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: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of a selective phosphodiesterase (PDE) type IV inhibitor, rolipram, on activation of neutrophil phospholipases in response to the chemotactic peptide formyl-methiony-leucyl-phenylalanine (fMLP) were investigated. fMLP caused liberation of arachidonic acid, a precursor of eicosanoids and in the presence of 0.3% butanol, production of phosphatidylbutanol, an indicator of phospholipase D activation. Rolipram inhibited arachidonic acid release and phosphatidylbutanol formation. The inhibition was considered to be mediated through a cAMP-dependent mechanism, probably protein kinase A, because selective inhibitors for protein kinase A, H-8 or H-89 overcame the action of rolipram. The concentration-dependent inhibitory profile for phospholipase D activation was similar to that for lysosomal enzyme release, providing additional evidence for the functional link of these two events. In contrast, rolipram was without effect on fMLP-induced inositol trisphosphate production. These results indicate that this selective PDE IV inhibitor had no effect on phosphatidylinositol-specific phospholipase C activation but effectively prevented activation of phospholipases A2 and D coupled to arachidonic acid liberation and lysosomal enzyme release, respectively.
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PMID:Effects of selective phosphodiesterase type IV inhibitor, rolipram, on signal transducing phospholipases in neutrophil: inhibition of phospholipases A2, D but not C. 878 85

Rat peritoneal neutrophils stimulated by N-formyl-methionyl-leucyl-phenylalanine (fMLP) produce an aggregation response that can be inhibited by prostaglandin E2 (PGE2) with an IC50 value of 2.6 x 10(-9) M. Although PGE2 can stimulate [3H]cAMP production in neutrophils (EC50 4.3 x 10(-8) M), the anti-aggregation response cannot be significantly attenuated by inhibitors of adenylate cyclase or protein kinase A, neither can it be potentiated by inhibition of phosphodiesterase activity. Despite these observations, it still remains possible that PGE2-mediated inhibition of rat neutrophil aggregation is a cAMP-dependent response mediated by highly localized changes in neutrophil cAMP. The inhibitory effect of PGE2 does not appear to depend on effects on intracellular calcium or K(ATP) channels. Similarities exist between PGE2 and the profile of activity of phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors, suggesting that PI 3-kinase is a possible target for PGE2 action in rat neutrophils.
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PMID:The inhibitory effect of prostaglandin E2 on rat neutrophil aggregation. 886 32

Polymorphonuclear cells (PMN) are the dominating inflammatory cell population in acute tissue injury and contribute to host-defence mechanisms by formation and release of chemical mediators. The aim of the present study was to investigate whether chemoattractant-induced PMN stimulation can be synergistically antagonized by vasodilatory prostaglandins and nitric oxide (NO), both being formed by the vasculature in inflamed areas. PGE1 (10 nM-10 microM) inhibited concentration-dependently formyl-methionyl-leucyl-phenylalanine (fMLP)-induced beta-glucuronidase and oxygen radical (O2.) release from human PMN. The NO donor linsidomine (100 microM) was ineffective, but significantly enhanced PGE1 effects on oxygen radical generation and enzyme release. The non-selective phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) (0.5 mM) potentiated PGE1 effects on all parameters measured. The combination linsidomine (100 microM) plus IBMX (0.5 mM) did not additionally reduce beta-glucuronidase release, but abolished fMLP-stimulated O2. generation. There was a stimulation of cAMP formation by PGE1 but not by linsidomine, both in the absence and presence of IBMX. It is concluded that the effects of linsidomine on PMN function and its synergism with PGE1 are not tightly correlated with total cAMP accumulation. Alternatively, the inhibition of O2. generation by linsidomine may be related to its ability to modulate the activation of the NADPH oxidase system or to scavenge free oxygen radicals.
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PMID:Synergistic inhibition of human polymorphonuclear function by prostaglandin E1 and linsidomine. 886 34

Human neutrophils, plated in fibronectin-coated wells and stimulated with N-formyl-methionylleucyl-phenylalanine (fMLP), were found to undergo a massive and prolonged respiratory burst, as measured by monitoring superoxide production. The beta 2-agonist salmeterol inhibited the respiratory burst in a dose-dependent manner. In contrast, salbutamol was ineffective. Moreover, the neutrophil respiratory burst was partially suppressed by prostaglandin E2 (PGE2) and the phosphodiesterase type IV (PDE-IV) inhibitor RO 20-1724. When salmeterol was used in combination with PGE2 or RO 20-1724, additive inhibitory effects were observed. The inhibitory activity of salmeterol was not reversed in the presence of the beta-blocker propranolol, and did not correlate with its ability of increasing cyclic AMP (cAMP) levels. Finally, the compounds used did not affect neutrophil adherence to fibronectin-coated wells. The results suggest that salmeterol is capable of down-regulating the neutrophil oxidative response to fMLP, also of co-operating with PGE2 and PDE-IV inhibitor RO 20-1724 in a manner not related to its beta 2-receptor binding activity. In other words, salmeterol displays neutrophil-directed effects, susceptible to be amplified by natural mediators such as PGE2 or PDE-IV inhibitors, consistent with possible anti-inflammatory properties of the drug.
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PMID:Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils. 887 Jul 5

1. SCA40 (0.1 nM-0.1 mM) produced concentration-dependent suppression of the spontaneous tone of human isolated bronchus (-log EC50 = 6.85 +/- 0.09; n = 10) and reached a maximal relaxation similar to that of theophylline (3 mM). The potency (-log EC50 values) of SCA40 compared to other relaxants was rolipram (7.44 +/- 0.12; n = 9) > SCA40 > or = levcromakalim (6.49 +/- 0.04; n = 6) > SKF94120 (5.87 +/- 0.10; n = 9). 2. When tested against the activity of the isoenzymes of cyclic nucleotide phosphodiesterase (PDE) isolated from human bronchus, SCA40 proved highly potent against PDE III (-log IC50 = 6.47 +/- 0.16; n = 4). It was markedly less potent against PDE IV (4.82 +/- 0.18; n = 4) and PDE V (4.32 +/- 0.11; n = 4). 3. Human polymorphonuclear leukocytes (PMNs) stimulated with N-formylmethionyl-leucyl-phenylalanine (FMLP) produced a concentration-dependent superoxide anion generation and elastase release. SCA40 (1 nM-10 microM) produced a concentration-related inhibition of FMLP (30 nM approximately EC50)-induced superoxide production (-log IC50 = 5.48 +/- 0.10; n = 6) and elastase release (-log IC50 = 5.50 +/- 0.26; n = 6). Rolipram was an effective inhibitor of superoxide generation and elastase release (-log IC50 values approximately 8) while SKF94120 and levcromakalim were scarcely effective. 4. FMLP (30 nM) and thimerosal (20 microM) induced leukotriene B4 production and elevation of intracellular calcium concentration in human PMNs. The production of leukotriene B4 was inhibited by SCA40 in a concentration-related manner (-log IC50 = 5.94 +/- 0.22; n = 6) but SCA40 was less effective against the elevation of intracellular calcium. Rolipram was an effective inhibitor of leukotriene B4 synthesis (-log IC50 approximately 7) and intracellular calcium elevation (-log IC50 approximately 6) while SKF94120 and levcromakalim were scarcely effective. 5. It is concluded that SCA40 is an effective inhibitor of the inherent tone of human isolated bronchus. The bronchodilatation produced by SCA40 appears mainly related to PDE inhibition since the potency of SCA40 as a relaxant of human isolated bronchus was found to be close to its potency as inhibitor of PDE III activity isolated from human bronchus. In addition, SCA40 exhibited inhibitory effects on human PMN function stimulated by FMLP. These effects may be related to the ability of SCA40 to inhibit PDE IV from human PMNs while the contribution of PDE V inhibition is uncertain. We found no evidence of a role for levcromakalim-sensitive plasmalemmal K+-channels in human PMNs.
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PMID:Effects of SCA40 on human isolated bronchus and human polymorphonuclear leukocytes: comparison with rolipram, SKF94120 and levcromakalim. 887 62

A 19-amino acid residue peptide, Gly-Trp-Leu-Lys-Ile-Lys-Ala-Ala-Met-Arg-Trp-Gly-Phe-Phe-Val-Arg-Lys-Lys- Ala, corresponding to the basic amphiphilic alpha-helix (BAA) motif at the C-terminus of a recombinant tobacco calmodulin-binding protein, TCB60, was synthesized. The interaction of the synthetic binding domain with calmodulin (CaM) was analyzed by gel mobility shift assays, phosphodiesterase competition assays, and fluorescence, circular dichroism, and nuclear magnetic resonance spectroscopy. Mobility shift assays showed an apparent 2 kDa increase in CaM Mr in presence of synthetic peptide and CaCl2 in 4 M urea polyacrylamide gel electrophoresis. HPLC measurements of hydrolysis of cyclic AMP by CaM-dependent phosphodiesterase indicated the synthetic peptide competitively inhibits (Ki = 15-20 nM) stimulation of phosphodiesterase activity by CaM. Upon binding CaM, the fluorescence emission maximum of the synthetic peptide, which contained two tryptophanyl residues, shifted toward blue and increased in intensity. The circular dichroism spectra indicated the ellipticity of CaM increased at 208 and 222 nm upon complex formation with the synthetic peptide. 1H NMR studies showed that the peptide interacts with the aromatic residues in domains I and III of CaM. Taken together, these data provide direct evidence that the structurally conserved basic amphiphilic alpha-helix CaM-binding domain of the recombinant tobacco CaM-binding protein interacts with CaM at physiologically significant nanomolar concentrations and the microenvironments of both CaM and the synthetic binding domain are modified upon complex formation.
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PMID:Characterization of the basic amphiphilic alpha-helix calmodulin-binding domain of a 61.5 kDa tobacco calmodulin-binding protein. 904

A concentration response study was performed to clarify whether vasoactive drugs, routinely used in intensive care patients, inhibit oxygen radical production of neutrophils. Moreover, in a cell-free system, it was investigated whether these drugs exert free radical scavenging properties. Vasoactive agents were incubated with neutrophils from healthy human volunteers, which were stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP) and by opsonized zymosan to produce oxygen radicals, detected by chemiluminescence measurements. Sympathomimetics (epinephrine greater than norepinephrine, dopamine and dobutamine) as well as phosphodiesterase-inhibitors (amrinone and enoximone) inhibited FMLP-induced and zymosan-induced oxygen radical production of neutrophils in a concentration-dependent and drug-specific fashion. With the exception of amrinone, FMLP-induced chemiluminescence of neutrophils was impaired nearly 10-fold more markedly than zymosan-induced chemiluminescence. Glyceryl trinitrate, nifedipine and prostacyclin had no effect on oxygen radical production of neutrophils. In the cell-free system, epinephrine, norepinephrine, dopamine, amrinone and enoximone demonstrated oxygen free radical scavenging properties. This study shows that vasoactive drugs, frequently used in the clinical setting, may suppress oxidative burst after FMLP-receptor stimulation. As demonstrated in the cell-free system, this suppression was, at least in part, due to oxygen radical scavenging.
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PMID:Vasoactive drugs inhibit oxygen radical production of neutrophils. 913 8

Bronchial epithelial cells express the intercellular adhesion molecule-1 that mediates binding of activated neutrophils via interaction with Mac-1 and/or leukocyte function-associated antigen-1. In this study, we examined whether increased intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) affected neutrophil adhesion to the human bronchial epithelial cells. It was found that the N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated neutrophil adhesion was concentration dependently inhibited when the cAMP analogs dibutyryl adenosine 3',5'-cyclic monophosphate or 8-bromoadenosine 3',5'-cyclic monophosphate were present. The beta-adrenergic receptor agonists isoprenaline and salmeterol, in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), were also able to inhibit the fMLP-stimulated adhesion of neutrophils to bronchial epithelial cells. These agonists in combination with IBMX significantly increased the intracellular cAMP level in both neutrophils and epithelial cells. Preincubation of neutrophils with the long-acting beta2-adrenergic receptor agonist salmeterol (in the presence of IBMX) inhibited their fMLP-stimulated adhesion to epithelial cells, whereas pretreatment of epithelial cells did not influence the adhesion process. When ethanol-fixed epithelium was used, salmeterol pretreatment also diminished the adhesion of stimulated neutrophils. Moreover, combinations of salmeterol or isoprenaline with IBMX inhibited fMLP-upregulated Mac-1 expression. Therefore, we conclude from these data that elevation of intracellular cAMP in the neutrophil inhibits stimulated neutrophil adhesion to bronchial epithelial cells via Mac-1.
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PMID:Increased cAMP levels in stimulated neutrophils inhibit their adhesion to human bronchial epithelial cells. 914 28

Wine has been part of human culture for 6,000 years, serving dietary and socio-religious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high-density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl-CoA derivatives. Polymeric aggregation gives rise, in turn to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low-density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo-oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signalling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans.
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PMID:Wine as a biological fluid: history, production, and role in disease prevention. 929 95

The effects of PF-904 (4-amino-1-ethyl-6-methylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide), a pyrazinothiadiazine derivative, were examined in guinea-pig airways in vivo, in human isolated bronchus and human polymorphonuclear leukocytes. PF-904 (12.5-200 mg/kg, intraduodenal) reduced bronchoconstriction in response to histamine, arachidonic acid, platelet-activating factor (PAF) and methacholine. PF-904 (50-200 mg/kg) prevented PAF-induced airways hyperreactivity and inhibited antigen-induced bronchoconstriction, airway microvascular leakage and eosinophil lung accumulation, but antigen-induced airways hyperresponsiveness was not reduced. PF-904 (1 microM-1 mM) produced complete inhibition of spontaneous (-logEC50 = 3.57+/-0.04; n = 10) and histamine-stimulated tone (-logEC50 = 3.66+/-0.07; n = 10) of human isolated bronchus. Glibenclamide (10 microM) or precontraction with KCl (80 mM) did not impede PF-904-induced bronchial relaxation. PF-904 inhibited cyclic AMP (-logIC50 = 2.83+/-0.25; n = 8) and cyclic GMP (-logIC50 = 2.90+/-0.21; n = 8) phosphodiesterase activity in human bronchus. The activity of type IV phosphodiesterase was inhibited by PF-904 (-logIC50 = 3.43+/-0.11; n= 3). PF-904 also inhibited superoxide release by N-formylmethionyl-leucyl-phenylalanine-stimulated human polymorphonuclear leukocytes, but the maximal effect was approx. 50% of that produced by rolipram (10 microM). This profile of activities of PF-904 suggests that this compound has potential therapeutic value as an anti-asthma drug.
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PMID:Pharmacological activity of PF-904 in guinea pig in vivo, and on human bronchus and neutrophils in vitro. 931 63


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