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

Enoximone is a new inotropic agent, which acts by the inhibition of the type III phosphodiesterase (PDE) enzyme. The present report describes a 81-year-old female patient with severe heart failure following aortic valve replacement. Her cardiac activity was paced. The addition of enoximone (two doses of 0.5 mg/kg) to an intravenous infusion of dobutamine (8 mcg/kg/min) and sodium nitroprusside significantly increased cardiac output (CO) from 3.2 to 3.9 l/min and decreased pulmonary artery occlusive pressure (PAOP) from 22 to 16 mmHg. Another dose of enoximone 12 h later had similar effects. However, another 12 h later, after dobutamine had been discontinued, two successive injections of 0.5 mg/kg of enoximone were totally ineffective (CO from 2.6 to 2.5 l/min, PAOP 23 mmHg). When the dobutamine infusion was restarted (at 8 mcg/kg/min), the positive effects of 0.5 mg/kg of enoximone were again present (CO from 3.0 to 3.6 l/min, PAOP from 19 to 14 mmHg). This observation underscores the therapeutic value of the combination of PDE inhibitors such as enoximone with adrenergic agents such as dobutamine in the management of severe heart failure.
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PMID:Potentiation of the effects of enoximone by a dobutamine infusion. 253 56

Cardiac phosphodiesterase III (PDE) inhibitors derived from pyridinone, imidazolone, pyridazinone and related structures form a new class of positive inotropic vasodilator agents (e.g. milrinone) that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. Drugs such as milrinone have a wider therapeutic index than the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of PDE inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity. Individual PDE inhibitors differ in terms of both chronotropic and extracardiac properties. The reasons for this are not yet fully understood.
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PMID:Pharmacology of positive inotropic phosphodiesterase III inhibitors. 255 11

Beta-adrenergic sympathomimetic agents such as dobutamine and dopamine, and phosphodiesterase inhibitors such as amrinone, milrinone, and enoxamone, exert a direct positive inotropic effect upon the myocardium by causing an increase in cyclic AMP levels. The phosphodiesterase inhibitors also exert a substantial direct vasodilator effect. Both the sympathomimetic agents and the phosphodiesterase inhibitors can be of value in the acute, short-term management of myocardial failure. At present, the use of these agents for long-term therapy of congestive heart failure is unproven, and remains investigational.
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PMID:Positive inotropic/vasodilator agents. 256 61

The direct negative inotropic actions of calcium channel blockers limit the use of these otherwise effective systemic and coronary vasodilators in patients with heart failure. We studied the effects of amrinone pretreatment on the dose--hemodynamic response curve of diltiazem in order to test the hypothesis that amrinone might potentiate diltiazem's positive effects in anesthetized dogs. The control group (no pretreatment, n = 6) had a typical dose-related response to diltiazem (50, 100, and 150 micrograms/kg): coronary and systemic vasodilation, increased stroke volume, and no change in myocardial work and power. Amrinone pretreatment of the study group (n = 7) altered the hemodynamic response, thus maximal systemic vasodilation and stroke volume increase at a lower diltiazem dose, a 15 to 35% increase in myocardial work and power, and more profound coronary vasodilation. We propose that amrinone, by inhibiting phosphodiesterase, potentiates diltiazem vasodilation and reflexly secreted catecholamines' actions on the heart. This positive interaction may permit effective use of lower doses of diltiazem, thus circumventing its dose-limiting direct negative effects while still profitting from beneficial peripheral, reflex, and coronary actions.
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PMID:Positive hemodynamic interaction between amrinone and diltiazem in anesthetized dogs. 259 32

Controlled and uncontrolled hemodynamic and clinical studies have noted that the long-term treatment of patients with chronic heart failure with phosphodiesterase (PDE) inhibitors, such as amrinone, milrinone, enoximone and imazodan, may accelerate progression of the underlying disease and provoke serious ventricular arrhythmias. However, in an experimental model of chronic progressive left ventricular dysfunction, milrinone has been reported to reduce mortality to a degree comparable to that seen with the converting-enzyme inhibitors. These discordant observations suggest that either the deleterious hemodynamic and electrophysiologic effects of the PDE inhibitors are not translated into an adverse effect on mortality, or the animal model used to evaluate the effects of milrinone cannot be used to investigate the action of these drugs in human heart failure. Unfortunately, no trial has prospectively evaluated the effect of PDE inhibition on the survival of patients with heart failure. To address this need, the Prospective Randomized Milrinone Survival Evaluation (PROMISE Trial) has been launched in 75 to 90 clinical research centers in the United States and Canada. This study will enroll 750 patients with severe (class IV) heart failure, who have symptoms refractory to conventional therapy with digitalis, diuretics, converting-enzyme inhibitor and direct-acting vasodilators. Patients will be randomly assigned to additional treatment with either oral milrinone or placebo, and followed until death or to the conclusion of the study. The primary end point will be all-cause mortality, but the effect of milrinone on functional capacity will also be evaluated. The results of the study should define the place of PDE inhibitors in the treatment of chronic heart failure.
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PMID:Effect of phosphodiesterase inhibitors on survival of patients with chronic congestive heart failure. 264 29

New cardiotonic agents are an original approach in the treatment of severe heart failure. They can be classified into two groups: --beta-adrenergic agonists which stimulate beta-adrenergic receptors and, therefore, increase cyclic AMP production and intracellular calcium concentration; --phosphodiesterase inhibitors which block the cyclic AMP intracellular degradation pathway. Rapid tachyphylaxis may occur with beta-adrenergic agonists through a down-regulation phenomenon and, therefore, limits the value of this group to short-term treatment. Several different biochemical compounds are under evaluation in the second group. Short-term effects appear beneficial but cardiac side-effects may occur. The value and indications of these drugs in long-term treatment of chronic congestive heart failure remain to be determined.
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PMID:[Value and limitations of new cardiotonic agents]. 267 75

Heart failure remains a major therapeutic problem with a poor prognosis despite therapy with digitalis, diuretics and vasodilator drugs. Because impaired myocardial contractility is a principal feature of persistent heart failure, the development of phosphodiesterase inhibitors, e.g. milrinone, has presented important therapeutic possibilities. Milrinone exerts both positive inotropic and vasodilator activity, and improves systemic haemodynamics by increasing left ventricular stroke volume and decreasing left ventricular filling pressure and systemic vascular resistance. In addition to improving systolic pump function, milrinone has also been shown to improve impaired diastolic relaxation of the failing heart. Importantly, treatment with milrinone does not significantly increase myocardial oxygen consumption. In moderate to severe heart failure (NYHA class III and IV), intravenous and oral milrinone have been shown not only to produce acute haemodynamic improvement but also to relieve the associated symptom of breathlessness, with improvement in quality-of-life indices. In placebo-controlled, double-blind studies oral milrinone has enhanced exercise tolerance and increased total body oxygen consumption in mild (class II), moderate and severe heart failure. There is no evidence of a substantial pro-arrhythmic effect or other significant non-cardiovascular side-effects associated with the use of milrinone. The possibility of improved survival, which is still the ultimate goal of therapy with phosphodiesterase inhibitors, remains to the studied. Similarly, the role of these agents in the management of mild heart failure, alone or in addition to therapy with diuretics and angiotensin-converting enzyme (ACE) inhibitors, warrants further evaluation.
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PMID:Therapeutic achievements of phosphodiesterase inhibitors and the future. 268 Apr 98

The major determinants of myocardial oxygen consumption (MVO2) were examined in the isolated, servo-regulated, canine heart in which coronary perfusion pressure, heart rate, ventricular volume and pressure could be individually monitored and controlled. We found that the integral of systolic wall force and the time derivative of systolic force development were major determinants of MVO2, Net MVO2, seen in response to increments in contractility (dobutamine) and heart rate, were the result of the relative increments in each of these determinants. Additional studies were performed to assess the heart's metabolic reserve and aerobic limit (i.e., before the onset of lactate production). We found that with increments in left ventricular work, mediated by increments in filling volume, heart rate, and contractility (dobutamine), myocardial lactate production could be induced, but was dependent on the level of coronary perfusion pressure. When the aerobic limit of the myocardium was exceeded, its performance declined and pulsus alternans appeared. In patients with cardiomegaly and advanced heart failure given the phosphodiesterase inhibitors enoximone and piroximone we did not observe a rise in MVO2 or the appearance of lactate production in the majority of patients. When patients with documented idiopathic (dilated) cardiomyopathy and marked heart failure received hemodynamically significant doses of dobutamine alone or in combination with amrinone, there again was no evidence of lactate production or a rise in MVO2, while a marked improvement in ventricular function was noted. Thus, these agents served to improve the efficiency of the dilated failing heart. Hence we would conclude that in most cases, the dilated failing heart has an adequate metabolic reserve. It performance, and indeed its efficiency, can be improved with pharmacologic agents having positive inotropic properties without adversely altering myocardial energetics.
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PMID:Myocardial energetics: experimental and clinical studies to address its determinants and aerobic limit. 281 57

In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 microM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found: 1. Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres. 2. During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles. 3. In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment. 4. Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts. Mild isoprenaline overload and hereditary cardiomyopathy both are forms of heart failure which are presumably not associated with a lack of activator Ca. It is concluded that cardiotonic agents increasing the cardiac myofibrillar sensitivity to Ca ions would be beneficial in both cases, representing a phenomenologically causative treatment in hearts failing due to isoprenaline pretreatment. A main advantage over "classical" cardiotonic agents like cardiac glycosides, beta adrenergic stimulants or phosphodiesterase inhibitors would be the absence of the risk of drug-induced Ca overload.
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PMID:Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533. 282 79

A novel series of pyrimidine derivatives was synthesized and evaluated for positive inotropic activity. Inotropic and chronotropic effects were determined in vitro in cat papillary muscle and right atrium, respectively. Selected compounds were then evaluated in vivo in a dog heart failure model. Changes in ventricular dP/dt, heart rate, and blood pressure were monitored. Several of these agents produced relatively minor changes in heart rate. This class of agents demonstrated a varying degree of vasodilator effects concomitant with increases in ventricular contractility. The most potent analogues, 9, 48, and 49, were evaluated orally in conscious dogs with implanted Konisberg pressure transducers, and their effect on left ventricular dP/dt was compared with that of milrinone. Mechanistically, the agents of this novel class appear not to mediate their effect via beta-receptors or inhibition of Na+/K+-ATPase. A major component of their inotropic effect is mediated by the inhibition of cardiac phosphodiesterase (PDE)-Fr. III. This was clearly demonstrated by 9, 48, and 49. Compound 48 was found to be the most potent inhibitor of PDE-Fr. III from among the compounds tested in this assay.
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PMID:Chemistry and positive inotropic effect of pelrinone and related derivatives. A novel class of 2-methylpyrimidones as inotropic agents. 283 2


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