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)

Continuous intravenous infusion of prostacyclin (prostaglandin I2, PGI2) in rabbits induced refractoriness to PGI2-induced inhibition of platelet function. Although inhibited during earlier stages, platelet response to adenosine diphosphate and thrombin became normal within 24 hours of PGI2 infusion. Cross-mixing experiments with platelets and plasma from infused and control animals suggested that the altered response to PGI2 was caused by a defect intrinsic in the platelets. PGI2-stimulated cyclic adenosine monophosphate (cAMP) production was reduced in platelets from infused rabbits as compared with those from controls. Platelets refractory to PGI2 were refractory to PGE1 and PGD2, as well. Because PGE1 but not PGD2 shares the same platelet receptor as PGI2, the phenomenon could not be ascribed to receptor-specific downregulation, which was also shown by refractoriness of platelets from infused rabbits to the nonprostanoid inhibitor of platelet function adenosine. Either increased concentrations of ineffective inhibitors or their combination with phosphodiesterase inhibitors overcame refractoriness of resistant platelets, which also responded to inhibition by dibutyryl cAMP, indicating residual activity of adenylate cyclase. That at least the catalytic subunit of the enzyme was still working in refractory platelets was shown by inhibition of aggregation induced by forskolin, a non-receptor-mediated activator of adenylate cyclase. Impairment of the adenylate cyclase regulatory subunit, possibly accompanied by multireceptor downregulation, may explain the paradoxical refractoriness of platelets to prolonged infusion of PGI2. Such an effect may limit the benefit of PGI2 in treatment of thromboembolic disease.
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PMID:Refractoriness of platelets to prostaglandins after infusion in rabbits. 299 53

The action of three compounds reported to elevate intracellular cyclic adenosine monophosphate (cAMP) namely 3-isobutyl-1-methylxanthine (IBMX) and prostaglandins D2 and E1 (PGD2 and PGE1), on histamine release was examined. Three test systems were used: (i) the perfused ovalbumin-sensitized guinea pig lung and (ii) isolated cells from ovalbumin-sensitized guinea pig lung, both of which are IgG-mediated models of anaphylaxis, and (iii) an IgE model of anaphylaxis, using isolated rat peritoneal mast cells from sensitized rats. Both PGD2 and PGE1 were without effect at concentrations likely to be found during anaphylaxis. In contrast, the phosphodiesterase inhibitor, IBMX, was highly active in all three test systems. The role of raised intracellular cAMP levels in the inhibition of histamine release is discussed.
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PMID:Action of 3-isobutyl-1-methylxanthine and prostaglandins D2 and E1 on histamine release from rat and guinea pig mast cells. 619

The present study examined the involvement of prostaglandins (PGs) in the mechanisms of ACTH and beta-endorphin release from rat anterior pituitary quarters incubated in vitro. Various cyclooxygenase inhibitors (indomethacin, diclofenac, flurbiprofen) had no effect on basal release of ACTH-like or beta-endorphin-like immunoreactivity (beta-EI), but enhanced ACTH-immunoreactivity/beta-EI release upon stimulation by arginine-vasopressin (AVP) or synthetic ovine corticotropin-releasing factor [CRF-(1-41)]. The lowest effective concentration of indomethacin was just sufficient to prevent PG synthesis. Indomethacin was similarly active after blockade of the phosphodiesterase by 3-isobutyl-1-methylxanthine. When added to the incubation media in concentrations up to 1 microM, PGE2, D2, F2 alpha, or prostacyclin (PGI2) did not alter basal beta-EI release; however, with stimulation by AVP or CRF-(1-41), PGE2 but not PGD2, F2 alpha, or I2 inhibited beta-EI release by about 60%. The concentrations of PGE2 in the incubation media, as measured by RIA, were somewhat higher than those of any other cyclooxygenase product (PGD2, F2 alpha, 6-keto-PGF1 alpha, thromboxane B2). Upon stimulation by AVP or CRF-(1-41), the concentrations of PGE2 increased, whereas those of PGD2 or F2 alpha remained unchanged. The release of beta-EI stimulated by high potassium concentration was not enhanced by indomethacin, although this release was sensitive to inhibition by PGE2. We conclude that PGE2 is formed locally subsequent to binding of the neurohormones and may act as a negative feedback-modulator of vasopressin's and CRF-(1-41)'s activity in the anterior pituitary gland.
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PMID:Adrenocorticotropin and beta-endorphin release from rat adenohypophysis in vitro: inhibition by prostaglandin E2 formed locally in response to vasopressin and corticotropin-releasing factor. 620 54

An analysis of prostaglandin-stimulated adenosine 3',5'-cyclic monophosphate (cyclic AMP) accumulation in cultured human umbilical vein endothelial cells showed prostacyclin (PGI2) to be the most potent agonist followed by prostaglandin (PG)H2, which was more potent than PGE2, while PGD2 was essentially inactive. The endothelial cells studied apparently have a high rate of cyclic AMP phosphodiesterase activity because significant PGI2-mediated increases in cyclic AMP could not be shown in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (MIX). Endoperoxide PGH2-stimulation of cyclic AMP accumulation was inhibited 75--80% by the prostacyclin synthetase inhibitors 12-hydroperoxyeicosatetraenoic acid or 9,11-azoprosta-5,13-dienoic acid. These data indicate that the PGH2-stimulation is due primarily to conversion to PGI2. The beta-adrenergic agonist L-isoproterenol stimulated cyclic AMP accumulation in the endothelial cells. This accumulation was completely blocked by propranolol. However, stimulation of cyclic AMP accumulation by the beta-adrenergic agent did not equal that induced by PGI2. Furthermore, the PGI2 response could not be blocked by propranolol. Thrombin-stimulated PGI2 biosynthesis was attenuated by PGE1 or isoproterenol in the presence of MIX. MIX alone was less effective than a combination of PGE1 or isoproterenol plus MIX. These data suggest two potential effects of PGI2 biosynthesis by endothelial cells: first, the PGI2 can elevate cyclic AMP in platelets, and second, endothelial cell cyclic AMP can be elevated as well, so that subsequent PGI2 synthesis will be attenuated.
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PMID:Regulation of endothelial cell cyclic nucleotide metabolism by prostacyclin. 625 64

The possibility that histamine may play a functional role in modulating mast-cell secretion, as has been suggested for basophil degranulation, has both physiologic and pharmacologic implications. Therefore the capacity of histamine to influence rat peritoneal mast-cell (RPMC) cyclic AMP levels and reversed anaphylatic degranulation as reflected in the release of 3H-serotonin (5-HT) was examined. To ascertain that RPMC were functionally responsive to exogenous hormonal stimulation, assessment of prostaglandin (PG) D2 effects on cyclic AMP and 5-HT release were determined in parallel. Although PGD2 (100 microM) increased cyclic AMP and inhibited 5-HT release in the presence of 50 microM aminophylline, histamine (up to 1000 microM) was ineffective was ineffective in both. However, 1000 microM histamine in the presence of 500 microM aminophylline was capable of transiently increasing RPMC cyclic AMP (for 15 to 30 sec) and under these conditions of suppressing 5-HT release. The receptor subtype involved in the suppressive actions of histamine appeared to be of the H-1 type as reflected in the capacity of specific H-1 agonists to reproduce the inhibition of 5-HT release, whereas neither H-2 agonists nor H-2 antagonists had any influence. Thus, under conditions in which phosphodiesterase enzymatic action is impaired, histamine in extremely high concentrations is able to modulate mast-cell secretion. However, it seems very unlikely that this action of histamine has any physiologic significance.
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PMID:The effects of histamine and prostaglandin D2 on rat mast-cell cyclic AMP and mediator release. 627 62

Activation of platelets by thrombin rapidly increases cytoplasmic free calcium, [Ca2+]i, measured by Quin -2, and induces secretion. Stimulators of adenylate cyclase (i.e. PGI2, PGD2, forskolin) suppressed or reversed the increase of [Ca2+]i. Inhibitors of adenylate cyclase (i.e. epinephrine, ADP), added before or after thrombin, counteracted PGI2, PGD2 and forskolin and thereby increased [Ca2+]i and restored secretion. Responses to epinephrine (via alpha-2 adrenoreceptors) and ADP were independent of extracellular Ca2+, but required maintained occupancy of thrombin receptors and intact cAMP-phosphodiesterase activity. These results indicate that cAMP serves as an inhibitory second-messenger that antagonizes the mobilization of Ca2+, an activator second-messenger.
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PMID:Cytoplasmic Ca2+ in platelets is controlled by cyclic AMP: antagonism between stimulators and inhibitors of adenylate cyclase. 632 75

Prostaglandin (PG) E1, PGD2 and the unstable PGI2 are inhibitors of human platelet aggregation and increase the concentration on cAMP in human platelets, presumably by stimulation of the adenylate cyclase. Methylxanthines exert their antiaggregatory effect by inhibiting the platelet cAMP phosphodiesterase. We examined whether caffeine-indomethacin is able to block PGI2 release from gastric mucosa less than the administration of indomethacin alone. PGI2 production was determined on aliquots of incubated mucosal strips, tested for ADP-induced aggregation of human platelet rich plasma. The obtained data indicate that the PGI2 production found in rats treated with the association was higher than that observed in rats treated with indomethacin alone. The present preliminary findings suggest that caffeine when given together with indomethacin reduces the indomethacin-induced inhibition of PGI2 release from the gastric mucosa.
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PMID:[Effect of the association of caffeine-indomethacin on the production of prostacyclin in the rat stomach]. 676 86

The effects of several selective thromboxane synthetase inhibitors, alone and in combination with inhibitors of cyclic AMP phosphodiesterase, on the aggregation of human platelets in response to collagen, ADP, 1-0-alkyl-2-acetyl-sn-glycerophosphocholine (1-alkyl-2-acetyl-GPC), 9,11-azo-PGH2 and sodium arachidonate were studied in vitro. The thromboxane synthetase inhibitors caused little or no inhibition of aggregation at the concentrations used, while the phosphodiesterase inhibitors caused partial to complete inhibition of aggregation induced by all of the aggregating agents, with anagrelide being the most potent inhibitor and sodium arachidonate the agent most susceptible to inhibition. Combination of inhibitors of thromboxane synthetase with inhibitors of cyclic AMP phosphodiesterase, at concentrations of each which caused little or no effect when used alone, produced marked inhibition of platelet aggregation induced by collagen or arachidonic acid but not by the other aggregating agents studied. This interaction between the two classes of inhibitors appears to be due to the accumulation of cyclic AMP as it can be reversed by 9-(tetrahydro-2-furyl) adenine, an inhibitor of adenylate cyclase. Furthermore, as no synergistic inhibition was found using aggregating agents that are poor inducers of thromboxane formation, or using collagen after the ingestion of aspirin, it is most likely that activation of adenylate cyclase occurs because of diversion of thromboxanes into prostaglandins particularly PGD2. The present results suggest that combined use of inhibitors of thromboxane synthetase and inhibitors of cyclic AMP phosphodiesterase may provide a new approach to antithrombotic therapy.
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PMID:Effect of thromboxane synthetase inhibitors on platelet function: enhancement by inhibition of phosphodiesterase. 689 43

The effects of prostaglandins on the fibrinolytic activity of cultured human foreskin fibroblasts have been measured by a [125I]fibrin dish assay. Prostaglandin (PG) E1, added to fibroblasts in serum-containing medium, produced dose-dependent increases in the fibrinolytic activity of both cellular extracts and conditioned medium. PGE2 and PGI2, but not PGD2 or 6-keto-PGF1 alpha, also stimulated fibrinolytic activity. In each case, activity was due to the protease plasminogen activator because it was abolished by omitting plasminogen from the fibrinolytic assays. The effects of PGE1 were observed at 10 ng/ml and maximal stimulation occurred at 1 microgram/ml. Levels of both intra- and extracellular plasminogen activator increased, indicating that PGE1 stimulated the overall synthesis and release of the protease. The effects of PGE1 were slow in onset and persistent (greater than 48 hr) and were abolished by cycloheximide and actinomycin D. Cellular plasminogen activator was stimulated by 10 microM isoproterenol and 250 microM dibutyryl cyclic AMP; the effects of PGE1, isoproterenol and dibutyryl cyclic AMP were potentiated by the phosphodiesterase inhibitors 1-methyl-3-isobutylxanthine (100 microM) and dipyridamole (20 microM). The induction of plasminogen activator by PGE1 may therefore be initiated by stimulation of cellular adenylate cyclase. Increased fibrinolytic stimulation of cellular adenylate cyclase. Increased fibrinolytic activity could contribute to the prolonged beneficial effects which have been reported after the administration of PGE1 and PGI2 in the treatment of occlusive vascular disease.
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PMID:Stimulation of fibrinolytic activity in human skin fibroblasts by prostaglandins E1, E2 and I2. 705 Mar 42

The role of blood platelets in the pathogenesis of atherosclerosis, thrombosis, thromboembolism and stroke (hemorrhagic/thrombotic) is well established. In view of this recognized role played by platelets in the complications associated with coronary artery disease and cerebrovascular disease, there is considerable interest in the pharmacology of platelet activation inhibitory drugs. These drugs exert their effect by blocking several different activation signalling mechanisms. Some of the known compounds that modulate platelet function include: inhibitors of arachidonic acid metabolism (nonsteroidal anti-inflammatory drugs and thromboxane synthetase inhibitors), drugs that alter membrane phospholipid composition (omega 3 fatty acids), stimulators of adenylyl cyclase and guanylyl cyclase (PGE1, PGI2, PGD2/ERRF [nitric oxide], nitroglycerin, nitroprusside), phosphodiesterase inhibitors (dipyridamole and methylxanthines) and calcium antagonists (verapamil, nifedipine, diltiazem). Current research on the pharmacology of platelet activation inhibitory drugs is focused on the development of specific receptor antagonists (antibodies, peptides, receptor antagonists). Since platelets have multiple mechanisms for achieving activation, and the process of thrombosis involves multicellular modulation of platelet activity, it will be rather difficult to develop a compound that is capable of causing complete inhibition of activation mechanisms. Therefore, future research will be devoted to development of designer drugs that will be used for preventing discrete platelet responses. This approach may be useful as total inhibition of platelet activation, although it may prevent thrombotic events, may possibly precipitate hemorrhagic conditions. A better understanding of cell signalling pathways and the mechanisms involved in the pathogenesis of cardiovascular cerebrovascular disease will facilitate the development of efficient antiplatelet drugs.
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PMID:Pharmacology of platelet activation-inhibitory drugs. 806 66


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