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)

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

Binding of intracellular Ca2+ was measured in intact human blood platelets using the fluorescent Ca2+ probe, chlortetracycline, and a photon-counting microspectrofluorometer. Low doses of epinephrine, A23187, or prostaglandin endoperoxide analog U46619 induced a release of intraplatelet membrane-bound Ca2+. When platelet transmembrane Ca2+ flux was blocked by verapamil or ethylenediaminetetraacetic acid (EDTA), Ca2+ mobilization in response to epinephrine was inhibited, whereas A23187- or U46619-induced Ca2+ release was unchanged. When indomethacin was used to inhibit cyclo-oxygenase activity, Ca2+ mobilization in response to epinephrine or U46619 was partially blocked, whereas Ca2+ release in response to A23187 was unaltered. The relationship between platelet cyclic adenosine 3',5'-monophosphate (cAMP) and intraplatelet Ca2+ binding was also investigated. Prostaglandin E1 or prostacyclin was found to markedly elevate cAMP as well as enhance platelet Ca2+ binding. These effects were augmented by inhibition of phosphodiesterase activity using RO201724. The relationship between cAMP and Ca2+ binding was linear in the range of 10-60 pmoles cAmP/ml platelet-rich plasma. In addition the increase in cAMP stimulated by prostaglandin E1 or prostacyclin reduced the ability of epinephrine, A23187, or U46619 to induce intraplatelet Ca2+ mobilization.
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PMID:Ca2+ mobilization in blood platelets as visualized by chlortetracycline fluorescence. 627 7

The activity of N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104) on arachidonic acid metabolism, the 3',5'-cyclic AMP-phosphodiesterase and the serum clearance of a lipid emulsion is reported in order to clarify its mechanism of action on platelet aggregation and lipid metabolism. Plafibride did not act on the arachidonic acid metabolism as far as platelet aggregation was concerned, since it did not modify the generation of prostaglandin endoperoxides nor prostacyclin. Neither did it act on the generation of thromboxane A2. Plafibride inhibited the activity of 3',5'-cyclic AMP-phosphodiesterase, which is one of the principal mechanisms of inhibition of platelet aggregation. The serum c clearance of a commercial lipid emfy the generation of prostaglandin endoperoxides nor prostacyclin. Neither did it act on the generation of thromboxane A2. Plafibride inhibited the activity of 3',5'-cyclic AMP-phosphodiesterase, which is one of the principal mechanisms of inhibition of platelet aggregation. The serum clearance of a commercial lipid emulsion was increased by plafibride which also possessed a strong hypotriglyceride activity. The correlation between platelet antiaggregant and hypolipemic activity of plafibride is discussed in this paper.
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PMID:Influence of plafibride, an antiplatelet and hypolipemic agent, on prostacyclin and thromboxane synthesis, 3',5'-cyclic AMP phosphodiesterase activity and serum clearance of a lipid emulsion. 627 63

Incubation of primary monolayer cultures of human umbilical vein endothelial cells with buffer, thrombin (0.5 unit/ml), ionophore A23187 (10 microM), arachidonic acid (20 microM), prostaglandin H2 (PGH2) (4 microM) resulted in prostacyclin (PGI2) production in nanomolar quantities to the extent of 36 +/- 2, 276 +/- 13, 485 +/- 32, 533 +/- 22, and 532 +/- 22, respectively, as measured by radioimmunoassay of 6-keto-PGF alpha. Preincubation of the endothelium with 1 mM 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate, an antagonist of cytoplasmic Ca2+, or with 4 mM 1-methyl-3-isobutylxanthine (MIX), an inhibitor of cyclic nucleotide phosphodiesterase activity, blocked PGI2 release induced by thrombin or A23187, decreased arachidonic acid-induced release by approximately 50%, but had no effect on PGH2-induced release. Radioimmunoassay of cAMP in the endothelium showed that the basal level (1.85 +/- 0.14 pmol of cAMP per 4.5 x 10(5) cells) was increased by an average of 3.9-fold with 4 mM MIX. PGI2 (0.4 microM) had no significant effect on cAMP levels in the absence of MIX, but caused a 2-fold increase with 4 mM MIX. The findings suggest that: (i) the stimulation of PGI2 biosynthesis is mediated by Ca2+, (ii) increased cAMP inhibits PGI2 production, and (iii) cAMP phosphodiesterase activity modulates PGI2-induced increases in the intracellular concentration of cAMP.
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PMID:Role of Ca2+ and cyclic AMP in the regulation of the production of prostacyclin by the vascular endothelium. 628 72

The effect of 3 prostaglandins (PG's) (I2, D2 and E1) on the adhesion of platelets to purified type III collagen has been investigated. A quantitative method for a specific evaluation of the adhesion has been applied and has revealed an inhibition of adhesion by low concentrations (10(-10)M) of PGs added before collagen; the effect varied as a function of the dose of PGs (maximum at 10(-6)M) which also induced an increase in the level of platelet cAMP. The inhibition of adhesion and the elevation of platelet cAMP followed the same time course and were either of short duration (rapid decrease in the induced effects after 15 and 45 seconds in the case of PGE1) or longer lasting (maximum effect maintained for 5 minutes in the case of PGI2 and D2). These effects were potentiated by a phosphodiesterase inhibitor such as theophylline (10(-3)M). The addition of PGs after collagen resulted in a reduction of the enhancement of cAMP, associated with a decrease in the inhibition of adhesion. Moreover, the addition of exogenous cAMP (dibutyryl N6-02' cAMP) induced a comparable inhibition. A correlation between the adhesion of platelets to collagen and the level of either endogenous or exogenous cAMP has been established. The PGs also inhibited the platelet release reaction from the alpha granules (beta TG) and the dense bodies. (5-HT and ADP). A greater inhibition of release than of adhesion was observed for the same doses of PGs added.
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PMID:Prostaglandins: specific inhibition of platelet adhesion to collagen and relationship with cAMP level. 628 36

Nafazatrom (Bay g 6575) was explored for its ability to inhibit platelet aggregation. In vitro, it had no effect on ADP, serotonin, epinephrine, or collagen induced platelet aggregation in platelet rich plasma of monkeys. On the other hand, in vivo it was a powerful inhibitor of ADP induced platelet aggregation as measured by the in vivo platelet aggregation recording instrument described previously (Ambrus et al., 1976). This effect was potentiated by dipyridamole. On the other hand, following parenteral administration of Bay g 6575, no ex vivo inhibition was noticed of ADP, serotonin, epinephrine, and collagen induced platelet aggregation. The hypothesis was presented that Bay g 6575 acts by increasing prostacyclin synthesis and/or release or interferes with its decomposition. This may explain in vivo activity; rapid decomposition may explain inability to demonstrate ex vivo activity. This also explains potentiation by the phosphodiesterase inhibitor dipyridamole. Bay g 6575 also was highly effective as a platelet aggregation inhibitor in monkeys after oral administration. In mice, Bay g 6575 increased circulation time of intravenously injected polyploid Ehrlich ascites tumor cells. In Furth-Wistar rats implanted with Furth-Columbia Wilms' tumor, in A/J mice implanted with C1300 neuroblastoma and in Wistar rats implanted with SMT-2A (Kim) breast cancer, Bay g 6575 significantly reduced spontaneous pulmonary metastasis. On the other hand, no effect was seen in the metastatic rate of NIH renal adenocarcinoma in BALB/cCr mice.
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PMID:Study of platelet aggregation in vivo. IX. Effect of nafazatrom on in vivo platelet aggregation and spontaneous tumor metastasis. 628 24

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

The new pyrimido-isoquinoline compound HL 725 is an extremely potent inhibitor of the aggregation of human platelets induced in vitro by ADP, collagen, thrombin and epinephrine. The aggregation induced by 0,5 mM arachidonic acid is inhibited about 50% with 50 pM HL 725. Thus the potency of HL 725 is higher than that of prostacyclin, the most active natural inhibitor of aggregation. We hypothesize that HL 725 inhibits the enzymatic degradation of cyclic adenosine 3', 5'-monophosphate (cAMP) in the platelets. In accordance with this proposal is the strong inhibitory action on cAMP phosphodiesterase extracted from human platelets. About 250 pM HL 725 inhibited 50% of the activity of this enzyme at a substrate concentration of 0.5 microM. A marked elevation of cAMP levels in human platelets could be demonstrated after incubation in vitro with 100 nM HL 725.
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PMID:HL 725, an extremely potent inhibitor of platelet phosphodiesterase and induced platelet aggregation in vitro. 629 26

A first level of pharmacological interference with platelet function is located at the site of the agonist-receptor interaction (receptors for collagen, adenosine diphosphate, serotonin, fibrinogen). A second level of interaction is to prevent the mobilization of intracellular calcium ions which can be obtained by inhibition of phosphodiesterase, activation of cAMP (e.g. with prostacyclin analogues), inhibition of thromboxane A2 formation or blocking of its receptors. Compounds preventing the platelet contractile process or platelet secretion could theoretically also prevent some platelet functions.
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PMID:A pharmacological approach to the inhibition of platelet adhesion and platelet aggregation. Wright-Schulte Lecture. 629 96

Antithrombotic activity and the mechanism of action of trapidil were investigated, as compared with those of aspirin and dipyridamole. Trapidil at oral doses of 30 and 100 mg/kg inhibited arterial thrombosis in rats, while aspirin and dipyridamole at doses up to 300 mg/kg showed only a mild activity. This action may be explained by the fact that trapidil at concentrations ranging from 139 microM to 251 microM exerted 50% inhibition of platelet aggregation induced by ADP, arachidonic acid, thrombin or thromboxane A2 mixture, inhibition of platelet release reaction induced by ADP, arachidonic acid or thrombin, disaggregatory effect on aggregated rabbit platelets by arachidonic acid and potentiating action on antiaggregatory action of prostacyclin in vitro. In vitro actions of trapidil were apparently different from those of aspirin and dipyridamole. Trapidil also showed inhibition of platelet phosphodiesterase activity and thromboxane synthetase activity. Trapidil was expected to be an effective antithrombotic agent. The antithrombotic action of trapidil may be mediated by the inhibition of platelet function which is characterized by the inhibition of both thromboxane synthetase and phosphodiesterase activities, and by the potentiation of the antiaggregatory action of prostacyclin.
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PMID:Antithrombotic activity and the mechanism of action of trapidil (Rocornal). 629 85


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