Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

A central working hypothesis in our laboratory is that deficient cellular cyclic AMP concentrations may be responsible, at least in part, for striated muscle dysfunction, both cardiac and skeletal, in heart failure. These results suggest that therapy aimed at restoring cyclic AMP to normal levels may be effective with regard to improving systolic and diastolic function in the heart and may decrease the development of fatigue in skeletal muscle of patients with failure. The use of cyclic AMP-dependent drugs in clinical practice has been limited by side effects associated with raising total cellular content of this cyclic nucleotide. However, evidence suggesting that separate pools of cyclic AMP may exist within the cell raises the possibility that those pools associated with excitation/contraction coupling could serve as more specific therapeutic targets.
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PMID:Alterations in heart failure of cyclic AMP-dependent inotropic and lusitropic properties of cardiac and skeletal muscle. 1060 49

We recently demonstrated that rapid ventricular pacing caused cardiac failure (Failure) in dogs with aortic stenosis-induced left ventricular hypertrophy (Hypertrophy) and isoproterenol caused no significant increases in function, O2 consumption and intracellular cyclic AMP level in the failing hypertrophied hearts. We tested the hypothesis that alterations in the beta1-adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to beta-adrenergic stimulation during the transition from the compensated hypertrophy to failure. Pressure overload-induced left ventricular hypertrophy was created using aortic valve plication in 10 dogs over a 6-month period. Five months after aortic valve plication, congestive heart failure was induced in 5 dogs by rapid ventricular pacing at 240 bpm for 4 weeks. The density of myocardial beta1-adrenoceptors (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduced in the Failure dogs (176+/-19; 755+/-136) when compared to those of the Control (344+/-51; 1,551+/-203) and the Hypertrophy (298+/-33; 1,721+/-162) dogs. The receptor affinities were not significantly different among all groups. There was a small but significant decrease in the percentage of beta1-adrenoceptors of the failing hypertrophied hearts (62+/-3%) when compared to that of the hypertrophied hearts (77+/-5%). The basal myocardial adenylyl cyclase activity (pmoles/mg protein/min) was significantly lower in the Failure dogs (45+/-4) than in the Control (116+/-14) and Hypertrophy (86+/-6) dogs. The forskolin (0.1 mM)-stimulated adenylyl cyclase activity was also significantly lower in the Failure dogs (158+/-17) than in the Control dogs (296+/-35) and slightly lower than in the Hypertrophy dogs (215+/-10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude that down regulation of beta1-adrenoceptors and reduced adenylyl cyclase activities contribute to the decreases in myocardial functions and beta-adrenergic responses in the failing hypertrophied hearts induced by rapid ventricular pacing.
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PMID:Down regulation of myocardial beta1-adrenoceptor signal transduction system in pacing-induced failure in dogs with aortic stenosis-induced left ventricular hypertrophy. 1082 23

Recent evidence suggests that inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-alpha), may play a role in heart disease. Elevated plasma levels of the cytokine have been reported in congestive heart failure and severe angina and after myocardial infarction. The exact role of TNF-alpha in heart disease and how production is stimulated and regulated in the heart are current areas of investigation. Regarding regulation of production, isoproterenol elevates cyclic AMP and inhibits TNF-alpha release in macrophages. Therefore we hypothesized that stimulation of beta-adrenergic receptors of the sympathetic nervous system would inhibit release of the cytokine from heart tissue. With Institutional Review Board approval and patient consent atrial tissue was obtained during preparation for cardiac bypass. The tissue was divided into segments, placed in culture medium, and incubated for various times in the presence or absence of lipopolysaccharide (LPS) (20 microg/mL) and/or isoproterenol (1 microM). The medium was removed and analyzed for biologically active TNF-alpha by the L929 cell cytotoxicity assay. Tissue samples were weighed and TNF-alpha release was expressed as pg TNF-alpha/mg tissue. Initially, to determine the time course of release, measurements were made at 2, 5, 10, 15, 30, 60, 120, 180, and 360 minutes after the addition of LPS. Elevated TNF-alpha levels in the culture medium were reliably detected at 360 minutes after exposure to LPS. In atrial tissue obtained from seven patients TNF-alpha released into the culture medium at 360 minutes was 6 +/- 3 pg/mg tissue. In the presence of LPS, levels of the cytokine in the culture medium increased to 604 +/- 233 pg/mg tissue (P < 0.05 vs LPS alone). When isoproterenol and LPS were simultaneously added to the culture medium release of TNF-alpha was reduced by 87 per cent to 82 +/- 40 pg/mg tissue (P < 0.05 vs LPS alone). Our results show that activation of the beta-adrenergic receptor inhibits myocardial production of TNF-alpha. This finding suggests that the sympathetic nervous system inhibits production of the cytokine and that impaired sympathetic function in heart failure may play a role in the elevated levels of TNF-alpha.
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PMID:Isoproterenol inhibits bacterial lipopolysaccharide-stimulated release of tumor necrosis factor-alpha from human heart tissue. 1126 22

This study was designed to investigate the effects on single skeletal muscle fibers of a novel thienylhydrazone, referred to as LASSBio-294, which is a bioisoster of pyridazinone compounds that inhibit the cyclic AMP-specific phosphodiesterase (PDE) 4. Twitch and fatigue were analyzed in single skeletal muscle fibers isolated from either the semitendinous or the tibialis anterior muscles dissected from the frog Rana pipiens. LASSBio-294 (12.5-100 microM) increased twitch tension, accelerated the maximal rate of tension decay during relaxation, and had very little effect in the maximal rate of tension development of muscle fibers directly stimulated at < or =30 Hz. The positive inotropic effect of LASSBio-294 developed slowly, reaching its maximum at 40 min and was inversely proportional to the frequency of stimulation, becoming negligible at 60 and 90 Hz. The concentration-response relationship for LASSBio-294-induced potentiation of twitch tension was bell-shaped, with maximal effect occurring at 25 microM. In addition, LASSBio-294 reduced development of fatigue induced by tetanic stimulation of the muscle fibers and reduced the time needed for 80% prefatigue tension recovery after fatigue had developed to 50% of the maximal pretetanic force. These effects of LASSBio-294 can be fully explained by stimulation of the sarcoplasmic reticulum Ca2+ pump and could be ascribed to an increase in cellular levels of cyclic AMP due to PDE inhibition. The novel thienylhydrazone LASSBio-294 may be useful for treatment of patients suffering from conditions in which muscle fatigue is a debilitating symptom (e.g., chronic heart failure).
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PMID:A novel thienylhydrazone, (2-thienylidene)3,4-methylenedioxybenzoylhydrazine, increases inotropism and decreases fatigue of skeletal muscle. 1160 67

Beta-adrenergic receptor (AR) subtypes are archetypical members of the G protein-coupled receptor (GPCR) superfamily. Whereas both beta1AR and beta2AR stimulate the classic G(s)-adenylyl cyclase-3',5'-adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade, beta2AR couples to both G(s) and G(i) proteins, activating bifurcated signaling pathways. In the heart, dual coupling of the beta2AR to G(s) and G(i) results in compartmentalization of the G(s)-stimulated cAMP signal, thus selectively affecting plasma membrane effectors (such as L-type Ca(2+) channels) and bypassing cytoplasmic target proteins (such as phospholamban and myofilament contractile proteins). More important, the beta2AR-to-G(i) branch delivers a powerful cell survival signal that counters apoptosis induced by the concurrent G(s)-mediated signal or by a wide range of assaulting factors. This survival pathway sequentially involves G(i), G(beta)(gamma), phosphoinositide 3-kinase, and Akt. Furthermore, cardiac-specific transgenic overexpression of betaAR subtypes in mice results in distinctly different phenotypes in terms of the likelihood of cardiac hypertrophy and heart failure. These findings indicate that stimulation of the two betaAR subtypes activates overlapping, but different, sets of signal transduction mechanisms, and fulfills distinct or even opposing physiological and pathophysiological roles. Because of these differences, selective activation of cardiac beta2AR may provide catecholamine-dependent inotropic support without cardiotoxic consequences, which might have beneficial effects in the failing heart.
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PMID:Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins. 1160 49

Ca2+ sensitizers act on the central mechanism (Ca2+ binding affinity of troponin C) and/or downstream mechanisms (thin filament regulation of actin and direct action on crossbridge cycling) of cardiac E-C coupling. Ca2+ sensitizers have mechanistic and energetic advantages over the agents that act through the upstream mechanism (intracellular Ca2+ mobilization). Ca2+ sensitizers and the agents that act through cyclic AMP-mediated signaling process have been postulated to belong to different classes, however, recent experimental findings revealed that certain Ca2+ sensitizers, such as levosimendan, OR 1896 and UD-CG 212 Cl, require cyclic AMP-mediated signaling for induction of the Ca2+ sensitizing effect. No clinically available agents act primarily via Ca2+ sensitization, but the positive inotropic effect of pimobendan and levosimendan is partly due to an increase in myofilament Ca2+ sensitivity. These agents are the hybrid of Ca2+ sensitizer and PDE III inhibitor. The extent of contribution of Ca2+ sensitizing effect of these agents to the clinical effectiveness to improve the hemodynamics in patients with heart failure is uncertain. Nevertheless pieces of evidence have been accumulating that these agents with Ca2+ sensitizing effect are clinically more effective than the agents that act purely via the upstream mechanism.
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PMID:Mechanism of action of Ca2+ sensitizers--update 2001. 1185 58

Adrenergic receptors transduce signals through the G proteins to regulate cardiac function. The catecholamines, via alpha- and beta-adrenergic receptor (beta-AR) stimulation, may play a role in the development of heart failure. Norepinephrine and isoproterenol can induce cardiac myocyte apoptosis. Studies suggest that alpha-, beta1-, and beta2-adrenergic pathways differentially regulate cardiac myocyte apoptosis. The stimulation of beta1-AR leads to cyclic AMP-dependent apoptosis, whereas that of the beta2-AR elicits concurrent apoptosis and survival signals in cardiac myocytes coupled to Gs protein. Overexpression of alpha1-adrenergic receptors does not induce apoptosis in wild-type mice. In contrast, the heart failure observed in some murine models has to be related to an enhanced beta-AR kinase expression. These recent advances make it possible to understand the beneficial effects of beta-blockers in the treatment of chronic heart failure and provide novel therapeutic modalities through the stimulation of beta2-ARs or the inhibition of beta-AR kinase expression.
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PMID:Positive inotropic stimulation. 1235 6

Two forms of the activated beta1-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant beta1-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-failing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (-logEC50[M] 7.3+/-0.1, E(max) 23+/-1% relative to maximal (-)-isoprenaline stimulation of beta1- and beta2-adrenoceptors, n=86 patients), shortening of the time to reach peak force (-logEC50[M] 7.4+/-0.1, E(max) 37+/-5%, n=61 patients) and shortening of the time to reach 50% relaxation ( t(50%), -logEC50[M] 7.3+/-0.1, E(max) 33+/-2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-beta1-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (-logEC50[M] 7.7+/-0.1, E(max) 68+/-6%, n=6 patients, P<0.0001). In the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine, the potency (-logEC50[M] 7.4+/-0.1, P=0.0013, n=9 patients) but not the maximal effect of (-)-CGP 12177 was reduced in right atrium from failing hearts, which was associated with 64% and 52% reductions in the densities of low-affinity and high-affinity (-)-[3H]CGP 12177 binding sites. In the presence of (-)-propanolol and 3-isobutyl-1-methylxanthine, (-)-CGP 12177 increased atrial cyclic AMP levels and activated cyclic AMP-dependent protein kinase in right atrium from non-failing hearts. In right ventricle from failing hearts (-)-CGP 12177 increased contractile force (-logEC50[M] 7.4+/-0.1, E(max) 34+/-3%, n=13 patients) and hastened the time to peak force (-logEC50[M] 7.6+/-0.1) and time to reach 50% relaxation (-logEC50[M] 7.4+/-0.1) in the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine. Our results show that (-)-CGP 12177 increases contractility and hastens relaxation through a cyclic AMP pathway in human myocardium, consistent with mediation through a (-)-propranolol-resistant state of the beta1-adrenoceptor. The reduction in heart failure of atrial inotropic potency of (-)-CGP 12177, as well as of the high-affinity and low-affinity binding sites for (-)-[3H]CGP 12177, is consistent with the beta1-adrenoceptor nature of these sites.
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PMID:(-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the beta 1-adrenoceptor. 1261 36

Infarct-induced heart failure is usually associated with cardiac hypertrophy and decreased -adrenergic responsiveness. However, conflicting results have been reported concerning the density of L-type calcium current (I Ca(L)), and the mechanisms underlying the decreased -adrenergic inotropic response. We determined I Ca(L) density, cytoplasmic calcium ([Ca2+]i) transients, and the effects of -adrenergic stimulation (isoproterenol) in a model of postinfarction heart failure in rats. Left ventricular myocytes were obtained by enzymatic digestion 8-10 weeks after infarction. Electrophysiological recordings were obtained using the patch-clamp technique. [Ca2+]i transients were investigated via fura-2 fluorescence. -Adrenergic receptor density was determined by [ H]-dihydroalprenolol binding to left ventricle homogenates. Postinfarction myocytes showed a significant 25% reduction in mean I Ca(L) density (5.7 0.28 vs 7.6 0.32 pA/pF) and a 19% reduction in mean peak [Ca2+]i transients (0.13 0.007 vs 0.16 0.009) compared to sham myocytes. The isoproterenol-stimulated increase in I Ca(L) was significantly smaller in postinfarction myocytes (Emax: 63.6 4.3 vs 123.3 0.9% in sham myocytes), but EC50 was not altered. The isoproterenol-stimulated peak amplitude of [Ca2+]i transients was also blunted in postinfarction myocytes. Adenylate cyclase activation through forskolin produced similar I Ca(L) increases in both groups. -Adrenergic receptor density was significantly reduced in homogenates from infarcted hearts (Bmax: 93.89 20.22 vs 271.5 31.43 fmol/mg protein in sham myocytes), while Kd values were similar. We conclude that postinfarction myocytes from large infarcts display reduced I Ca(L) density and peak [Ca2+]i transients. The response to -adrenergic stimulation was also reduced and was probably related to -adrenergic receptor down-regulation and not to changes in adenylate cyclase activity.
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PMID:Impaired beta-adrenergic response and decreased L-type calcium current of hypertrophied left ventricular myocytes in postinfarction heart failure. 1271 84

During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as beta-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca(2+) mobilisation (upstream mechanism). These agents are associated with the risk of Ca(2+) overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca(2+) overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca(2+) ions (central and/or downstream mechanisms). Novel Ca(2+) sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca(2+) sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.
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PMID:The therapeutic potential of novel cardiotonic agents. 1272 Apr 86


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