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)

This study evaluated the effect of prostaglandin I2 (PGI2) on fibronectin-mediated macrophage phagocytosis in vivo and in vitro. Phagocytosis measured in vivo in rats by the vascular clearance rate and hepatic localization gelatinized sheep erythrocytes was inhibited in a dose-dependent manner after intravenous administration of PGI2. Phagocytosis was assessed in vitro in terms of uptake of fibronectin-dependent gelatinized sheep erythrocytes by monolayers of casein-elicited rat peritoneal macrophages. Concentrations of 1 ng/ml PGI2 or greater resulted in inhibition of particle internalization but not attachment to macrophages. This inhibitory effect was enhanced by aminophylline, a phosphodiesterase inhibitor. PGI2 increased cAMP levels and these were further increased in the presence of aminophylline. These data indicate that PGI2 inhibits macrophage uptake of gelatinized particles and support the idea that this is mediated by increased intracellular levels of cyclic AMP. PGI2 should thus be considered a potential etiologic factor in the phagocytic depression observed in association with thrombosis.
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PMID:Influence of prostaglandin I2 on fibronectin-mediated phagocytosis in vivo and in vitro. 298 44

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 ADP-hydrolyzing enzyme apyrase inhibited platelet aggregation and phosphorylation of a 40,000 dalton platelet protein (P40) induced by 1-oleoyl-2-acetyl glycerol (OAG), indicating a dependence on secreted ADP. Apyrase also enhanced OAG-induced potentiation of forskolin or prostaglandin I2 activation of cyclic AMP formation in platelets. Cyclic AMP formation induced by OAG alone could be demonstrated in the presence of a phosphodiesterase inhibitor. Elevation of cyclic AMP level inhibits platelet aggregation so that secreted ADP may be required to inhibit OAG-activated adenylate cyclase for aggregation to proceed. In contrast, apyrase only partially affected phosphorylation of P40 and aggregation induced by the tumor promoter 12-0-tetradecanoyl phorbol-13-acetate (TPA). TPA caused marked inhibition of forskolin-stimulated cyclic AMP formation. TPA inhibition of cyclic AMP formation was largely reversed by apyrase, indicating that it was mainly due to release of ADP.
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PMID:Differences in the mode of action of 1-oleoyl-2-acetyl-glycerol and phorbol ester in platelet activation. 299 4

Forskolin, epinephrine, and prostaglandin I2 were used to examine the adenylate cyclase-phosphodiesterase system of intact thrombopathic and normal canine platelets. The results provide indirect support for the hypothesis that the elevation of intraplatelet c-AMP in this unique hereditary defect is due to impaired phosphodiesterase activity. The inhibitory (Nj) and stimulatory (Ns) components of adenylate cyclase appeared functionally intact. Cytosolic fractions of normal and thrombopathic platelets had similar cAMP hydrolytic activities. The failure of intact forskolin-stimulated thrombopathic platelets to return elevated cAMP to non-stimulated levels after 15 min, despite significant phosphodiesterase activity in cytosolic fractions, implies that the platelet isoenzymes are under regulatory control.
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PMID:Evidence for regulatory control of canine platelet phosphodiesterase. 302 25

32P-labelling of phosphatidylinositol (PI), PI-4-monophosphate (PIP), PI-4,5-bisphosphate (PIP2) and phosphatidic acid (PA) in 32P-labelled intact human platelets was investigated in the presence of various agents which alter intracellular level of cAMP or Ca2+. Addition of dibutyryl cAMP to intact platelets pre- or pulse labelled with 32P resulted in increased 32P-labelling of PIP and in concomitant decreased 32P-labelling of PI without affecting that of PIP2 or PA. Similar changes were observed in intact platelets treated by prostaglandin I2 (PGI2) or a new low Km phosphodiesterase inhibitor (DN-9693). When intracellular Ca2+ was chelated by loading quin 2-AM to intact platelets, 32P-labelling of PIP was significantly increased in a dose related manner. From these observations it was concluded that PI kinase is activated by elevation of cAMP or chelation of Ca2+ in intact platelets.
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PMID:Phosphorylation of phosphoinositides in human platelets. 302 54

Fibrinogen binds to human platelets after specific receptor sites are exposed by thrombin, ADP, epinephrine, and other stimuli. Since prostaglandin I2 (PGI2), a potent activator of platelet adenylate cyclase, prevents mobilization of the fibrinogen receptor by aggregating agents, we investigated the relationship between platelet cAMP levels and fibrinogen receptor status in thrombin-stimulated human platelets. A dose-dependent rise in platelet cAMP in response to two adenylate cyclase agonists, PGI2 and forskolin, correlated with progressive inhibition of fibrinogen binding. Moreover, the receptor inhibition produced by either agonist was sustained up to 2 h and was associated with a persistent increase in cAMP levels. The phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine, in the presence of a subthreshold concentration of PGI2 also raised cAMP and inhibited fibrinogen binding. In contrast, the effects of PGI2 on both cAMP and fibrinogen binding were markedly attenuated by 9-(tetrahydro-2-furyl) adenine, an adenylate cyclase inhibitor. These results indicate that the inhibition of fibrinogen binding by PgI2 is linked to its effect on cAMP levels and suggest that elevation of platelet cAMP levels from any cause prevents exposure of the fibrinogen receptor.
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PMID:Evidence that changes in platelet cyclic AMP levels regulate the fibrinogen receptor on human platelets. 629 72

Acetyl glyceryl ether phosphorylcholine induces human neutrophil aggregation. Incubation of neutrophils with either prostaglandin I2, or the cyclic AMP-dependent phosphodiesterase inhibitor, RO 20-1724 before the addition of PAF-acether attenuates subsequent aggregation. Paradoxically, a small elevation in cyclic AMP is observed coincident with the initiation of PAF-acether-stimulated aggregation. The elevation in cyclic AMP in response to PAF-acether is amplified by RO 20-1724, and the magnitude of the response is dependent upon the concentration of PAF-acether. The elevation in cyclic AMP is not due to prostaglandins, because indomethacin actually enhances the elevation in cyclic AMP induced by PAF-acether. The involvement of the neutrophil 5-lipoxygenase, and subsequent leukotriene B4 synthesis, is suggested by the observation that 5-lipoxygenase inhibitors limit both the elevation in cyclic AMP induced by PAF-acether, and the indomethacin enhancement. This indirect evidence is supported by the fact that leukotriene B4 itself elevates neutrophil cyclic AMP levels in intact cells, and stimulates the adenylate cyclase in broken cell preparations. Although the elevation in cyclic AMP induced by either PAF-acether or leukotriene B4 is coincident with the onset of neutrophil aggregation, it is not obligatory for aggregation. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine blocks the PAF-acether-stimulated increase in cyclic AMP, and actually enhances aggregation. It is suggested that the increase in cyclic AMP observed after the addition of PAF-acether is due to concomitant leukotriene B4 synthesis, and is not obligatory for neutrophil aggregation, but is actually part of a feed-back regulatory system through which PAF-acether and leukotriene B4 can limit their own activity in neutrophils.
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PMID:Evidence for mediation of acetyl glyceryl ether phosphorylcholine stimulation of adenosine 3',5'-(cyclic)monophosphate levels in human polymorphonuclear leukocytes by leukotriene B4. 631 71

Depending on the time of addition, prostaglandin I2 (PGI2; greater than or equal to 10(-9) M) either inhibits or reverses platelet agglutination mediated by human factor VIII-related von Willebrand factor activity (FVIIIvWF) and ristocetin, or bovine FVIIIvWF alone. 6-Keto-PGF1 alpha, the inactive metabolite of PGI2, is without effect, PGI2 inhibition is potentiated by the phosphodiesterase inhibitor, theophylline, and is not the result of PGI2 suppression of ADP release. PGI2 (+/- theophylline) does not inhibit ristocetin-induced binding of purified human 125I-FVIIIvWF multimers to washed platelets or to platelets treated with PGI2 and then formalin fixed (although subsequent agglutination of these platelets is impaired). Washed platelets treated previously with 2-aminoethylisothiouronium bromide (AET), an agent that reduces disulfide bonds and alters platelet membranes, also bind human 125I-FVIIIvWF multimers without agglutinating. We conclude that FVIIIvWF-mediated agglutination requires both functional platelet FVIIIvWF binding sites and platelet-platelet cohesion sites, and that platelet surface cohesion sites are altered by AET and PGI2. PGI2 from adjacent intact endothelial cells may prevent excessive platelet accumulation on exposed subendothelium without suppressing an essential hemostatic process--the binding of platelets to subendothelial FVIIIvWF.
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PMID:Platelets, von Willebrand factor, and prostaglandin I2. 678 37

Effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on cyclic AMP (cAMP) levels were studied in the isolated rat anterior and intermediate-posterior pituitary slices. In the anterior pituitary, ET-1 increased cAMP levels in a concentration-dependent manner (10(-7)-10(-5) M). ET-3 also increased the levels at the same concentration range, but ET-1 was more potent than ET-3 at an approximate ED50, 10(-6) M. The stimulatory effects of ET-1 and ET-3 (10(-6) M) on cAMP levels were antagonized by the ETA receptor antagonist BQ 123, 2 x 10(-6) M, and the ETB receptor agonist IRL 1620 evoked only a weak increase in cAMP levels. Moreover, the effects of ET-1 and ET-3 were completely abolished by the cyclooxygenase inhibitor indomethacin, 2 x 10(-5) M. On the other hand, among prostaglandins, prostaglandin E2 (PGE2) increased cAMP levels in a concentration-dependent manner (10(-7)-10(-5) M), whereas prostaglandin D2 and prostaglandin I2 did not exhibit such effects. PGE2 levels were increased by application of ET-1 (10(-8)-10(-5) M). The ET-1-induced PGE2 accumulation was strongly inhibited by indomethacin and BQ 123, but not by treatment with pertussis toxin (100 ng/ml, 6 hr). Treatment with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also elevated the cAMP level by approximately 9-fold above the basal cAMP level. After 3-isobutyl-1-methylxanthine, ET-1 failed to increase PGE2 and cAMP levels. In the intermediate-posterior pituitary, ET-1 and ET-3 did not affect cAMP levels. The results suggest that endothelins increase cAMP levels via ETA receptor activation interacting with the pertussis toxin-insensitive G-protein, in which PGE2 production is involved in the rat anterior pituitary, whereas endothelins lack these effects in the intermediate-posterior pituitary.
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PMID:Endothelins stimulate cyclic AMP accumulation in the isolated rat anterior pituitary gland: possible involvement of ETA receptor activation and prostaglandin E2 production. 751 15

DQ2511, a possible antiulcer agent, relaxed dog, monkey and human arterial strips from various organs; the effect was most evident in the gastroepiploic artery. The relaxation was not influenced by timolol, atropine, dopamine receptor antagonists, and K+-channel blockers, but partially attenuated by oxyhemoglobin endothelium denudation. Treatment with DQ2511 increased the relaxant response to sodium nitroprusside and a prostaglandin I2 analog in dog gastroepiploic arteries and potentiated the stimulating effect of these agonists on the contents of cyclic GMP and cyclic AMP, respectively. It is concluded that DQ2511 relaxes gastroepiploic arteries predominantly over the other arteries; the relaxation appears to be derived partially from phosphodiesterase inhibition.
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PMID:Characteristics of DQ2511-induced relaxation in isolated dog, monkey and human arteries. 756 36


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