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

The formation and prevention of coronary platelet thrombi (CPT) was studied in a modified Folts model in 23 anaesthetized dogs. The left circumflex coronary artery was acutely damaged and narrowed until resting flow started to fall. Spontaneous sharp decrease of flow indicated the acute formation of CPT. Intravenous infusion of 30 ng/kg/min of PGI2 prevented the formation of CTP. The effect lasted 3-7 min after termination of the infusion. RX-RA 69 a potent inhibitor of platelet phosphodiesterase (IC50 of 1 X 10(-9) mol/1) inhibited the formation of CPT for 9 and 18 min when 60 and 120 micrograms/kg were administered i.v. The results demonstrate that platelet aggregation induced by acute damage of the vascular wall can be inhibited by a potent PDE inhibitor.
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PMID:Prevention of coronary platelet aggregation with a phosphodiesterase inhibitor RX-RA 69. 298 3

Prostacyclin (PGI2) inactivates platelets by stimulation of adenylate cyclase, and its effect can be potentiated in vitro by simultaneous inhibition of cyclic AMP phosphodiesterase. The interaction of synthetic PGI2 and the potent phosphodiesterase inhibitor HL 725 was studied in a model of systemic platelet activation by intravenous injection of collagen. Platelet aggregate formation was evaluated by continuous on-line measurement of the circulating platelet count. Collagen injection in rabbits receiving vehicle caused a 30 +/- 3% decrease in the circulating platelet count. Infusion of PGI2 (0.05, 0.1 and 0.75 micrograms kg-1 min-1) dose-dependently inhibited this decrease. HL 725 (0.5, 1 and 3 micrograms kg-1 min-1) caused a slight but significant effect. Combinations of PGI2 and HL 725, respectively, at 0.25 + 1.0 and 0.1 + 0.5 micrograms kg-1 min-1 inhibited platelet aggregate formation to a greater extent than when either substance was used alone and produced a comparable inhibition to PGI2 at 0.75 micrograms kg-1 min-1. Collagen induced an acute fall in the mean arterial blood pressure (MABP) which also was inhibited by PGI2, HL 725 and their combinations. The infusion of a combination of PGI2 and HL 725 before collagen produced a decrease in the MABP which was greater than when either compound was used on its own. Thus, PGI2 and the phosphodiesterase inhibitor HL 725 interact in vivo to inhibit platelet aggregation and lower MABP.
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PMID:In vivo interaction of prostacyclin with an inhibitor of cyclic nucleotide phosphodiesterase, HL 725. 298 63

When rat peritoneal leucocytes were incubated with carbon tetrachloride, a PLA2 was activated, eicosanoids were generated and lysosomal and cytoplasmic enzymes were released. The predominant eicosanoid generated was TXB2 with lesser amounts of PGE2, 6-keto PGF1 alpha and LTB4. Preincubation of the cells with two structurally unrelated thromboxane synthetase inhibitors reduced PLA2 activity and enzyme release and also reduced the total amounts of eicosanoids liberated. An anti-PGI2 antibody partially reversed the effects of thromboxane synthetase inhibitors indicating a role for endogenous PGI2 generation in the cytoprotective effects of these agents in this system. Exogenous PGI2 was also cytoprotective but the timing of its administration was critical. The cytoprotective effect of PGI2 was potentiated by a phosphodiesterase inhibitor, indicating a possible pivotal role of cAMP in cell protection.
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PMID:Carbon tetrachloride-induced eicosanoid synthesis and enzyme release from rat peritoneal leucocytes. 298 50

This study with the new analog Ro 15-2041 (7-bromo-1,5-dihydro-3,6-dimethylimidazo[2,1-b]quinazolin-2(3H)-on e) confirms and substantially extends the activity spectrum of imidazoquinazolinones as potent platelet function inhibitors. Ro 15-2041 inhibited platelet aggregation induced by all common platelet agonists in platelet-rich plasma obtained from various species including man (IC50 = 1-3 microM). The compound potentiated platelet inhibition by prostacyclin, the prostacyclin-induced increase of intraplatelet cyclic (c) AMP levels and inhibited the collagen-induced release of serotonin and beta-thromboglobulin. Ro 15-2041 reduced the increase and accelerated the normalization of cytosolic free Ca++ in thrombin-stimulated human platelets. Ro 15-2041 is a potent (IC50 = 70 nM) and selective inhibitor of platelet cAMP-phosphodiesterase activity. Whereas Ro 15-2041 caused complete inhibition of cAMP-phosphodiesterase activity in human platelet supernatants, breakdown of cAMP in cardiac homogenates was depressed to maximally 50%. In human brain and rabbit uterus Ro 15-2041 was at least 1000 times less potent. By comparison, papaverine fully inhibited phosphodiesterase activity in all four tissues with similar IC50 values of about 5 microM. Furthermore, Ro 15-2041 selectively inhibited cAMP-phosphodiesterase activity of a bovine calmodulin-independent but not of a calmodulin-dependent enzyme preparation. The compound exhibited significant p.o. activity in various ex vivo and in vivo platelet function tests.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:7-Bromo-1,5-dihydro-3,6-dimethylimidazo[2,1-b]quinazolin-2(3H)- one (Ro 15-2041), a potent antithrombotic agent that selectively inhibits platelet cyclic AMP-phosphodiesterase. 299 47

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

The metabolism of cAMP which appears to be the intracellular mediator of various relaxing agents was studied in biopsies obtained during elective caesarean section from inner and outer myometrial layers outside the placental insertion. In the inner layer, L-epinephrine, PGE1, PGE2, PGF2 alpha and PGI2 stimulated the cAMP formation process while 6-keto PGF1 alpha was ineffective. The fact that some of these prostaglandins are well-known to promote contraction, confirms that the effects of drugs on uterine motility are not necessarily related to changes in the cAMP level. On the other hand, L-epinephrine and prostaglandins did not strongly influence the cAMP formation process in the outer layer. Kinetic analysis and purification assays of phosphodiesterase (PDE) which catalyzes the degradation of cAMP revealed the presence of multiple molecular forms of the enzyme in human pregnant myometrium. Qualitative and quantitative differences between the two layers appeared in the two forms separated from the soluble fraction by DEAE-cellulose chromatography. An unequal distribution of calmodulin was also observed in the inner and outer layers. Our results support the concept of the regulatory heterogeneity of the pregnant human uterus and suggest that the myometrial inner layer plays an important role in the regulation of uterine motility at the end of pregnancy.
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PMID:Cyclic AMP metabolism in the inner and outer layers of human myometrium near term. 301 Jun 38

Patients were treated with defibrotide (3 X 200 mg/day) for 7 days. Plasma PGI2 and TXB2 levels were measured by RIA using EDTA-aspisol as anticoagulant and cyclooxygenase inhibitor. Isolated platelet c-AMP levels were also determined by RIA, using EDTA-dipyridamole as anticoagulant and phosphodiesterase inhibitor. Blood PGI2 levels were found to increase significantly upon treatment while the increase in TXB2 levels was not significant. Blood PGI2/TXB2 ratio increased 51%, 30 min after intravenous injection and it remained 28% higher during therapy than the predrug blood level. Significantly higher platelet c-AMP levels were also obtained after the injection of drug (0.02 less than p less than 0.05).
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PMID:In vivo effects of defibrotide on platelet c-AMP and blood prostanoid levels. 301 17

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


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