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

Quantitative autoradiography was used to determine the location and density of beta 1- and beta 2-adrenoceptors in the right atrium (RA), left ventricular free wall (LVFW), right ventricular free wall (RVFW), interventricular septum (IVS), right atrium from an area near the atrioventricular node (RAAV) and cardiac nerves (N) taken from a patient with end-stage cardiac failure. The densities of beta-adrenoceptors detected by the non-selective beta-adrenoceptor antagonist radioligand (-)-[125I] cyanopindolol (50pM) were 4.93 (N), 10.6 (RVFW), 12.2 (RA), 12.4 (IVS), 15.8 (LVFW) and 18.7 fmol (mg protein)-1 (RAAV). The proportion of beta 2-adrenoceptors ranged from 19.5% (RAAV) to 95% (N). RA taken from patients with ischaemic heart disease had a higher density of beta-adrenoceptors (29.3 fmol (mg protein)-1). The results suggest that both beta 1- and beta 2-adrenoceptors are down-regulated in patients with end-stage cardiac failure. Positive inotropic responses were established to (-)-isoprenaline, RO363 (beta 1-selective), procaterol (beta 2-selective) and dopexamine in the absence or presence of the antagonist CGP 20712A (beta 1-selective) or ICI 118,551 (beta 2-selective) in electrically driven human right atrial appendage strips. RO363 and procaterol were nearly full agonists in this preparation and produced their responses through activation of beta 1- or beta 2-adrenoceptors, while dopexamine was a partial agonist which produced its inotropic responses through activation of both receptor subtypes. These studies demonstrate the presence and location of beta 1- and beta 2-adrenoceptors in the human heart.
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PMID:Coexistence and localization of beta 1- and beta 2-adrenoceptors in the human heart. 255 7

Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20. At a concentration less than its low affinity (beta 2) Kl, betaxolol, a highly selective beta 1-antagonist, inhibited isoproterenol (non-selective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are all capable of stimulating AC through beta 1-receptor activation. At a concentration less than its low affinity (beta 1) Kl, ICI 118,551, a highly selective beta 2-agonist, inhibited both isoproterenol and zinterol stimulation of AC, indicating that isoproterenol and zinterol stimulate AC through beta 2-receptors. Zinterol stimulation of AC was mediated entirely by beta 2-receptors, inasmuch as 10(-7) M betaxolol had no effect on the zinterol dose-response curve and ICI 118,551 produced a degree of blockade (KB = 5.2 +/- 1.6 X 10(-9) M), consistent with the beta 2-receptor Kl of the latter (2.0 +/- .4 X 10(-9) M, p, not significant). In nonfailing myocardium, analysis of beta 1 versus beta 2 stimulation by the nonselective agonist isoproterenol revealed that the numerically small (19% of the total) beta 2 fraction accounted for the majority of the total adenylate cyclase stimulation. In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001). Moreover, in preparations from failing heart, the component of denopamine stimulation that was inhibited by 10(-7) M betaxolol (beta 1 component) was reduced by 77% (p less than 0.05). Finally, in preparations derived from failing ventricular myocardium, beta 2-receptor density was not significantly decreased, but zinterol stimulation of AC was reduced by 32% (p less than 0.05). We conclude that heart failure results in subsensitivity to both selective beta 1 and beta 2 stimulation of adenylate cyclase, with beta 1 subsensitivity due to selective beta 1 receptor down-regulation and beta 2 subsensitivity due to partial uncoupling of beta 2 receptors from subsequent events in the beta 2-adrenergic pathway.
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PMID:Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. 256 29

1. A bicycle exercise test was used to investigate functional capability and haemodynamics in 30 patients with heart failure (13 NYHA Class II, 17 Class III), before and after i.v. xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) 0.2 mg kg-1. 2. Resting heart rate fell from 78 to 74 beats min-1 (P less than 0.05) and cardiac index rose from 2.5 to 2.8 l min-1 m-2 (P less than 0.001) after xamoterol. Blood pressure fell slightly, and systemic vascular resistance was reduced. Stroke work index improved and double product decreased. There were no changes in pulmonary artery wedge pressure ejection fraction or plasma noradrenaline concentrations. 3. On exercise, xamoterol produced a considerable reduction in heart rate increase, improved stroke volume and left ventricular stroke index and lowered double product. Exercise duration increased by 10%, but this did not quite achieve statistical significance. 4. These results are consistent with the concept that a beta 1-partial adrenoceptor agonist with the level of intrinsic sympathomimetic activity (43%) of xamoterol provides moderate inotropic support at rest, and protects the heart against overstimulation on exercise, when sympathetic drive is high. 5. Reduction of double product on exercise implies a lowered oxygen demand, which could be of considerable importance in patients with ischaemic heart disease.
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PMID:Effects of xamoterol on resting and exercise haemodynamics in patients with chronic heart failure. 257 50

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587), a beta 1-adrenoceptor partial agonist, improves both systolic and diastolic function in heart failure patients. 2. Double-blind, randomised studies comparing xamoterol with placebo showed that the beneficial haemodynamic effects of xamoterol produced significant improvements in exercise capacity and symptoms in patients with mild to moderate heart failure. These studies formed the basis for a large European multicentre study programme which recruited over 1000 patients, randomised to xamoterol (200 mg twice daily, n = 617), digoxin (0.125 mg twice daily, n = 135) or placebo (n = 300) for 3 months. 3. Efficacy was assessed by measuring exercise capacity and symptoms. The xamoterol group improved exercise capacity by 37% compared with an 18% improvement in the placebo group. Differences in the symptom scores measured by visual analogue scales and Likert scores indicated significant improvements by xamoterol in the cardinal symptoms of heart failure, dyspnoea and fatigue. 4. Analyses of data from subsets of patients in the study showed that elderly patients, patients on no other heart failure therapy and patients with cardiomegaly all had similar improvements in exercise and symptoms to those seen in the whole study population. In the subset which included digoxin treatment, xamoterol produced significantly greater improvements in exercise capacity than digoxin (33% vs 17%, P less than 0.05) and was associated with fewer side-effects. 5. Xamoterol is therefore a promising addition to heart failure therapies currently available.
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PMID:Xamoterol, a beta 1-adrenoceptor partial agonist: review of the clinical efficacy in heart failure. 257 51

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) is a beta-adrenoceptor partial agonist which is of benefit in the chronic treatment of heart failure (e.g. The German and Austrian Xamoterol Study Group, 1988). These results contrast with those obtained with other beta-adrenoceptor drugs, prenalterol and pirbuterol which were unsuccessful on chronic dosing (Currie et al., 1984; Glover et al., 1985). 2. Unlike prenalterol and pirbuterol, xamoterol has no significant agonist activity at the beta 2-adrenoceptor and has shown no tachyphylaxis in animals or man. 3. The overall action of xamoterol is to modulate sympathetic control of the heart such that at rest and at low levels of exercise the heart receives inotropic support whilst during more severe exercise, heart rate is reduced. In patients with left ventricular dysfunction these effects lead to an improvement in the relation between filling pressure and cardiac output at all levels of activity such that a given cardiac output is achieved with a lower filling pressure. It is suggested that this alteration in the pattern of cardiac activity over a long period of time results in a beneficial adaptation of the myocardium and is a possible explanation of the observed clinical improvement.
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PMID:The pharmacology of xamoterol: a basis for modulation of the autonomic control of the heart. 257 52

1. Although heart failure is commonly associated with depressed systolic function, there is increasing evidence that impaired diastolic performance is also universally present and might be a key determinant of symptoms, physical capacity and even survival in some subsets of patients. 2. Reduced diastolic distensibility increases cardiac filling pressure not only at rest, but even more during exercise when diastolic filling time is reduced. The increases in filling pressure and diastolic wall stress lead to pulmonary congestion and subendocardial ischaemia, it also triggers myocardial hypertrophy and a detrimental remodelling of the ventricular cavity. Perhaps even more importantly, impaired ventricular distensibility limits the use of the Frank-Starling mechanism, impairing systolic pump function and cardiac output adaptation during exercise. Therapies able to improve the distensibility of the ventricle are, therefore, desirable in heart failure. 3. Nitrates, angiotensin converting enzyme (ACE) inhibitors and diuretics may indirectly increase left ventricular chamber compliance by their effects on the right side of the heart. Cardiac glycosides do not improve myocardial relaxation and may even cause diastolic contracture at toxic doses. The new beta 1-adrenoceptor partial agonist, xamoterol, on the other hand, consistently lowers left ventricular filling pressure at rest and during exercise, and produces an increase in left ventricular dynamic compliance through the direct lusitropic effect of beta 1-adrenoceptor stimulation. These beneficial effects are maintained during prolonged therapy and also appear sufficient to slow the remodelling of the ventricular cavity. The improvement in symptoms and in exercise tolerance observed during xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) therapy might, therefore, be related to the improvement in left ventricular diastolic distensibility induced by this drug.
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PMID:Focus on diastolic dysfunction: a new approach to heart failure therapy. 257 54

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) is a beta 1-adrenoceptor partial agonist which, unlike full beta-adrenoceptor agonists, does not down-regulate beta-adrenoceptors in the rat ventricle during chronic administration. 2. Improvements in myocardial performance have been demonstrated following acute administration of xamoterol to patients with mild or moderate heart failure, and these are sustained during at least 1 year of continued treatment. 3. Exercise duration is increased by xamoterol in patients with left ventricular dysfunction and benefit is still apparent after at least 1 year of therapy. 4. Despite sustained cardiac stimulation, xamoterol does not appear to affect adversely mortality in patients with mild or moderate heart failure. 5. Few adverse events directly attributable to xamoterol were reported during 3 month efficacy studies in more than 600 patients, and the laboratory safety profile over 1 year of treatment is good. 6. Xamoterol is a promising, well-tolerated addition to established therapies for chronic mild or moderate heart failure.
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PMID:Long-term studies with xamoterol in heart failure. 257 55

1. Current therapy of heart failure leaves much to be desired. Not all patients respond, and many agents lose their effects with time. 2. Newer agents may be effective but toxic, and some which have a beneficial action when given intravenously have proved disappointing when used orally. 3. The value of digoxin in patients in sinus rhythm is open to debate, and diuretics, although useful acutely in reducing fluid overload, do not appear to improve prognosis. 4. Vasodilators increase effort capacity and reduce symptoms, possibly conferring some long-term benefit, and angiotensin converting enzyme (ACE) inhibitors improve symptoms and decrease mortality in a wide range of patients. 5. Positive inotropes may be effective in the short term, but they increase myocardial oxygen demand and show tachyphylaxis with no prognostic benefit. 6. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) is a partial sympathetic agonist with approximately 50% of the activity of a pure agonist, which provides inotropic support at rest, and protection against excess sympathetic activity on exercise. 7. It is compatible with other therapies and has shown no serious toxicity. 8. It should be considered at present as an adjunct to diuretic and/or ACE inhibitor therapy, although it may be useful alone; its role will become clearer as its effects on mortality are established.
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PMID:The management of heart failure and the scope for new therapies: what role for xamoterol? 257 56

The aim of this study was to compare the effects of intravenous ICI 118.587 (Corwin), a new cardioselective partial beta-agonist, and placebo given q. 12 h for 4 consecutive days, with invasive and noninvasive methods. Twelve patients with mild to moderate cardiac failure after a myocardial infarction were studied. We could not show any significant effect of Corwin on hemodynamics, systolic time intervals, heart rates, or blood pressures. We conclude that Corwin does not affect left ventricular function, as measured by hemodynamics and systolic time intervals, in the immediate postinfarction period in patients with mild to moderate heart failure.
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PMID:Hemodynamic effects of ICI 118.587 (Corwin) in patients with mild cardiac failure after myocardial infarction. 258 Jan 58

The ideal sympathomimetic derivative should possess the positive inotropic and relaxing effects of catecholamines whilst remaining free of their side-effects. Theoretically, such properties could be present in beta 1-adrenoceptor partial agonists. Xamoterol (ICI 118,587, Corwin; ISA 43 p. 100) seems to be the most promising beta 1 partial agonist. The aim of the study was to determine if the beneficial effects of Xamoterol were maintained during long term administration. Xamoterol (200 mg twice dialy) was administered to 14 patients with anterior myocardial infarction and moderate heart failure (class II-III NYHA). After 3 months' therapy, left ventricular function improved as indicated by reduction in left ventricular (LV) end-diastolic pressure (23 +/- 5 to 16 +/- 5 mm Hg; P less than 0.0005), LV end-diastolic volume (153 to 140 ml/m2; P less than 0.05) and in LV end-systolic volume especially in 11 patients with a control end-systolic volume less than 100 ml/m2 (- 15 p. 100; P less than 0.05). LV inotropic state was also enhanced as indicated by 21 p. 100 increases in EMax, the maximal LV pressure/volume ratio (P less than 0.02) and 20 p. 100 increases in the ratio end-systolic stress/ end-systolic volume (P less than 0.02). Myocardial oxygen consumption was unchanged, global lactate extraction fraction increased from 20 +/- 18 to 33 +/- 14 p. 100 (P less than 0.05) and LV alanine release was reduced (-1.7 to -0.2 muMol/min; P less than 0.05). The rate of LV pressure fall accelerated from 57 to 52 ms (P less than 0.05) and the mean diastolic wall stress was reduced by 35 p. 100 (P less than 0.05), reflecting the improvement in LV relaxation and diastolic function. Thus, the beneficial effects of Xamoterol were maintained after prolonged therapy particularly in patients with class II-III heart failure; patients in class IV benefited less from this therapy. No tachyphylaxis or side-effects were observed.
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PMID:[Role of adrenergic beta receptor partial agonists in left ventricular failure of ischemic origin. Value of xamoterol (ICI 118,587, Corwin)]. 286 23


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