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)

Trehalose diesters (natural 6,6'-trehalose dimycolate from Mycobacterium tuberculosis or synthetic (a 76 carbon atom analogue)), when suspended in water, give stable and well-defined emulsions. These emulsions, injected i.p. in mice significantly limit the growth of P815 syngeneic mastocytoma cells. They elicit macrophages with a cytostatic activity against P815 cells in vitro, strong enough to be expressed at low effector to target ratios (E/T = 1.4) or after a short coincubation period (2 hr). The antitumor potential of these macrophages seems to coincide with their ability to release H2O2 upon pharmacologic triggering. Depressed levels of alkaline phosphodiesterase and beta-galactosidase are proposed as other biochemical markers of cytostatic macrophages.
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PMID:Antitumor activity and hydrogen peroxide release by macrophages elicited by trehalose diesters. 680 86

Neutrophil-derived hydrogen peroxide (H2O2) is believed to play an important role in inflammatory lung injury. We investigated the influence of pharmacological agents that increase intracellular c-AMP levels on endothelial and epithelial leakage in response to intravascular H2O2 challenge in buffer-perfused rabbit lungs. Endothelial permeability was assessed by determination of the capillary filtration coefficient (Kfc) and lung weight gain. Measurement of the clearance rate of inhaled aerosolized technetium-99m-labeled diethylenetriamine pentaacetic acid ([99mTc]DTPA) from the lungs into the perfusion fluid was used as an index of alveolar epithelial permeability. Experiments were performed in the presence of acetylsalicylic acid to suppress H2O2-induced lung prostanoid generation and concomitant vasoconstriction. Under these conditions, H2O2 admixture to the perfusate (250 microM) caused a greater than eight-fold increase in Kfc values, resulting in > 30 g lung weight gain within 30 min in the absence of any significant vasopressor response. Pretreatment with the adenylate cyclase activators prostaglandin E1 (0.1 microM) and forskolin (0.1 microM), the dual phosphodiesterase type III/IV inhibitor zardaverine (10 microM) as well as combinations of these drugs all caused a nearly complete suppression of this early Kfc increase; and severe edema formation (> 30 g) was retarded to approximately 50-55 min. In addition to the microvascular leakage response, H2O2 caused a four- to five-fold increase in the [99mTc]DTPA clearance rate, starting within 15 min and culminating after approximately 35 min. Adenylate cyclase activation reduced this epithelial leakage response by approximately 30%, whereas zardaverine exerted no significant effect. We conclude that both microvascular endothelial and alveolar epithelial barrier function are severely compromised by intravascular H2O2 challenge in intact lungs. Pharmacological approaches to increase c-AMP levels, including both adenylate cyclase activation and phosphodiesterase inhibition, partially block the endothelial response and, to a lesser extent, the epithelial response.
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PMID:Hydrogen peroxide-induced increase in lung endothelial and epithelial permeability--effect of adenylate cyclase stimulation and phosphodiesterase inhibition. 747 70

1. Recent studies have suggested that the generation of nitric oxide (NO) and hydrogen peroxide (H2O2) by islet NO synthase and monoamine oxidase, respectively, may have a regulatory influence on insulin secretory processes. We have investigated the pattern of insulin release from isolated islets of Langerhans in the presence of various pharmacological agents known to perturb the intracellular levels of NO and the oxidation state of SH-groups. 2. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) dose-dependently increased L-arginine-induced insulin release. D-Arginine did not influence L-arginine-induced insulin secretion. However, D-NAME which reportedly has no inhibitory action on NO synthase, modestly increased L-arginine-induced insulin release, but was less effective than L-NAME. High concentrations (10 mM) of D-arginine as well as L-NAME and D-NAME could enhance basal insulin release. 3. The intracellular NO donor, hydroxylamine, dose-dependently inhibited insulin secretion induced by L-arginine and L-arginine+L-NAME. 4. Glucose-induced insulin release was increased by NO synthase inhibition (L-NAME) and inhibited by the intracellular NO donor, hydroxylamine. Sydnonimine-1 (SIN-1), an extracellular donor of NO and superoxide, induced a modest suppression of glucose-stimulated insulin release. SIN-1 did not influence insulin secretion induced by L-arginine or the adenylate cyclase activator, forskolin. 5. The intracellular 'hydroperoxide donor' tert-butylhydroperoxide in the concentration range of 0.03-3 mM inhibited insulin release stimulated by the nutrient secretagogues glucose and L-arginine. Low concentrations (0.03-30 microM) of tert-butylhydroperoxide, however enhanced insulin secretion induced by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). 6. Islet guanosine 3':5'-cyclic monophosphate (cyclic GMP) content was not influenced by 10 mML-arginine or tert-butylhydroperoxide at 3 or 300 micro M but was markedly increased (14 fold) by a high hydroxylamine concentration (300 micro M). In contrast, islet adenosine 3':5'-cyclic monophosphate (cyclicAMP) content was increased (3 fold) by L-arginine (10 mM) and (2 fold) by tert-butylhydroperoxide(300 micro M).7. Our results strongly suggest that NO is a negative modulator of insulin release induced by the nutrient secretagogues L-arginine and glucose. This effect is probably not mediated to any major extent by the guanylate cyclase-cyclic GMP system but may rather be exerted by the S-nitrosylation of critical thiol groups involved in the secretory process. Similarly the inhibitory effect of tert-butylhydroperoxide is likely to be elicited through affecting critical thiol groups. The mechanism underlying the secretion promoting action of tert-butylhydroperoxide on IBMX-induced insulin release is probably linked to intracellular Ca2+-perturbations affecting exocytosis.8. Taken together with previous data the present results suggest that islet production of low physiological levels of free radicals such as NO and H202 may serve as important modulators of insulin secretory processes.
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PMID:Influence of nitric oxide synthase inhibition, nitric oxide and hydroperoxide on insulin release induced by various secretagogues. 753 13

The pharmacological profile of a novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, Org 20241, has been characterized. The compound selectively inhibits PDE IV (pIC50, 5.2-6.1) and PDE III (pIC50, 4.4-4.6) from animal and human tissues. Org 20241 relaxed preparations of bovine trachea (pD2, 5.9 and 5.4), guinea pig trachea (pD2, 6.2 and 4.9) and human bronchi (pD2, 5.3 and 4.7) for histamine and methacholine-induced contractions, respectively. Rolipram and Org 20241 inhibited leukotriene B4-induced thromboxaneB2 (IC50, 0.3 and 1.4 microM, respectively) and H2O2 (IC50, 2.1 and 0.4 microM, respectively) production in guinea pig eosinophils. In phenylephrine (0.3 microM) precontracted rabbit aorta preparations, the PDE III inhibitor Org 9935 (pD2, 6.3 and 6.1 in the presence and absence of endothelium, respectively) was the most effective relaxant, whereas Org 20241 (pD2, 5.3 and 5.4 in the presence and absence of endothelium, respectively) was more effective than rolipram (pD2, 4.6 and 4.1 in the presence and absence of endothelium, respectively). Org 20241 relaxed rabbit aorta preparations and airway preparations at similar concentrations. In electrically stimulated rabbit cardiac papillary muscles, Org 20241 had little effect on contractility at concentrations up to 30 microM. Lower concentrations (10 microM) potentiated the inotropic effect of Org 9935. Whereas the PDE III inhibitor milrinone (1-100 microM) enhanced the rate of repolarization of guinea pig papillary muscles and shortened the effective refractory period, Org 20241 and rolipram (1-100 microM) did not reduce the action potential duration. In the presence of Org 20241 or rolipram, isoproterenol did not produce a greater increase in the rate of repolarization or reduction in the effective refractory period than in the absence of these PDE inhibitors. Org 20241 is a dual PDE IV/III inhibitor with some PDE IV selectively. This compound relaxes airways smooth muscle and inhibits eosinophil activation. The data indicate that such PDE IV/III inhibitors may be effective for the long-term therapy of asthma.
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PMID:Characterization of ORG 20241, a combined phosphodiesterase IV/III cyclic nucleotide phosphodiesterase inhibitor for asthma. 763 28

The production of hydrogen peroxide (H2O2) as an essential process for iodide organification is a key reaction in TSH-induced thyroid hormone synthesis. Here we characterize the signal transduction pathway involved in TSH-induced H2O2 production in FRTL-5 thyroid cells. At higher than 1 nM TSH, N6-(L-2-phenylisopropyl)adenosine (PIA), an adenosine receptor agonist having, by itself, no influence on H2O2 generation, potentiated this TSH action, whereas the TSH increase and PIA addition reduced cAMP accumulation. RO 20-1724, a phosphodiesterase inhibitor, amplified the TSH-induced cAMP accumulation, but did not change H2O2 generation in the whole range of TSH used. Ca(2+)-mobilizing agonists, GTP and ATP, also induced H2O2 production without stimulating cAMP accumulation. Chelation of intracellular Ca2+ markedly inhibited the TSH action, but intracellular Ca2+ increases by either thapsigargin or ionomycin mimicking it. All of the findings show the participation of Ca2+, but not cAMP, in the action of TSH. Desensitization of protein kinase-C (PKC) did not influence the receptor-mediated H2O2 production, suggesting the reduced importance of PKC activation compared to Ca2+ signaling to the reaction. A rise in intracellular Ca2+ independent of receptor activation also induced H2O2 production as well as arachidonate release, and both were potentiated by PIA. In addition, inhibitors of phospholipase-A2 and the arachidonate metabolic pathway depressed H2O2 generation, suggesting the participation of an arachidonate cascade in the Ca(2+)-dependent H2O2 production. Lipoxygenase inhibitors depressed the Ca2+ action without influencing arachidonate release, suggesting the involvement of a lipoxygenase product(s) of arachidonate in the Ca(2+)-signaling mechanism. In conclusion, in FRTL-5 cells, TSH-induced H2O2 production is mediated not by cAMP, but by the phospholipase-C/Ca2+ cascade, possibly followed by the Ca(2+)-dependent phospholipase-A2/arachidonate cascade. PIA amplifies TSH-induced H2O2 production at the steps of phospholipase-C and phospholipase-A2 activation in a pertussis toxin-sensitive manner.
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PMID:Thyrotropin-induced hydrogen peroxide production in FRTL-5 thyroid cells is mediated not by adenosine 3',5'-monophosphate, but by Ca2+ signaling followed by phospholipase-A2 activation and potentiated by an adenosine derivative. 782 20

The effects of theophylline upon human alveolar macrophage function were assessed and compared with its action upon macrophage cyclic nucleotide phosphodiesterase (PDE) activity and cyclic adenosine monophosphate (cAMP) levels. In the concentration range of 10 mumol/liter to 1 mmol/liter, theophylline caused a concentration-dependent inhibition of opsonized zymosan-stimulated hydrogen peroxide (H2O2) generation and PDE-catalyzed cAMP hydrolysis and increased the cellular cAMP content. Macrophage H2O2 generation was also inhibited by forskolin, an activator of adenylyl cyclase, but whereas theophylline (1 mmol/liter) and forskolin (1 mumol/liter) exhibited a synergic elevation of macrophage cAMP, there was no synergy between the two agents in the inhibition of respiratory burst. The inhibition of H2O2 generation by theophylline was reversed by the competitive inhibitor of cAMP-dependent protein kinase, (Rp)8-bromoadenosine cyclic 3':5'-monophosphorothioate (Rp-8-Br-cAMPS; 100 mumol/liter), indicating that the functional effect of theophylline was mediated through the elevation of cAMP. The inhibition of H2O2 generation by theophylline was not affected by adenosine deaminase (0.1 U/ml), indicating that the inhibition did not involve adenosine antagonism. It is concluded that theophylline exerts a direct inhibitory action upon human alveolar macrophage function through the elevation of cAMP levels as a result of PDE inhibition, and that this effect is observed at concentrations of theophylline that may be achieved in serum during therapy.
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PMID:Theophylline suppresses human alveolar macrophage respiratory burst through phosphodiesterase inhibition. 817 21

The effects of K2CrO4, H2O2, benzoyl peroxide, menadione, KBrO3 and UV365nm on gap junctional intercellular communication (GJIC) have been studied in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-sensitive Syrian hamster embryo (SHE) cell line BPNi. All agents were found to increase the level of GJIC by 50-100%. Also, in early passage SHE cells, a tendency for increased GJIC was found for the oxidative agents studied. Hydrogen peroxide was used as a model compound in the subsequent studies. The increase in GJIC was reversible, and it was not due to an increased non-junctional permeability. Hydrogen peroxide counteracted the TPA-induced decrease in GJIC, regardless of whether the cells were exposed to the compounds simultaneously or the cells were pre-exposed to TPA before addition of H2O2. The GJIC enhancement by H2O2 was slightly reduced by the addition of the hydroxyl radical scavenger dimethylsulphoxide or by the inhibition of catalase by amitrole. The cAMP/protein kinase A system is the only characterized signal transduction system that is known to increase GJIC in most cell types. Hydrogen peroxide did not increase the amount of cAMP (or cGMP) in BPNi cells, while forskolin and a phosphodiesterase inhibitor had to increase the cAMP level several-fold to affect GJIC to the same degree as the oxidative agents. Some inhibitors of protein kinase A were assayed for their ability to inhibit the increases in GJIC caused by H2O2 and forskolin. Staurosporine inhibited the forskolin-induced increase in GJIC, with much less effect on the H2O2-induced increase. H8, H88 and H89 had less effect than staurosporine on the forskolin-induced increase in GJIC. The results suggest that the cAMP/protein kinase A system may not be involved in the increase in GJIC caused by H2O2, although this cannot be completely ruled out.
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PMID:Increased gap junctional intercellular communication in Syrian hamster embryo cells treated with oxidative agents. 831 32

Neutrophil-derived hydrogen peroxide (H2O2) is believed to play an important role in the pathogenesis of vascular injury and pulmonary edema. H2O2 time- and dose-dependently increased the hydraulic conductivity and decreased the selectivity of an endothelial cell monolayer derived from porcine pulmonary arteries. Effects of H2O2 on endothelial permeability were completely inhibited by adenylate cyclase activation with 10(-12) M cholera toxin or 0.1 microM forskolin. 10(-8) M Sp-cAMPS, a cAMP-dependent protein kinase A agonist, was similarly effective. The phosphodiesterase (PDE) inhibitors motapizone (10(-4) M), rolipram (10(-6) M), and zardaverine (10(-8) M), which specifically inhibit PDE-isoenzymes III, IV, and III/IV potently blocked H2O2-induced endothelial permeability when combined with 10(-6) M prostaglandin E1. Overall cellular cAMP content and inhibition of H2O2 effects on endothelial permeability were poorly correlated. H2O2 exposure resulted in a rapid and substantial decrease in endothelial cAMP content. The analysis of the PDE isoenzyme spectrum showed high activities of isoenzymes II, III, and IV in porcine pulmonary endothelial cells. The data suggest that adenylate cyclase activation/PDE inhibition is a powerful approach to block H2O2-induced increase in endothelial permeability. This concept appears especially valuable when endothelial PDE isoenzyme pattern and PDE inhibitor profile are matched optimally.
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PMID:Role of phosphodiesterases in the regulation of endothelial permeability in vitro. 838 87

Regulation of endothelial permeability is poorly understood. Previous studies have shown that endothelial cells contain phosphodiesterase (PDE) isoenzymes II-IV and that simultaneous adenylate cyclase activation and/or PDE inhibition blocked endothelial hyperpermeability (J.Clin.Invest. 91: 1421-1428, 1993). We now focused on a possible role for guanosine 3',5'-cyclic monophosphate (cGMP)-dependent mechanisms and studied H2O2-exposed porcine pulmonary artery endothelial cell monolayers. Pretreatment of cells with different nitric oxide (NO) donors or atrial natriuretic peptide (ANP) increased endothelial cGMP-content severalfold and blocked H2O2-related effects on permeability; opposite results were obtained with a NO synthase inhibitor. Determination of cGMP degradation in nitroprusside-exposed endothelial cells identified PDE II as the major cGMP metabolizing pathway, whereas PDE III and IV contributed little or nothing. Inhibition of PDE II reduced H2O2-related endothelial hyperpermeability, an effect that could be enhanced synergistically by simultaneous guanylate cyclase activation. In summary, these studies indicate that cGMP-dependent mechanisms (NO donors, ANP, and dibutyryl-cGMP) blocked H2O2-related increases in endothelial permeability. The major cGMP degrading pathway in endothelial cells was PDE II, thereby substituting the missing PDE V in these cells. Simultaneous guanylate cyclase activation and/or PDE II inhibition may be a valuable approach to treat endothelial hyperpermeability.
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PMID:Role of nitric oxide and phosphodiesterase isoenzyme II for reduction of endothelial hyperpermeability. 863 57

Apoptosis or programmed cell death (PCD) was measured in two human cell models by flow cytometric analysis. Blood neutrophils underwent spontaneous apoptosis in short-term culture. Pentoxifylline (PTX) inhibited spontaneous neutrophil PCD. We confirmed that granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibited apoptosis of polymorphonuclear neutrophils. Treatment with both GM-CSF and PTX did not increase the inhibition of PCD by either GM-CSF or PTX alone. Because apoptosis could be due to the accumulation of H2O2 in the culture medium, and because PTX has been described to reduce peroxide production, we studied the effect of adding catalase to the medium. Catalase reduced the neutrophil apoptosis and this effect was cumulative with the effect of PTX. Camptothecin, an inhibitor of topoisomerase I, induces a block in the S-phase of the cell cycle followed by apoptosis of the U937 cell line. This drug-induced apoptosis was partially inhibited by PTX, whereas the S-phase cell block was not affected. In conclusion, PTX was found to inhibit apoptosis in two different human cell types. In neutrophils, this effect appears to occur regardless of the inhibition of phosphodiesterase activity and inhibition of H2O2 release.
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PMID:Effect of pentoxifylline on apoptosis of cultured cells. 869 66


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