Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterase (PDE) inhibitors are used as therapeutic agents for management of congestive heart failure. PDE inhibitors are potent inotropic and vasodilator drugs, which have also been shown to inhibit tumor necrosis factor alpha (TNF-alpha) production. TNF-alpha is a pleiotropic cytokine that has the ability to produce cardiac depressant and other cardiovascular effects in many disease conditions. TNF-alpha levels are elevated in patients with chronic congestive heart failure, and it is possible that TNF-alpha may play a role in this condition. The effects of PDE inhibitors on TNF-alpha secretion from rat heart were evaluated in this study. Rat left ventricle was minced and incubated for 4 hr with various PDE inhibitors, and the amount of TNF-alpha secretion was evaluated by cytotoxicity assay. Ro-20, 1724, etazolate, amrinone, milrinone and pentoxifylline inhibited unstimulated TNF-alpha production, with IC50 values of 1.87, 2.07, 13.9, 153 and 201 microM, respectively. Lipopolysaccharide-induced TNF-alpha secretion from rat left ventricle was also evaluated in this study. Amrinone, milrinone and pentoxifylline inhibited lipopolysaccharide-induced TNF-alpha secretion, with IC50 values of 14.8, 81.6 and 748 microM, respectively, whereas Ro-2D, 1724 and etazolate had no effect on lipopolysaccharide-induced TNF-alpha secretion. These results demonstrated that TNF-alpha was secreted from rat left ventricle after 4 hr and different pharmacological manipulations were able to inhibit the secretion of TNF-alpha from left ventricle. These initial pharmacological results may provide an important tool for further investigation into the beneficial effects of PDE inhibitors in congestive heart failure or other conditions where TNF-alpha levels are elevated.
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PMID:Pharmacological modulation of myocardial tumor necrosis factor alpha production by phosphodiesterase inhibitors. 885

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and IL-6 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited TNF-alpha production, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1 beta production, whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 production and pimobendan slightly decreased IL-6 production, whereas amrinone had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1 beta and TNF-alpha and also tended to inhibit IL-6 production; its modulation of cytokine production was similar to the effects of vesnarinone. Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differential modulation of cytokine production may play a role in the therapeutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulating properties.
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PMID:Differential modulation of cytokine production by drugs: implications for therapy in heart failure. 900 65

The level of intracellular cyclic nucleotides is a regulatory factor in a variety of immune processes. Increases in intracellular cyclic AMP (cAMP) and/or cyclic GMP (cGMP) concentration by the inhibition of phosphodiesterase have been shown to modulate the inflammatory response. Amrinone is a clinically used positive inotropic agent which elevates intracellular cAMP and cGMP levels by selective inhibition of the phosphodiesterase III isoenzyme. In the current study, we investigated the effect of various concentrations (1-300 microM) of amrinone on lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and of nitric oxide (NO) in vitro. In cultured murine J774.1 macrophages, 1 ng/ml-10 microg/ml of lipopolysaccharide from Escherichia coli O55:B5 induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-10, and nitrite (breakdown product of NO). Pretreatment of cells with amrinone caused a dose-dependent suppression of TNF-alpha production in the concentration range of 1-100 microM. Furthermore, this drug suppressed NO production in the range of 30-300 microM. Similarly to the results in the J774.1 cells, amrinone also inhibited TNF-alpha and NO production in the range of 10-100 microM in primary rat peritoneal macrophages. At 300 microM, but not at lower concentrations, amrinone inhibited interleukin-10 production in lipopolysaccharide-treated J774.1 macrophages. Pretreatment of the macrophages with 100 and 300 microM amrinone increased the lipopolysaccharide-elicited translocation of nuclear factor-kappa B. Taken together, our results indicate that the phosphodiesterase III inhibitor amrinone modulates the activation/production of many pro- and anti-inflammatory factors in endotoxin-stimulated cells. It remains to be further investigated how such immunomodulatory effects contribute to the clinical profile of the agent.
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PMID:Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774.1 macrophages. 947 38

The aim of this study was to investigate the role of the inhibitors of different PDE isoenzymes (PDE 1-5) on the production of two pro-inflammatory cytokines - tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Two in vitro models were used to compare the antiinflammatory properties of PDE inhibitors with that of glucocorticoids. The effect on TNF release from diluted human blood following lipopolysaccharide (LPS from Salmonella abortus equi) stimulation as well as the GM-CSF and TNF release from human nasal polyp cells following allergic stimulation were investigated. Both models proofed to be well suited for the characterisation of the antiinflammatory properties of new chemical entities. In diluted human blood and dispersed human nasal polyp cells the induced TNF release was most potently suppressed by selective PDE4 inhibitors. Amrinone and milrinone, selective PDE3 inhibitors, suppressed TNF secretion to a lesser extent. The effects of theophylline (unspecific PDE inhibitor), vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor) and the PDE5 inhibitors zaprinast and E 4021 were weak. In human blood, the tested glucocorticoids beclomethasone, dexamethasone and fluticasone inhibited the LPS induced TNF release potently in a concentration dependent manner, whereas in dispersed human nasal polyp cells, the effect of the glucocorticoids on allergically induced TNF release, with the exception of dexamethasone, was much less pronounced. Glucocorticoids were the most potent inhibitors of GM-CSF release and the effect correlates well with the affinity to the glucocorticoid receptor. The selective PDE 4 inhibitors, and to a certain extent the PDE3 inhibitors amrinone and milrinone, reduced the GM-CSF release in a concentration dependent manner. In all investigations selective PDE4 inhibitors reduced TNF release to a much higher degree (4-10 fold) than GM-CSF release.
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PMID:Modulation of TNF and GM-CSF release from dispersed human nasal polyp cells and human whole blood by inhibitors of different PDE isoenzymes and glucocorticoids. 1196 59