Improvement of left ventricular contractility and relaxation with the beta 1-adrenergic receptor partial agonist xamoterol at rest and during exercise in patients with postinfarction left ventricular dysfunction. A placebo-controlled randomized trial. 196 62

Dopexamine hydrochloride is a novel synthetic catecholamine, structurally related to dopamine, with marked intrinsic agonist activity at beta 2-adrenoceptors, lesser agonist activity at dopamine DA1- and DA2-receptors and beta 1-adrenoceptors, and an inhibitory action on the neuronal catecholamine uptake mechanism. The drug is administered by intravenous infusion, and is characterized by a rapid onset and short duration of action. Short term haemodynamic studies in volunteers and patients with severe chronic heart failure have indicated that dopexamine hydrochloride reduces afterload through pronounced arterial vasodilatation, increases renal perfusion by selective renal vasodilation and evokes mild cardiac stimulation through direct and indirect positive inotropism. Preliminary small-scale noncomparative studies indicate that dopexamine hydrochloride displays beneficial haemodynamic effects in patients with acute heart failure and those requiring haemodynamic support following cardiac surgery, and that these effects are substantially maintained during longer term administration (less than or equal to 24 hours). Dopexamine hydrochloride appears to be generally well tolerated. Nausea and vomiting are the most frequently reported adverse effects, and respond to dosage reduction. Occasional reports of chest pain/angina pectoris precipitated by tachycardia indicates the need for caution in the use of dopexamine hydrochloride in patients with ischaemic heart disease. Thus, dopexamine hydrochloride may prove to be a useful alternative to dopamine and dobutamine in the treatment of acute heart failure and the postoperative management of low cardiac output states, although controlled studies are required to establish its efficacy and tolerability with respect to that of established therapies.
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PMID:Dopexamine hydrochloride. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in acute cardiac insufficiency. 197 Feb 88

As the dual pharmacological action of partial beta 1-adrenoceptor agonists should improve left ventricular function while also protecting the myocardium against excessive sympathetic stimulation they may be useful in the treatment of heart failure. Therefore, we studied the pharmacological effects of xamoterol (Corwin, ICI 118, 587), a compound with mixed agonist and antagonistic properties at cardiac beta-adrenoceptors in electrically driven human papillary muscle strips from failing human hearts. Specimens were obtained from patients with different grades of myocardial failure who underwent mitral valve replacement (NYHA II-III) or heart transplantation (NYHA IV). Xamoterol (0.0001-100 mumol l-1) produced only negative inotropic effects, as measured by changes in isometric force of contraction in diseased human papillary muscle strips. However, isoprenaline (0.0001-10 mumol l-1) and ouabain (0.01-0.3 mumol l-1) enhanced force of contraction in the same hearts. Prestimulation with noradrenaline (3 mumol l-1) augmented the negative inotropic effect of xamoterol. It is concluded that xamoterol exerts primarily beta-adrenoceptor antagonistic activity in the failing human myocardium.
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PMID:The effect of xamoterol in failing human myocardium. 197 May 36

Xamoterol is a beta 1-selective adrenoceptor partial agonist. The acute effects of xamoterol were studied in 30 patients with ischaemic heart failure. Haemodynamic data were assessed at baseline, at rest and after supine bicycle exercise (50 W for 3 min), and repeated 15 min after xamoterol (0.2 mg kg-1) given by infusion over 5 min. At rest, xamoterol increased heart rate, mean blood pressure and cardiac index, and reduced pulmonary wedge pressure. On exercise, heart rate fell while cardiac index was maintained and pulmonary wedge pressure fell slightly but significantly. There was a tendency for plasma renin activity and plasma noradrenaline to fall both at rest and on exercise. The clinical relevance of these haemodynamic and neurohumoral changes were examined in conjunction with the German-Austrian Xamoterol Group's study, screening 443 patients with mild to moderate heart failure and giving xamoterol or placebo for 3 months as part of a randomized, double-blind study. The German experience was then placed in context of the pooled world-wide database of efficacy and safety in three other large (greater than 100 patients) studies with xamoterol in mild to moderate heart failure. In brief, this overview demonstrated a 2.98 +/- 0.68 kJ improvement in work done over placebo, equivalent to 14% (xamoterol) and 6% (placebo) improvements over baseline (P less than 0.0001). Xamoterol is thus a promising new approach to the treatment of mild to moderate heart failure.
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PMID:Sympathetic modulation in practice: the German clinical experience. 197 86

This study reports the effects of the new beta 1 adrenoceptor partial agonist, xamoterol, on neuroendocrine activity after acute myocardial infarction (AMI). Fifty-one consecutive patients with AMI were randomized to treatment with xamoterol, 200 mg twice a day, or placebo; patients were also stratified as to whether or not diuretic therapy was given for left ventricular dysfunction. Noradrenaline, plasma renin activity (PRA), and atrial natriuretic factor (ANF) were measured over a 10-day period. Noradrenaline concentrations are higher (p less than 0.05) in patients treated with diuretics at the time of admission and fell over the subsequent 10 days (p less than 0.01). Treatment with xamoterol did not affect this noradrenaline response to myocardial infarction. PRA was also significantly higher in the patients treated with diuretics, and there was a nonsignificant trend for xamoterol to blunt the PRA response in these patients. There was no difference in ANF levels between those patients who were treated with diuretics and those who were not; xamoterol did not affect ANF. Thus xamoterol does not further elevate noradrenaline levels as do conventional beta blockers, and it does not activate the renin-angiotensin system as do potent nonselective beta agonists. Furthermore, xamoterol does not increase ANF levels, probably because it is not negatively inotropic. We conclude that xamoterol does not cause deleterious neuroendocrine changes in patients with AMI even in those treated for heart failure.
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PMID:Neuroendocrine changes post myocardial infarction: effects of xamoterol. 197 61

Recently completed controlled clinical trials suggest that the functional status and natural history of patients with chronic heart failure can be modified by drugs that enhance or interfere with the effects of the sympathetic nervous system. Long-term treatment with beta-receptor agonists can produce clinical benefits in some patients by improving left ventricular diastolic function, even if tolerance develops to the effects of these drugs on cardiac output and left ventricular ejection fraction. beta-Receptor stimulation, however, may also provoke ventricular arrhythmias by a direct effect on the failing heart or by promoting the development of hypokalemia. Similarly, long-term treatment with beta-receptor antagonists may improve left ventricular systolic performance, ameliorate symptoms, and reduce mortality in chronic heart failure. beta-Receptor blockade, however, may lead to worsening heart failure by interfering with the positive inotropic or the peripheral vasodilator actions of endogenous catecholamines. It is noteworthy that many of the benefits of beta-adrenergic agonists and antagonists seem to be mediated by the effects of these drugs on the beta 1-receptor, whereas many of the deleterious responses to treatment appear to be related to the interaction of these agents with the beta 2-receptor. These observations support the concept that beta 1-receptors are the principal mediators of cardiac sympathetic nerve activity in states of circulatory stress, are most likely to be altered by the abnormal pathophysiological conditions of chronic heart failure, and consequently, provide a rational target for the development of novel therapeutic agents.
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PMID:Pathophysiological mechanisms underlying the effects of beta-adrenergic agonists and antagonists on functional capacity and survival in chronic heart failure. 197 43

The existence of two dopamine receptor subtypes (DA1 and DA2) has been firmly established. Activation of DA1 receptors is associated with vasodilation, primarily in the renal, mesenteric, cerebral, and coronary arterial beds, and a natriuresis. DA2 receptors located on postganglionic sympathetic nerves and sympathetic ganglia mediate a decrease in the release of norepinephrine from sympathetic nerve terminals. The DA receptor activity of dopamine (which activates beta 1- and alpha-adrenoceptors as well as DA receptors) plays a prominent role in determining the beneficial hemodynamic responses to this drug in patients with heart failure. As a result, recent research efforts have been directed toward the development of dopamine analogues, which are orally effective and exhibit more selective agonist activity at DA receptors. Limited clinical experience in heart failure is now available for analogues with different spectra of receptor activity than dopamine, including selective DA1 and DA2 agonists. A review of these data is presented with an attempt to define the clinical relevance of the DA receptor-agonist properties of the compounds. Although the results of early clinical studies with some of these first-generation dopamine congeners are encouraging, analysis of ongoing large-scale placebo-controlled trials will provide valuable insight into their utility as therapeutic agents for patients with heart failure.
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PMID:Role of dopamine receptors and the utility of dopamine agonists in heart failure. 197 45


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