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)

In heart failure, a strong sympathetic activation has been observed and is regarded as the cause of beta-adrenergic desensitization in this condition. On the receptor level, there is a down-regulation of beta1-adrenergic receptors. In myocardium of patients on catecholamine treatment, the number of beta-adrenergic receptors can be further reduced. An uncoupling of beta2-adrenoceptors has been related to an increased activity and gene expression of beta-ARK in failing myocardium leading to phosphorylation and uncoupling of receptors. Beta3-adrenoceptors mediate negative inotropic effects, but alterations of these receptors are not known. In addition, an increase of inhibitory G-protein alpha-subunits (Gialpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G-protein alpha-subunits and betagamma-subunits have been observed to be unchanged. In patients with catecholamine-refractory septic or cardiogenic shock, an increase of Gialpha has been observed and related to the reduced effects of catecholamines in these conditions. The discovered mechanisms set the stage for the development of alternative strategies to increase force of contraction like the combination of PDE-inhibitors and catecholamines or Ca2+ sensitizing agents.
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PMID:Catecholamine refractoriness and their mechanisms in cardiocirculatory shock and chronic heart failure. 982 78

Clinical trials of beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors in heart failure have demonstrated a reduction in survival in treated patients despite initial inotropic responses. These findings have led many to infer that activation of the mechanisms through which contractility is increased has deleterious effects on failing myocardium. It should be remembered, however, that these agents act proximately by raising intracellular cyclic adenosine monophosphate (cAMP) content and stimulating protein phosphorylation by cAMP-dependent protein kinase, and that the proteins whose phosphorylation contributes to the inotropic responses may be different from the proteins whose phosphorylation contributes to the reduction in survival. Evidence in support of the latter interpretation is presented, and potential therapeutic approaches through which the phosphorylation of different proteins might be selectively affected are considered.
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PMID:Beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors: shifting the focus from inotropy to cyclic adenosine monophosphate. 1044 Jan 39

Colforsin daropate hydrochloride (COL) is a water-soluble forskolin derivative for the treatment of acute heart failure. COL, like forskolin, stimulated adenylate cyclase (AC) directly and produced pharmacologic activities accompanied by the increase in cellular cAMP. COL was different from forskolin in water-solubility, duration of action, BBB permeability, oral activity and AC-subtype selectivity. COL was a inodilator with positive inotropic and vasodilator effects and was effective on a beta-receptor desensitized-heart model in which the effects of beta-agonists and PDE inhibitors were attenuated. COL improved cardiac function in some heart failure models. In the clinical studies, COL improved hemodynamics, subjective and objective symptoms of heart failure patients, and was also effective in the catecholamine-resistant heart failure patients. COL is a first clinically available adenylate cyclase activator. Further information from the post-marketing-surveillance will provide information that will enable more adequate usage of this drug.
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PMID:[Cardiovascular effects of colforsin daropate hydrochloride, a novel drug for the treatment of acute heart failure]. 1051 49

There are several reasons to believe that agents that augment cAMP-mediated signalling in cardiac myocytes should have beneficial effects in patients with heart failure. However, clinical trials of first-generation cyclic nucleotide phosphodiesterase (PDE3) inhibitors, which raise cAMP content by blocking its hydrolysis, have shown that chronic administration of these drugs affect survival adversely. The problem may be the non-selective activation of a broad spectrum of cAMP-regulated cellular responses these agents elicit. More selective (or alternatively selective) cyclic nucleotide PDE inhibitors might improve results by evoking a more restricted set of cellular responses.
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PMID:Therapeutic potential of cyclic nucleotide phosphodiesterase inhibitors in heart failure. 1106 Jul 20

Toborinone (OPC-18790, Otsuka Pharmaceutical Co. Ltd, 2(1H) -quinolone,6-[3-[ [3,4-dimethoxyphenyl)methyl] amino]-2-hydroxy prop oxyl]-,(.+-.)-) is a novel iv. inotropic agent. Positive inotropic effects are produced by PDE inhibition with the resulting increase in cAMP and intracellular calcium levels. Unlike other inotropic agents that increase cAMP, there is an absence of positive chronotropic effects, which are attributed to prolongation of the action potential due to blockade of delayed rectifier currents. There is also marked venous and arterial vasodilating properties. The absence of heart rate increases results in decreased myocardial oxygen consumption compared with conventional inotropes. Studies in human heart failure patients have been consistent with previous work in animal studies, confirming the effects of toborinone as being positive inotropy (relatively weak), marked arterial and venous vasodilatation and absence of increase in myocardial oxygen consumption. Data regarding safety in larger clinical trials, particularly regarding arrhythmias, is at present unavailable. This information will determine whether this agent becomes an accepted iv. therapeutic option for congestive heart failure.
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PMID:Clinical overview of the novel inotropic agent toborinone. 1106 Jul 31

Levosimendan (Simdax) is a new inodilator developed specifically for the treatment of decompensated heart failure. Its inotropic mechanism is based on calcium sensitisation of myofilaments and its vasodilator actions are related to the opening of ATP-dependent K-channels in the vasculature. Since the inotropic action of levosimendan does not require an increase in cytosolic free calcium, it is less arrhythmogenic than the conventional parenteral beta-agonist inotropes or PDE III inhibiting drugs. Due to the calcium-dependent binding of the drug to troponin C, levosimendan, unlike some other calcium-sensitising drugs, does not prolong diastolic relaxation of the myocytes but acts in synergy with the intramyocellular calcium levels. Furthermore, due to the anti-ischaemic effects of the K-channel opening in myocytes, levosimendan can be used during myocardial ischaemia. In clinical trials, levosimendan has dose-dependently increased cardiac output and decreased pulmonary capillary wedge pressure in patients with heart failure. On the other hand, it also increases heart rate and decreases blood pressure in these patients. In major clinical trials, where patients with decompensated heart failure have been treated with levosimendan, a reduction of overall mortality in comparison to placebo or dobutamine has been seen. This interesting finding should be verified in prospective outcome trials. In any case, the safety of levosimendan during myocardial ischaemia makes this drug valuable in the short-term treatment of decompensated heart failure.
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PMID:Levosimendan: a parenteral calcium-sensitising drug with additional vasodilatory properties. 1132 69

Cyclic nucleotide second messengers (cAMP and cGMP) play a central role in signal transduction and regulation of physiologic responses. Their intracellular levels are controlled by the complex superfamily of cyclic nucleotide phosphodiesterase (PDE) enzymes. Continuing advances in our understanding of the molecular pharmacology of these enzymes has led to the development of selective inhibitors as therapeutic agents for disease states ranging from cancer and heart failure to depression and sexual dysfunction. Several PDE types have been identified as therapeutic targets for immune/inflammatory diseases. This article briefly reviews the available in vitro, preclinical, and clinical data supporting the potential for selective PDE inhibitors as immunomodulatory agents.
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PMID:Cyclic nucleotide phosphodiesterases. 1169 87

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

Calcium (Ca(2+)) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca(2+) is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca(2+) store. These fluxes occur by the transient activity of Ca(2+)-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca(2+)-handling proteins, in particular the SR Ca(2+)-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca(2+) available for contraction. In the steady state, the Ca(2+)-content of the SR is essentially a balance between Ca(2+)-uptake via SERCA2a pump and Ca(2+)-release via the cardiac SR Ca(2+)-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca(2+) content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca(2+)-uptake, and (ii) reduction of SR Ca(2+)-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and/or Ca(2+)-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca(2+)-leak. Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMP-levels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca(2+)-cycling proteins may have the potential to fill this gap.
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PMID:Ca(2+)-handling proteins and heart failure: novel molecular targets? 1267 83

Sildenafil has proven effective in the therapy of male erectile dysfunction. However, little is known about other potential beneficial effects of sildenafil. Meanwhile, first observations have been made in numerous medical disciplines and disorders. Small doses of sildenafil may be a useful adjunct to inhaled iloprost in the management of pulmonary hypertension. In female sexual dysfunction and infertility, genital blood flow and endometrial thickening are enhanced after application of the compound. In gastrointestinal disorders, sildenafil also exerts several effects which might be of clinical relevance. In patients with heart failure, endothelial dysfunction is influenced by the phosphodiesterase-5 (PDE 5) inhibitor and exercise capacity might be improved. Moreover, in the treatment of Raynaud's phenomenon, a disease without highly effective medical treatment option yet, first observations with sildenafil seem to be promising.
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PMID:Non erectile dysfunction application of sildenafil. 1282 48


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