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

The pathophysiological understanding and management of acute and chronic heart failure have changed dramatically in the past decade. Since the early 1980s, a major effort has been made to develop nonglycosidic, noncatecholamine agents that combine inotropic and vasodilating properties, in order to treat myocardial dysfunction unresponsive to current therapy. Within this context, increasing attention has been paid to the role of intracellular cyclic adenosine monophosphate (cAMP) in myocardial contractility. The pharmacologic use of catecholamines to stimulate beta-receptors activates adenylate cyclase, which in turn leads to an increase in intracellular levels of cAMP. In addition, phosphodiesterase 3 (PDE 3) inhibition may prevent the degradation of cAMP, thus maintaining high intracellular levels of the substance. Intravenous amrinone has been shown clinically to improve hemodynamic status remarkably in the patient experiencing a low cardiac output syndrome, by increasing CO while decreasing filling pressures and pulmonary arterial pressures, without increasing myocardial O2 demand. This report will review several studies of different types of patients and explain the effects of amrinone alone and in combination with the more traditionally used catecholamines. It must be stressed that amrinone, in spite of its dual action of inotropy and vasodilation, should not be considered a rival to catecholamines but rather an enhancer of them, which clinicians should consider using in the early stages of therapy in many different settings.
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PMID:Historical perspectives and update of amrinone. 252 Oct 46

Milrinone and enalapril, which inhibit PDE-III and ACE, respectively, are able to prolong survival of myocardially infarcted (MI) rats. This study sought to identify oral hemodynamic effects of these agents which could underlie such efficacy in this heart failure model. Four weeks after ligation of the left main coronary artery, basal left ventricular (LV) systolic pressure and dP/dtmax, heart rate and mean blood pressure of the MI rats were significantly less than that of sham-operated controls, and LV end-diastolic pressure (LVEDP) was markedly elevated. Milrinone, at 2.0 mg/kg, reduced LVEDP and renal blood flow of these 4-week MI rats by an average of 39 and 18%, respectively (P less than 0.05) within 1 h. At 4.0 mg/kg, it reduced LVEDP by 46% and raised heart rate by 16% (P less than 0.05). Enalapril (1.0 mg/kg) increased small intestine blood flow of these compromised rats by 16% (P less than 0.05), and tended to reduce LVEDP (-28%) within 1.5 h. Treatment with milrinone (2.0 mg/kg) plus enalapril (1.0 mg/kg) promoted LV dP/dtmax, coronary blood flow, and heart rate by 48, 40 and 13%, and reduced LVEDP by 40% (P less than 0.05 for all effects). Thus these agents can reduce LVEDP and redistribute cardiac output of MI rats. Furthermore, the combination of enalapril and milrinone can restore LVEDP and LV dP/dtmax of MI rats to near normal and promote coronary blood flow without compromising cardiac output or renal blood flow. Such effects, it timely or sustained, may prolong survival.
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PMID:Beneficial hemodynamic effects of milrinone and enalapril in conscious rats with healed myocardial infarction. 255 83

Alterations of receptor-G-protein-regulated adenylyl cyclase activity have been suggested to represent an important alteration leading to contractile dysfunction in the failing human heart. Recent experiments suggest that the beta 1-adrenoceptor (beta 1 AR) density and mRNA levels are reduced, while beta 2-adrenoceptors and stimulatory G-proteins are unchanged (mRNA and protein level). Functional assays demonstrated that the catalyst of the adenylyl cyclase is not different between failing and nonfailing myocardium. Inhibitory G-proteins are increased (pertussis toxin substrates, protein and mRNA) and correlate to the reduced inotropic effects of beta-adrenoceptor agonists and of cAMP-PDE inhibitors. Gi alpha-coupled m-cholinoceptors and A1-adrenergic receptors are unchanged in density and affinity. Stimulation of these receptors resulted in an unchanged antiadrenergic effect on force of contraction. In conclusion, a downregulation of beta 1 AR and an increase of Gi alpha have been observed as signal transduction alteration in failing human myocardium. These alterations are due to alterations of gene expression in the failing heart and are related to a defective regulation of force of contraction in heart failure.
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PMID:Alterations of beta-adrenoceptor-G-protein-regulated adenylyl cyclase in heart failure. 749 44

The positive inotropic agents, including beta-adrenergic receptor agonists and PDE III inhibitors, are reviewed to explain their mechanisms of action, pharmacology, and clinical usage. New cardiotonic drugs, such as dopexamine and dobutamine (beta-adrenergic receptor agonists) and amrinone, milrinone, and enoximone (PDE III inhibitors), have important roles for the treatment of perioperative acute heart failure or acute deterioration of congestive heart failure. PDE III inhibitors have important roles as effective inodilator agents, and understanding their actions, pharmacology, and appropriate usage is important. Nicardipine, the first dihydropyridine calcium-channel blocker available for intravenous use, represents an arterial-specific vasodilator that offers an important therapeutic approach to treat perioperative hypertension.
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PMID:New cardiac drugs. 763 56

1. The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium-sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2. Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean-1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing-induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham-operated dogs (group 2) served as controls. 3. In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing. Thus, there was a marked reduction in LVSP (15%), +dP/dtmax (35%), -dP/dtmax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 +/- 1.4 to 20.0 +/- 2.2 mmHg). A marked elevation occurred in endocardial ST-segment (138%), lasting for 20 min.4. Levosimendan was administered intravenously in doses of 0.005, 0.01 and 0.03 micromol kg-1 to 2 groups of conscious dogs. In the sham-operated dogs (group 2), only the higher dose (0.03 micromol kg-1)produced significant increases in LVSP (19%), + dP/dtmax (37%), and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 micromol kg-1 levosimendan resulted in an improve mentin +dP/dtmax (26%, 38% and 49%), -dP/dtmax (20%, 25% and 38%) and in dP/dt/P (19%, 34%and 50%) and reduction in the elevated LVEDP (from 20 =/- 2.2 mmHg to 16 +/- 1.0, 10 +/- 1.3 and 9 +/- 1.0 mmHg, respectively).5. Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective under conditions of impaired left ventricular function than in normal hearts.
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PMID:Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction. 773 92

Tumor necrosis factor-alpha (TNF) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock. Elevated circulating levels of TNF have also been reported in patients with severe chronic heart failure. We studied the effect of amrinone, a class III cyclic nucleotide phosphodiesterase inhibitor used in the treatment of acute heart failure, on the synthesis of TNF in vitro. Peripheral blood mononuclear cells from healthy volunteers or cells of a permanent monoblast cell line were stimulated for 20 h with bacterial lipopolysaccharide and different doses of amrinone. TNF production is suppressed in a dose-dependent manner to a minimum of 9% of controls with 1000 microM of amrinone, reaching half-maximal inhibition at 80 microM amrinone. This effect appears to be mediated via cAMP, which accumulated nearly twofold in the presence of amrinone. Suppression of TNF synthesis by therapeutically administered phosphodiesterase inhibitors such as amrinone may contribute to their beneficial effect in the treatment of heart failure.
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PMID:Amrinone suppresses the synthesis of tumor necrosis factor-alpha in human mononuclear cells. 774 41

We analyzed 128 cardiopulmonary exercise tests (CPX), performed in normal subjects (n = 31), in patients with coronary artery disease (n = 41), with chronic heart failure before (n = 14) and after (n = 14) application of oral PDE-inhibitors and in patients with HIV-infection on a bicycle-ergometer in semi-supine position using a ramp-program (dependent on study-population with 15, 20 or 35 Watt/min increases) with respect to the ability to determine the respiratory anaerobic threshold non-invasively, using the main criteria described by Wasserman et al.: the V-slope-method according to Beaver, the increase of the ventilatory equivalent for O2 (VE/VO2), the increase of the end-tidal PO2 (PETO2) and the increase of the respiratory quotient (RQ) during exercise. In the different study-populations we calculated the detection rates of the AT for each criteria separately. The typical changes in the end-tidal PO2 (124/128 = 96.9%) and the V-slope-method (119/128 = 92.9%) were the most reliable parameters to detect the anaerobic threshold. The characteristic changes of the ventilatory equivalent for O2 (VE/VO2) and of the respiratory quotient (RQ) we found in 100/128 (= 78.1%) and in 107/128 (= 83.6%) of the tests respectively. 86/128 tests (67.2%) showed typical changes in all four mentioned criteria. In another 24/128 tests (19.8%) three of four criteria were fulfilled. Therefore, our investigations showed that in 110/128 cases (85.9%) the AT could be determined by typical changes by means of at least three of the four described parameters. In 15/128 (11.7%) tests only two of four criteria were fulfilled.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Comparison of four different methods for respiratory determination of the anaerobic threshold in normal people, and heart- and lung patients]. 794 70

Despite the justifiable concern about the use of oral cyclic adenosine monophosphate phosphodiesterase (cAMP PDE) inhibitors, the intravenous preparations are clearly effective in the treatment of acute heart failure, whether it occurs de novo or complicating chronic congestive heart failure (CHF), and in low output states following cardiac surgery. There are no grounds to curtail their use in these areas, though any advantages over conventional agents such as dobutamine need further investigation with regard to end-points other than haemodynamic parameters. The long term use of oral cAMP PDE inhibitors in the treatment of chronic CHF should remain restricted by the increase in mortality now confirmed in severe CHF. However, in view of the distressing nature of the condition there remain subgroups of patients in whom the benefits may outweight the risks.
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PMID:Phosphodiesterase inhibitors. Do the risks outweight the benefits? 812 62

Low heart stroke volume syndrome is clinically manifested with hypoperfusion of all body systems. Inotropic or mechanical support is applied. Acute heart failure is one of the most important complications after open heart surgery. Catecholamines have been up to non considered as a therapy of choice for the acute heart failure. Effectiveness of catecholamines could be limited with some side effects. Phosphodiesterase inhibitors promise a new therapeutic approach. PDE III primary act through phosphodiesterase inhibition which leads to a rise of aAPM levels. Thus they show positive inotropic and lusitropic effects, which could be monitored by occlusive pulmonary capillary pressure values. Amrinone is obviously superior to inotropic catecholamines.
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PMID:[Hemodynamic effects of amrinone, dobutamine and dopamine in the cardiac low output syndrome following open-heart surgery]. 864 47

Severe congestive heart failure and cardiogenic shock don't resemble a homogeneous clinical picture, but a syndrome that is based on very different etiologies. What all the etiologies have in common is the inadequate peripheral O2-supply to essential organs with or without signs of severe pulmonary congestion up to pulmonary edema. For prognosis and therapy is a fast diagnostical clarification of the causes crucial. The therapeutical procedure for the various etiologies may be diametrically opposed. For the therapy is it also dicisive to distinguish between acute myocardial failure, e.g. acute myocardial infarction, and the development of myocardial failure from a longer existing consistent congestive heart failure (cardiomyopathy). Whenever possible, next to symptomatically therapy of cardiogenic shock the basic conditions of the disease should be cured (e.g., PTCA, lysis with acute myocardial infarction, lysis in acute pulmonary embolism). In myogenic cardiogenic shock the use of positive-inotropic substances with and without simultaneous vasodilatory effects, if necessary in combination with other vasodilators, may be life-saving. Up until now there still doesn't exist an alternative to the catecholamines in the acute phase, initially they should be used as a first-line-therapy to stabilize the hemodynamics. The insertion of a Swan-Ganz-catheter for invasive therapy-monitoring, especially for the regulation of the therapy is a "condition sine qua non" for every patient with unstable hemodynamics. Because of the prompt beta-receptor-down-regulation during shock, caused by endogenous catecholamines, successful therapy with exogenous catecholamines is limited (adrenaline, dopamine, dobutamine), on account of the acceleration and intensification of the beta-receptor-down-regulation process. Possible beta-receptor independent alternatives are beta 2-agonists (dopexamine), PDE-III-inhibitors (amrinone, milrinone, enoximone) as well as H2-receptor agonists (impromidine, arpromidine) and finally the calcium-sensitisers (pimobendane). First results give rise to optimism to effectively reduce the mortality of congestive heart failure. The combination of these new pharmacological possibilities with interventional transcutaneous applicable assist-systems (aortic counterpulsationpump IABP, hemopump, transcutaneous heart-lung-machine) as well as the transitory application of an artificial heart (Novacor) can possibly increase the success of these therapeutic strategies. So far there are no convincing results shown in the world literature.
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PMID:[Pharmacotherapy of severe heart failure with inodilators--new approaches]. 902 10


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