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 nucleotide phosphodiesterase (PDE) isozymes isolated by DEAE-Sephacel or Mono-Q High Performance Liquid Chromatography from cardiac left ventricular tissue of normal subjects and patients with end-stage heart failure have been compared. With both separation techniques, four major peaks of PDE activity were evident in the soluble fractions; only one peak of activity was present in particulate fractions. The specific activity of the particulate PDE from myopathics was approximately 30-50% of that of normals while the specific activity of a soluble form of this PDE (peak IIIa) was reduced by 30% in myopathics. No differences in comparison of the other peaks of PDE activity were evident. The particulate PDE isozyme has a low Km for cAMP (0.27-0.29 microM), is inhibited by cGMP (60-80% at 1 microM), is sensitive to inhibition by submicromolar concentrations of CI-930 but not rolipram, and is competitively inhibited by milrinone (Kj = 0.3 microM). The first soluble peak of PDE activity hydrolyzes both cAMP and cGMP and is stimulated by calmodulin while cyclic AMP hydrolysis by peak II PDE is stimulated by cGMP. The other soluble peak III fractions (IIIa and IIIb) hydrolyze cAMP; peak IIIa is inhibited by cGMP or by CI-930 and milrinone, whereas peak IIIb is also inhibited by rolipram when the cardiotonic sensitive PDE is inhibited by CI-930. Thus, cardiotonic-sensitive, cGMP-inhibitable, low Km cAMP PDE is present in both the soluble and particulate fractions of human cardiac left ventricular muscle of hearts from normal and cardiomyopathic subjects while the rolipram-sensitive PDE is present in the soluble fraction. The major differences in PDE activity of myopathic relative to normal left ventricular tissue are a reduced specific activity and Vmax of particulate PDE and one of the soluble peak III PDEs.
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PMID:Cellular distribution and pharmacological sensitivity of low Km cyclic nucleotide phosphodiesterase isozymes in human cardiac muscle from normal and cardiomyopathic subjects. 228 32

In hypertensive cardiac hypertrophy, inotropic responsiveness of alpha and beta adrenergic stimuli is reduced. We have previously shown that hearts from two-kidney, one-clip renal hypertensive rats (RHR) have increased beta-adrenergic receptor density and a defect in the guanine nucleotide regulatory protein, leading to decreased adenylate cyclase activity. In spontaneously hypertensive rats (SHR), beta-receptor density was decreased with no change in adenylate cyclase. In these present experiments, we have shown that the alpha 1-adrenergic receptor changes are in the opposite direction, decreasing in RHR and increasing in SHR. All these changes are reversible within 4 weeks following removal of the clipped kidney in RHR, at which time blood pressure and heart weight have also returned towards normal. Further studies on the excitation-contraction pathway have indicated that c-AMP-stimulated protein kinase is decreased in SHR with no changes seen in RHR. Subcutaneous infusion of epinephrine leads to some increase of cardiac mass associated with decreased beta-adrenergic receptors element and decreased adenylate cyclase activity. However, following angiotensin II infusion, even though hypertrophy is more pronounced, no changes in receptors or cyclase are detected. We conclude that different models of hypertensive cardiac hypertrophy associated with different biochemical defects in the adrenergic excitation response pathway, and that if some of these changes become irreversible, further cardiac deterioration and even heart failure may ensue.
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PMID:Excitation-contraction coupling in hypertrophied myocardium. 241 74

Inotropic stimulation of the failing heart, although a logical adjunct in short-term efforts to maintain circulatory function in patients with heart failure, has several potentially deleterious effects that may limit its usefulness in long-term therapy for patients with congestive heart failure. These deleterious effects include cell damage caused by an increased rate of energy expenditure, exacerbation of relaxation abnormalities, and potential arrhythmogenic side effects that may result from increased cytosolic Ca++ and cyclic AMP concentrations in the inotropically stimulated myocardium. Recognition of these possible side effects should allow the therapeutic benefits of this approach to long-term therapy to be evaluated in carefully controlled clinical trials.
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PMID:Potential deleterious effects of inotropic agents in the therapy of chronic heart failure. 241 47

We studied the effects of different classes of inotropic drugs on human working myocardium in vitro that was isolated from the hearts of patients with end-stage heart failure, and compared the responses to these drugs with those noted in muscles from nonfailing control hearts. Although peak isometric force generated in response to increased extracellular calcium reached control levels in the muscles from patients with heart failure, the time course of contraction and rate of relaxation were greatly prolonged. The inotropic effectiveness of the beta-adrenergic agonist isoproterenol and the phosphodiesterase inhibitors milrinone, caffeine, and isobutylmethylxanthine was markedly reduced in muscles from the patients with heart failure. In contrast, the effectiveness of inotropic stimulation with acetylstrophanthidin and the adenylate cyclase activator forskolin was preserved. After a minimally effective dose of forskolin was given to elevate intracellular cyclic AMP levels, the inotropic responses of muscles from the failing hearts to phosphodiesterase inhibitors were markedly potentiated. These data indicate that an abnormality in cyclic AMP production may be a fundamental defect present in patients with end-stage heart failure that can markedly diminish the effectiveness of agents that depend on generation of this nucleotide for production of a positive inotropic effect.
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PMID:Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. 243 73

The number of cardiac beta-adrenoceptors and the positive inotropic effect of isoprenaline and milrinone were measured in cardiac membranes and isolated, electrically driven muscle strips from nonfailing donor hearts and from patients with mitral valve disease (NYHA II-III), ischemic heart disease, and dilated cardiomyopathy (NYHA IV). In nonfailing hearts, the number of beta-adrenoceptors were 41.5 fmol/mg protein (mean, n = 3). In ischemic heart disease and NYHA II-III, there was a loss of cardiac beta-adrenoceptors (22.1 fmol/mg protein, mean, n = 3; 23.2 +/- 2.7 fmol/mg protein, n = 30), respectively. In NYHA IV, there was a pronounced reduction of the number of cardiac beta-adrenoceptors to 12.1 +/- 1.5 fmol/mg protein (n = 15). The Kd value did not differ in either group. Correspondingly, the positive inotropic effect of isoprenaline was more pronounced in nonfailing myocardium, reduced in NYHA II-III and ischemic heart disease and almost blunted in NYHA IV. Similar results were observed with the phosphodiesterase inhibitor milrinone. A good correlation of the beta-adrenoceptor density to the maximal positive inotropic effect of isoprenaline and milrinone was observed. Neither the number of cardiac beta-adrenoceptors nor the positive inotropic effect of isoprenaline correlated with the age of the patients. We conclude that the number of cardiac beta-adrenoceptors and the positive inotropic effect of beta-adrenoceptor agonists are reduced in the failing human heart depending on the severity of heart failure. Furthermore, the positive inotropic effect of milrinone is also reduced and related to the reduction of beta-adrenoceptors. The lack of correlation with the age of the patients provides evidence for a predominant role of heart disease rather than aging in the reduction of beta-adrenoceptors and subsensitivity to cyclic AMP-increasing positive inotropic agents in the failing human heart.
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PMID:Subsensitivity of the failing human heart to isoprenaline and milrinone is related to beta-adrenoceptor downregulation. 246 92

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

1. The inotropic and chronotropic actions of N6-substituted adenosine 3':5'-cyclic monophosphate (cyclic AMP) derivatives (N6-R cyclic AMPs) were studied in guinea-pig isolated right atrial preparations and in the papillary muscle preparations from guinea-pig right ventricle. 2. All the N6-R cyclic AMPs except N6-C14H29 produced positive inotropic effects in papillary muscle. The C5H11, C6H13, C7H15, C8H17 and C9H19 compounds were the most potent as inotropic agents, the potency being lower with compounds having longer or shorter N6-side chains than these. 3. In right atria N6-C2H5-C7H15 cyclic AMPs produced negative chronotropic effects. However, after treatment of the preparations with 8-phenyltheophylline the negative chronotropic effects were either much attenuated or abolished, indicating the involvement of adenosine receptors. 4. All the N6-R cyclic AMPs except N6-C14H29 were more potent activators of bovine myocardial protein kinase than cyclic AMP. The partition coefficients between octanol and an aqueous phase of N6-R cyclic AMPs became greater as the numbers of carbon atoms increased, and there appeared to be a relationship between partition coefficient and inotropic potency. It was concluded that membrane penetrativeness rather than potency as activators of protein kinase determined the potencies of N6-R cyclic AMPs as positive inotropic agents. 5. Derivatives such as N6-C7H15 cyclic AMP, which have positive inotropic activity without any marked negative chronotropic effect, may be useful as cardiotonic agents in heart failure.
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PMID:Inotropic and chronotropic effects of N6-substituted derivatives of cyclic AMP as assessed in guinea-pig isolated right atria and papillary muscle. 254 73

1. The present study was designed to characterize the positive inotropic response to DPI 201-106 in isolated papillary muscle strips obtained from heart failure patients undergoing surgery. 2. The positive inotropic responses to isoprenaline and milrinone and cardiac beta-adrenoceptor density were also determined. 3. DPI 201-106 increased the force of contraction in papillary muscle strips from patients with moderate (NYHA II-III) and severe (NYHA IV) heart failure, in a concentration-dependent manner. This positive inotropic effect was more pronounced in tissues from NYHA IV patients. Furthermore, these responses were greater than those produced by milrinone or isoprenaline. The positive inotropic effects of isoprenaline and milrinone were reduced in NYHA IV compared to NYHA II-III. Consistently, there was also a smaller density of beta-adrenoceptors in myocardium from NYHA IV than in NYHA II-III. The positive inotropic effect of Ca2+ was similar in tissues from both groups of patients. 4. The positive inotropic effect of DPI 201-106 was not antagonized by adenosine or carbachol, whereas both compounds reduced the positive inotropic effect of isoprenaline. 5. DPI 201-106 did not increase the Ca2+ -sensitivity of chemically skinned ventricular fibres, whereas a significant increase of the Ca2+ -sensitivity was obtained with trifluoperazine. 6. It is concluded that DPI 201-106 produces significant positive inotropic effects in tissue excised from the failing human heart. The lack of inhibition by adenosine and carbachol might contribute to its greater effectiveness in NYHA IV than NYHA II-III and indicates that its mechanism of action is cyclic AMP-independent. A sensitization of the contractile proteins to Ca2+ does not appear to be important for the positive inotropic action of DPI 201-106 in the failing human heart.
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PMID:Inotropic response to DPI 201-106 in the failing human heart. 255 90

In heart failure a decrease in cardiac beta-adrenoceptors presumably due to endogenous down-regulation by the elevated catecholamines is a general phenomenon. Thus, attempts have been made to assess beta-adrenoceptor function in patients with chronic heart failure in order to monitor the functional state of cardiac beta-adrenoceptors. The model most widely used is that of circulating lymphocytes that contain a homogeneous population of beta 2-adrenoceptors coupled to the adenylate cyclase/cyclic AMP system. The biochemical and pharmacological properties of beta 2-adrenoceptors present in lymphocytes are quite comparable to those of beta 2-adrenoceptors in the human heart, but clearly different from those of human cardiac beta 1-adrenoceptors. Furthermore, beta-adrenoceptor agonists and antagonists regulate lymphocyte beta 2- and cardiac beta 1- and beta 2-adrenoceptors in a subtype-selective fashion: while non-selective agonists (independent of exogenously applied or endogenously elevated) and antagonists affect both cardiac beta 1- and beta 2- as well as lymphocyte beta 2-adrenoceptors, beta 1-selective agonists and antagonists influence only cardiac beta 1-, but not cardiac and lymphocyte beta 2-adrenoceptors. Finally, direct comparison of lymphocyte and cardiac beta-adrenoceptor densities revealed that changes in lymphocyte beta 2-adrenoceptors are significantly correlated with changes in cardiac beta 2-adrenoceptors, but not related to changes in cardiac beta 1-adrenoceptors. Since beta 1-adrenoceptors predominate in all parts of the human heart, the use of lymphocyte beta 2-adrenoceptors as a tool for predicting the status of cardiac beta-adrenoceptors is, therefore, quite limited.
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PMID:Beta-adrenoceptor regulation in the human heart: can it be monitored in circulating lymphocytes? 255 8

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


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