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)

Cyclic AMP plays a central role in modulating systolic and diastolic myocardial function. Consequently, the adrenergic nervous system, acting through myocardial beta-adrenergic receptors, very likely plays a significant role in regulating left ventricular systolic and diastolic function. Theoretically, beta-adrenergic agonists and antagonists may further modify myocardial systolic and diastolic function. Although the effects of beta-adrenergic agents are clearly demonstrable in vitro, it has been more difficult to evaluate the direct myocardial effects of beta-adrenergic agents in patients. These difficulties are related both to technical aspects of the measurement of systolic and diastolic parameters and to the potentially confounding effects of secondary nonmyocardial drug actions and reflex-mediated changes in myocardial and/or vascular adrenergic activity. A number of strategies for evaluating the direct myocardial actions of beta-adrenergic agents are discussed. Two promising approaches are the use of direct intracoronary drug infusion and the analysis of left ventricular pressure-volume relationships. The positive inotropic action of beta-adrenergic agonists is substantially attenuated in many patients with left ventricular failure due to end-organ desensitization of the beta-adrenergic pathway. Nevertheless, a beta-adrenergic agonist may still cause a substantial improvement in left ventricular pump function in such patients. There is less information available regarding the effect of beta-adrenergic agonists on myocardial relaxation. Preliminary data from the intracoronary infusion of dobutamine suggest that isovolumic relaxation is accelerated. Conversely, preliminary data suggest that a beta-adrenergic antagonist, esmolol, causes a slowing of isovolumic myocardial relaxation. Further studies will be needed to determine whether these drug effects result in a significant alteration in hemodynamic performance during diastole, and to evaluate the possibility that beta-adrenergic-mediated myocardial relaxation is attenuated in patients with heart failure.
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PMID:Effects of beta-adrenergic agents on systolic and diastolic myocardial function in patients with and without heart failure. 247 7

Cardiac failure is treated with increasing success by phosphodiesterase-III (PDE-III) inhibitors such as amrinone, milrinone, and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and beta-receptors. They have positive inotropic, positive lusitropic, and vasodilatatory properties; myocardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III, leading to an increased cAMP concentration in myocardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole, amrinone, and enoximone resulted in preload and afterload reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance; they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmax, while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myocardial oxygen consumption showed no clinically relevant alterations. In patients with angiographically documented coronary artery disease, the anti-ischemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myocardial efficacy, indicating its positive inotropic and lusitropic properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDE inhibitors. The anti-ischemic properties of these drugs need further evaluation.
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PMID:Present use of positive inotropic drugs in heart failure. 248 Apr 92

The rationale of combining vasodilatation with positive inotropic intervention in the treatment of chronic heart failure has found a new implementation in the "inodilator" drugs. Inodilators are characterized by the properties of exerting positive inotropic effect and inducing systemic vasodilatation. The cellular mechanisms involved in the regulation of contractility of cardiac and vascular muscle and the pathophysiological events occurring in heart failure are briefly discussed, and the pharmacological profile as well as the therapeutic use of these drugs are reviewed. On the basis of the mechanism of action, two groups of inodilators are distinguished, the phosphodiesterase inhibitors and the dopaminergic agents. The increase of [cAMP]i induced by the phosphodiesterase inhibitors is responsible for their vasodilating effect and for the positive inotropic action, but many of them have in addition the ability to enhance the Ca2+ sensitivity of cardiac contractile proteins. The complex organization and the cardinal role of the catecholaminergic receptor system in the control of cardiovascular function and its contribution to the pathophysiological events occurring in heart failure are the rational basis of the therapeutic use of dopaminergic agents. These drugs, acting on DA, beta-, and alpha-receptors, exert not only positive inotropic and vasodilating effects, but also a diuretic action, and can reduce aldosterone and renin secretion, blunt an excessive sympathetic activity, and possibly promote the release of atrial natriuretic peptide. The multireceptor mechanism of dopamine-like drugs, which accounts for their favorable hemodynamic, neurohumoral, and diuretic effects, represents the most promising approach to inodilator therapy.
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PMID:Present and future trends in research and clinical applications of inodilators. 248 38

We measured plasma concentrations of norepinephrine, cyclic AMP, cyclic GMP, atrial natriuretic peptides (ANP) and beta-adrenoceptor density (Bmax) and affinity (Kd) of lymphocytes in patients with congestive heart failure and correlated these parameters with symptoms and hemodynamic indices. Plasma concentration of norepinephrine, cyclic AMP, cyclic GMP and ANP significantly increased in patients with congestive heart failure. Plasma concentrations of norepinephrine were related to the severity of the heart failure, plasma cyclic AMP concentrations, and pulmonary artery pressures. Cyclic AMP concentrations fell rapidly after treatment of acute left ventricular failure. Peripheral blood lymphocytes were stimulated by isoproterenol, and cyclic AMP level in lymphocytes was assayed. In normal subjects the generation of cyclic AMP after stimulation decreased with age. The response of lymphocytes in patients of NYHA classes III and IV was significantly lower than in the normal age-matched controls. A significant correlation between plasma norepinephrine concentration and increase of lymphocyte cyclic AMP was demonstrated. From these results it was suggested that beta-adrenergic receptors in congestive heart failure were desensitized. Beta receptor numbers of lymphocytes significantly decreased in NYHA class III and IV, but did not decrease in class I and II. There was no significant difference in Kd associated with congestive heart failure. Plasma concentrations of cyclic GMP also depended on the severity of heart failure and the pulmonary artery pressure, and decreased sharply with treatment, although remaining at a high value. A significant correlation between the cyclic GMP and ANP concentration was found in patients with congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathophysiologic and prognostic considerations in circulatory insufficiency in congestive heart failure: receptor function. 254 Dec 67

Cardiac alpha- and beta-adrenoceptors and the positive inotropic effects of several adenylate cyclase dependent and independent agents have been measured in papillary muscle strips from patients without, as well as with moderate and severe heart failure. The number of beta-adrenoceptors was found to be decreased depending on the degree of heart failure. This does not apply to alpha-adrenoceptors, which remain unchanged. The antagonist affinity of adrenoceptors for the different ligands did not change in heart failure. Maximal increases in force of contraction were measured after raising Ca++ up to 15 mM in the muscle strips. In healthy human myocardium, isoprenaline, dobutamine, IBMX or cardiac glycosides increase force of contraction to the same maximal values as Ca++ does. However, in cardiac tissue from heart failure patients, positive inotropic agents which increase intracellular cAMP or are cAMP-dependent are less effective than Ca++. Furthermore, the results seem to indicate a homologous (agonist specific) downregulation of receptors in moderate heart failure and a heterologous downregulation in severe heart failure. Thus, many well known positive inotropic drugs lose their effectiveness just when they are needed most: in severe heart failure.
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PMID:Positive inotropic stimulation in the normal and insufficient human myocardium. 255 70

Prognosis of heart failure patients remains poor and stimulates research of new active drugs and therapeutic improvements. Besides diuretic and vasodilating agents, the place of positive inotropic drugs remains to be defined. Long term benefit remains to be demonstrated for Milrinone, Enoximone and Digitalis. However, absence of benefit has been established with Amrinone and beta adrenoceptor agonists. Too many uncontrolled studies have complicated the accurate evaluation of efficacy of these positive inotropic drugs. Purpose of heart failure treatment remains to improve functional status without deterioration of myocardial fibers contractility. The respective roles of cAMP, gAMP and intracellular calcium concerning myocardial fiber longevity remains to be clarified.
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PMID:[Treatment of chronic heart failure with positive inotropic agents]. 257 55

AR-L57 and AR-L115 have been of interest as inotropic agents for management of heart failure. Although their physiological effects are well documented, their mechanism(s) of action are unclear. Both AR-L57 and AR-L115 increased contractile force of cat papillary muscles in concentration-dependent manners; these effects were independent of either alpha- or beta-adrenoceptor stimulation. To determine if these effects occurred via a cAMP-dependent mechanism, cardiotonic actions were studied in the presence of carbachol. Muscarinic stimulation of papillary muscles attenuated contractile responses to AR-L115 thus implying a cAMP-mediated response. By contrast, carbachol did not alter the dose-response profile to AR-L57. In addition, AR-L115 potentiated the inotropic actions of isoproterenol whereas AR-L57 was ineffective. Both AR-L57 and ouabain increased diastolic resting tension in papillary muscles--a phenomenon associated with a state of Ca2+ overload; AR-L115 was without effect. In anesthetized dogs, i.v. AR-L57 and AR-L115 increased contractility and heart rate while reducing mean arterial blood pressure. Both agents had similar rates of onset (10-15 s) and durations of action (40-60 min). Although in vitro studies clearly indicate that AR-L57 and AR-L115 enhance inotropic state by distinct mechanisms, their in vivo cardiovascular profiles are comparable.
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PMID:A comparison of the cardiotonic effects of AR-L115 and AR-L57: evidence for distinct inotropic mechanisms. 258 Jan 41

Phosphorus 31 magnetic resonance spectroscopy (MRS) can be used to monitor the direct effect of drugs on energy metabolites of the heart. Using the isolated perfused heart of the cardiomyopathic hamster (late heart failure), drugs that exacerbate the diastolic level of calcium [Ca]i (e.g., dobutamine and digoxin) augment intracellular phosphomonoester sugars, while drugs which increase cyclic adenosine mono-phosphate [cAMP]i (e.g. isoprel, dibutyryl cAMP, and amrinone) lower phosphomonoester sugars. The phosphomonoester sugars are inversely related to developed pressure and oxygen consumption. Accumulation of sugar phosphates indicates inhibition of glycolysis and limited delivery of pyruvate to the mitochondria, thereby decreasing oxygen consumption. The phosphorylation potential obtained from standardized 31P MRS values showed a direct relationship to the rate pressure product in hamsters with heart failure; however, the two parameters were inversely related in control hamsters.
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PMID:Influence of drugs on diseased states of the heart. A 31P NMR and [Ca]i study. 260 35

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

Exposure of cultured heart muscle cells to noradrenaline led to a decrease in the effects of isoproterenol and prostaglandin E1 on cAMP formation and contraction velocity. However, heterologous desensitization, as measured by prostaglandin E1 stimulation, only occurred at higher noradrenaline concentrations than homologous desensitization (isoproterenol stimulation). As the defects of the adenylate cyclase system in heart failure are attributed to noradrenaline-induced desensitization, it is concluded from the results that, in comparison to the subsensitivity to beta-adrenoceptor agonists in failing human hearts, a decrease in the responsiveness to other receptor-dependent adenylate cyclase stimulators should also occur but only at higher degrees of heart failure.
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PMID:Homologous vs. heterologous desensitization of the adenylate cyclase system in heart cells. 284 30


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