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 purpose of this study was to elucidate the mechanisms by which arachidonic acid activates guanylate cyclase from guinea pig lung. Guanylate cyclase activities in both homogenate and soluble fractions of lung were examined. Guanylate cyclase activity was determined by measuring formtion of [32-P] cyclic GMP from alpha-[32-P] GTP in the presence of Mn2+, a phosphodiesterase inhibitor and a suitable GTP regenerating system. Arachidonic acid, and to a slight extent dihomo-gamma-linolenic acid, activated guanylate cyclase in homogenate but not soluble fractions. Similarly, phospholipase A2 activated homogenate but not soluble guanylate cyclase. Methyl arachidonate, linolenic, linoleic and oleic acids did not activate guanylate cyclase in either fraction. High concentrations of indomethacin, meclofenamate and aspirin inhibited activation of homogenate guanylate cyclase by arachidonic acid and phospholipase A2, without altering basal enzyme activity. These data suggested that a product of cyclooxygenase activity, present in the microsomal fraction, may have accounted for the capacity of arachidonic acid to activate homogenate guanylate cyclase. This view was supported by the findings that addition of the microsomal fraction to be soluble fraction enabled arachidonic acid to activate soluble guanylate cyclase, an effect which was reduced with cycloooxygenase inhibitors. Lipoxygenase activated guanylate cyclase in homogenate and soluble fractions. Arachidonic acid potentiated the activation of soluble guanylate cyclase by lipoxygenase, and this effect was inhibited with nordihydroguairetic acid, 1-phenyl-3-pyrazolidone and hydroquinone, but not with high concentrations of indomethacin, meclofenamate or aspirin. These data suggest that arachidonic acid activates guinea pig lung guanylate cyclase indirectly, via two independent mechanisms, one involving the microsomal fraction and the other involving lipoxygenase.
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PMID:Arachidonic acid activation of guinea pig lung guanylate cyclase by two independent mechanisms. 4 57

Thrombin rapidly induces the formation of labeled phosphatidic acid from platelets prelabeled with [17C]arachidonate or 32PO34- and specifically decreases by 50--75% the content of phosphatidylinositol. Ionophore A23187 also stimulates phosphatidate labeling, but less effectively than thrombin. This effect on phosphatidic acid is blocked by increasing the levels of cyclic AMP by preincubation with dibutyryl cyclic AMP, cyclic AMP-phosphodiesterase inhibitors or prostacyclin. Indomethacin and eicosatetraynoic acid do not alter the production of phosphatidate, indicating independence from cyclooxygenase or lipoxygenase products. Increased turnover of [14C]- or [32P]phosphatidate occurs within 2--5 s after platelet activation by thrombin and is observed before endogenous, 14C-labeled arachidonate can be detected. The rate of phosphatidate formation parallels the induced rate of serotonin release. Release of [3H]serotonin is not affected by eicosatetraynoic acid. Phosphatidate production reflects the generation of diacylglycerol by C-type phospholipase degradation of phosphatidylinositol. Diacylglycerol and phosphatidic acid may participate in the membrane modification related to the early changes in platelet shape, release reactions or aggregation which occur on stimulation.
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PMID:Stimulation of phosphatidic acid production in platelets precedes the formation of arachidonate and parallels the release of serotonin. 37 88

Pharmacological modulation of the in vivo induction of plasminogen activator inhibitor type-1 (PAI-1) synthesis was studied in rats using the induction of PAI-1 by endotoxin as a model system. Both the cyclooxygenase inhibitors acetylsalicylic acid and indomethacin enhanced PAI-1 induction. The combined cyclooxygenase-lipoxygenase inhibitor, BW755C, dose-dependently inhibited induction. Since five other lipoxygenase inhibitors, a phospholipase inhibitor, an inhibitor of leukotriene formation and dexamethasone had no effect on the endotoxin-induced increase in PAI-1 synthesis, the effect of BW755C could not be ascribed to its known pharmacological properties. In addition, induction of PAI was enhanced by isobutyl-methylxanthine, a phosphodiesterase inhibitor, but not, however, by other phosphodiesterase inhibitors, or by forskolin or NG-nitro-L-arginine, suggesting an effect of isobutyl-methylxanthine other than through cyclic nucleotides. Heparin and hirudin had no effect either. Overall, the data showed that the induction of PAI-1 synthesis by endotoxin in vivo can be up- and down-regulated pharmacologically, but the mechanisms involved remain elusive.
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PMID:Pharmacological modulation of the endotoxin-induced increase in plasminogen activator inhibitor activity in rats. 128 Apr 69

1. The potassium currents evoked by glutamate agonists on isolated and identified neurones of molluscan pedal ganglia were investigated using the voltage clamp technique. 2. Glutamate responses were not modified by increasing intracellular cyclic nucleotide concentrations (treatment with 8-Br-cAMP, 8-Br-cGMP, forskolin and/or the phosphodiesterase inhibitor isobutylmethylxantine, IBMX), whereas inward-going currents induced by the nucleotides were observed. It follows that glutamate currents are independent of intracellular cyclic nucleotide control. 3. Protein kinase C activation with phorbol esters or oleoylacetylglycerol induced a slowly developing outward current and reduced glutamate response amplitude. Staurosporine itself did not affect the glutamate responses but completely prevented the effects of phorbol esters and oleoylacetylglycerol. This indicated that protein kinase C was not involved in the transduction mechanism for the potassium component of the glutamate response. 4. The possible involvement of inositol-1,4,5-trisphosphate seems to be improbable because the glutamate responses were independent of intracellular calcium concentration. Intracellular injection of calcium buffer BAPTA, failed to affect any of the glutamate currents, although it effectively blocked the after-hyperpolarization following directly evoked action potentials. 5. Nordihydroguaiaretic acid (NDGA) and indomethacin, inhibitors of the lipoxygenase and cyclo-oxygenase pathways of arachidonic acid metabolism, correspondingly, did not change the glutamate responses of these neurones. 6. The failure to demonstrate the involvement of any known secondary messenger systems in glutamate response transduction favours two assumptions: (1) the receptor-G protein complex controls the potassium channel directly; or (2) some still unknown transduction system is used.
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PMID:Transduction mechanism for glutamate-induced potassium current in neurones of the mollusc Planorbarius corneus. 136 43

The effect of azelastine on intracellular cyclic AMP concentration and on various indexes of cell activation was evaluated in guinea-pig alveolar macrophages and in human platelets. The effect of azelastine was further investigated on adenylate cyclase activity using membranes and homogenates from guinea-pig alveolar macrophages. Pretreatment of alveolar macrophages with azelastine prevented the activation induced by PAF-acether and by the chemotactic peptide fMLP as estimated by the reduced liberation of arachidonic acid metabolites formed by the cyclooxygenase and the lipoxygenase pathways. The effect of azelastine was concentration-dependent (50 to 500 microM) and reversible. Similarly, a short pretreatment with azelastine (100 microM) prevented arachidonic acid-induced platelet aggregation. This effect was also reversible after washing the platelets. In guinea-pig alveolar macrophages, azelastine induced a concentration-dependent (10 to 500 microM) increase in intracellular cyclic AMP and markedly potentiated the increase induced by PGE2. In human platelets, azelastine alone increased intracellular cyclic AMP concentration marginally only but, as in the case of macrophages, synergized with PGI2. Azelastine did not activate significantly adenylate cyclase unless a cytosolic factor was included within the membrane fraction. This effect of azelastine was not due to Ca2+ movements and was not modified by GTP. Our findings show that azelastine interferes with cell activation through a mechanism related to an increase in intracellular cyclic AMP concentration. The increase in cyclic AMP was induced by azelastine in intact cells and in homogenates but not in a crude membrane fraction. Those results indicate that azelastine modifies a cytosolic factor that may be phosphodiesterase. In addition, similarities between the effects of azelastine and those of reference phosphodiesterase inhibitors (theophylline, isobutyl-methyl-xanthine) are shown in this study, suggesting that azelastine might behave as a phosphodiesterase inhibitor.
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PMID:Azelastine potentiates the prostaglandin-induced increase of cyclic AMP content in human platelets and in guinea-pig alveolar macrophages. 137 22

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca++-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H1-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF2 alpha which could originate from mast cell-derived PGD2. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Relationship between mediator release from human lung mast cells in vitro and in vivo. 240 26

The effects of prostaglandin E2 (PGE2), cyclic nucleotides, leukotriene B4 (LTB4), and interferons on interleukin 1 (IL 1) production by lipopolysaccharide (LPS)-stimulated C3H/HeNCrl mouse peritoneal macrophages were studied. IL 1 production was inhibited by PGE2, the adenosine 3':5'-monophosphate analog dibutyryl cAMP, the cAMP agonist isoproterenol, and the phosphodiesterase inhibitor isobutylmethylxanthine. These agents were more inhibitory when added early in the latent phase of IL 1 synthesis following stimulation with LPS rather than just prior to release of IL 1 into the medium. Production of both the intracellular and extracellular forms of IL 1 was blocked by PGE2 and cAMP. Suppression of LPS-induced IL 1 production by PGE2 was prevented by leukocyte alpha-interferon. Moreover, alpha-interferon augmented LPS-induced IL 1 production but did not stimulate IL 1 production in the absence of LPS. Immune gamma-interferon markedly inhibited LPS-stimulated IL 1 production. The lipoxygenase inhibitor eicosa-5,8,11,14-tetraynoic acid suppressed, whereas 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline augmented, LPS-induced IL 1 production. The opposing effects of these agents suggested that lipoxygenase metabolites do not act as inducers of IL 1 production. Purified LTB4 did not stimulate base-line or augment LPS-induced IL 1 production (both intracellular and extracellular forms). Moreover, calcium ionophore A23187 (a lipoxygenase activator) did not stimulate IL 1 production, alone or in combination with LTB4. Thus, net IL 1 production by macrophages may be regulated by a balance between the effects of PGE2, cAMP, alpha-interferon, and gamma-interferon, but not LTB4.
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PMID:Regulation of interleukin 1 production by mouse peritoneal macrophages. Effects of arachidonic acid metabolites, cyclic nucleotides, and interferons. 242

We have found that mouse ear oedema induced by the topical application of arachidonic acid is not a specific screen for compounds inhibiting the lipoxygenase or cyclo-oxygenase pathways of arachidonic acid metabolism. Although such compounds are able to reduce the oedema substantially, pharmacological agents such as histamine antagonists, phosphodiesterase inhibitors, free radical scavengers, and also various compounds not normally considered to have anti-inflammatory properties, can equally effectively reduce the oedema. A mutual potentiation of the effects of prostaglandins, leukotrienes and mast cell-derived histamine would allow many, but not all, of the active agents to be rationalised. The ability of compounds not influencing these three types of inflammatory mediators to reduce the oedematous response means the model is of limited value for directed screening.
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PMID:Inhibition of arachidonic acid-induced ear oedema as a model for assessing topical anti-inflammatory compounds. 243 76

Lipoxygenase products have been suggested as mediators of the hypoxic pulmonary pressor response in newborn animals. Data supporting this suggestion are equivocal, since lipoxygenase and leukotriene receptor antagonists that have been used may produce vasodilation because of phosphodiesterase inhibition. We used a leukotriene receptor antagonist L 649923, which appears not to have smooth muscle relaxant activity. L 649923 blocks pressor responses to leukotriene D4 (LTD4) without diminishing the pressor response to hypoxia. Also, BW 755C did not block the pressor response to hypoxia in newborn sheep and goats, whereas the pressor response to LTD4 (75 ng/kg) was depressed significantly. In newborn sheep there was an augmented response to hypoxia with BW 755C, which is consistent with cyclooxygenase inhibition. Finally, the thromboxane receptor antagonist SQ 29548 was investigated in both species. With this agent the pressor response to LTD4 in contrast to that of hypoxia was completely inhibited. We conclude that thromboxanes are involved in the pressor response to LTD4 in newborn lambs and goats. These data do not support the view that leukotrienes are involved in the ovine or caprine neonatal pulmonary pressor response to hypoxia.
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PMID:Do inhibitors of lipoxygenase and cyclooxygenase block neonatal hypoxic pulmonary vasoconstriction? 249 69

Cyclooxygenase (prostaglandin E2 and prostaglandin I2) and lipoxygenase [8(R), 15(S)-dihydroxyicosa-(5E-9,11,13Z)-tetraenoic acid] products of arachidonic acid metabolism are thought to produce peripheral hyperalgesia by a direct action on the primary afferent nociceptor. In this study we investigated the possibility that these eicosanoids generate hyperalgesia through a common second messenger in the rat. We report that 8-bromo cAMP, a membrane permeable analogue of cAMP, produces a dose-dependent hyperalgesia that is not affected by treatments that interrupt indirect routes of hyperalgesia production including sympathectomy with 6-hydroxydopamine, depletion of polymorphonuclear leukocytes (a source of hyperalgesic eicosanoids) with hydroxyurea, or blockade of the cyclooxygenase pathway of arachidonic acid metabolism with indomethacin. The phosphodiesterase inhibitor isobutyl-methylxanthine markedly prolongs the hyperalgesic effect of 8-bromo cAMP as well as those of the directly acting hyperalgesic agents prostaglandin E2, prostaglandin I2 and 8(R),15(S)-dihydroxyicosa-(5E-9,11,13Z)-tetraenoic acid. We conclude that the effect of all known hyperalgesic eicosanoids is mediated by the cAMP second messenger system and suggest, therefore, that cAMP mediates peripheral hyperalgesia in primary afferent nociceptors.
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PMID:Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system. 255 57


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