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)

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

The effects of dipyridamole on platelet aggregation ex vivo and in vitro and on platelet cyclic AMP phosphodiesterase (PDE) were studied, and the mechanism of the ex vivo effects was assessed. Both the ADP- and collagen-induced aggregations ex vivo were inhibited dose-responsively by oral administration of dipyridamole. Maximum dipyridamole levels in the plasma were reached at 30 min after the administration. The inhibitory effects of dipyridamole on platelet aggregation ex vivo reached a maximum at between 1 and 2 hrs. On the other hand, the ADP-induced aggregation in vitro and cyclic AMP PDE activity were not inhibited until after 10 min of incubation at a low concentration of dipyridamole. This mode of inhibition of platelet aggregation in vitro and of cyclic AMP PDE activity agreed with the mode of inhibition in the case of platelet aggregation ex vivo. It is suggested therefore that the ex vivo effects, observed with only a low dipyridamole concentration in the plasma, may be due primarily to inhibition by dipyridamole of the cyclic AMP PDE in platelets.
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PMID:Inhibitory mechanism of dipyridamole on platelet aggregation ex vivo. 629 Nov 92

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

Prostacyclin (PGI2), the major active metabolite of arachidonic acid in the vascular endothelium, is characterized by antiaggregatory and vasodilator properties. In this report, the significance of PGI2 and TxA2 on fetal platelets was studied. Platelet aggregation induced by ADP, collagen and adrenalin were found to be augmented in maternal blood but suppressed in umbilical cord blood. A much larger amount of PGI2-like substance was released from the umbilical cord artery and vein than from the intraplacental vein and chorionic tissue. On the other hand, the generation of this substance was reduced in the umbilical cord artery (4.4 +/- 2.7 nmoles/mg tissue/hour) and vein (2.9 +/- 2.1 nmoles/mg/tissue/hour) in patients with severe pre-eclampsia associated with IUGR. The plasma beta-thromboglobulin level is higher in maternal and umbilical cord blood, than in control group. Plasma 6-Keto-PGF1 alpha, TxB2, cyclic AMP and cyclic GMP values were significantly (p less than 0.05) higher in umbilical cord blood than in maternal blood, but serum phosphodiesterase activity showed no difference between mother and fetus. These results indicate that various factors, such as PGI2, TxA2 and cyclic nucleotides, may co-exist in high levels in the fetus, and the balance is needed for the maintenance of physical interaction between the platelet and vascular wall in the fetal blood vessels. PGI2 in particular may play an important role in this balance and in the regulation of placental-fetal circulation.
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PMID:[Metabolic significance of cyclic nucleotides in the environment for fetal growth--effects of PGI2-like substance on fetal platelet function]. 630 21

The short chemical half-life limits the potential therapeutic value of Prostacyclin (PGI2). Replacement of the acid-labile enolether structure of PGI2 by a beta-thia-imino group resulted in the orally active and chemically stable analogue Hoe 892. Incubation of rabbit platelet rich plasma with PGI2 and Hoe 892 caused a dose dependent inhibition of collagen and arachidonic acid (AA) induced platelet aggregation with ID50 of 4.2 and 20.1 ng/ml for PGI2 respectively 43.3 and 170.2 ng/ml for Hoe 892. These effects could be potentiated by the phosphodiesterase inhibitor theophylline. Single oral administration of Hoe 892 in conscious rabbits inhibited platelet aggregation for more than 3 hrs with an ID50 of 0.2 mg/kg using collagen and 1.5 mg/kg using AA. These doses were without influence on systemic blood pressure (BP) in conscious rabbits. Intravenous injection of Hoe 892 induced a dose dependent decrease of systemic BP in anesthetized rats (ED25 of 2.2 micrograms/kg) and in the rats with acute renal hypertension. Hoe 892 stimulated renin release in anesthetized rats. The hemodynamic profile in anesthetized dogs (0.5 micrograms/kg/min i.v.) was characterized by a decrease of systemic BP, left ventricular pressure, pulmonary artery pressure, total peripheral resistance and in increase in heart rate, cardiac output and dp/dt max, thus demonstrating arteriolar vasodilation. In conscious dogs with two kidney, two wrapped hypertension oral treatment for 1 or 5 days resulted in a marked reduction of BP.
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PMID:The orally active thia-imino-prostacyclin Hoe 892: antiaggregatory and cardiovascular activities. 640 94

The inhibitory effect of etafenone hydrochloride (etafenone) on platelet aggregation in rabbit platelet rich plasma and the involvement of the arachidonic acid (AA) cascade in the inhibitory mechanism for etafenone on platelet aggregation were studied. 1) Etafenone exhibited a dose-dependent inhibitory effect on collagen (15--20 micrograms/ml)-induced platelet aggregation, and its median inhibitory concentration (IC50) was 1.7 X 10(-5)M. 2) In ADP (20 microM)-induced aggregation, etafenone also exhibited a dose-dependent inhibitory effect, but its IC50 was 2.7 X 10(-4)M and was significantly higher than that in the case of collagen. 3) Etafenone inhibited AA (0.3--0.5mM)-induced platelet aggregation dose-dependently. Its IC50 was 2.8 X 10(-5)M. 4) In thromboxane (TX) A2-induced aggregation, etafenone exhibited a dose-dependent inhibition, and the IC50 was 3.2 X 10(-4)M. 5) Trapidil which was reported to inhibit platelet aggregation via phosphodiesterase (PDE) inhibition had a similar IC50 on ADP- and TXA2-induced platelet aggregation to that of etafenone, but in collagen- and AA-induced aggregation, its IC50 was higher than that of etafenone. 6) Etafenone (3 X 10(-6)--3 X 10(-4)M) dose-dependently inhibited the production of TXB2 in PRP induced by collagen. 7) Etafenone scarcely affected TXA2 synthetase activity in rabbit platelet homogenate. 8) The correlation between the inhibitory effect of etafenone on platelet aggregation and inhibition of AA metabolism activation and PDE inhibition was discussed.
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PMID:[Studies on the inhibitory effect of etafenone hydrochloride on platelet aggregation]. 661 41

Two SH-dependent proteinases (I and II) active in neutral media were isolated from bovine spleen and purified to apparent homogeneity. The histone-hydrolyzing activity of proteinase I was increased 3500-fold as compared to that of the original extract. Proteinase I hydrolyzed a variety of proteins (histones, azocasein, hemoglobin, collagen) but did not hydrolyze low molecular weight synthetic substrates, such as BAPA, BANA, BAEE, ATEE, Leu-beta-NA, Arg-beta-Na and Ala-beta-NA. The molecular weight of the enzyme as determined by SDS electrophoresis was found to be about 23,000. Isoelectrofocusing of the enzyme resulted in one major component with pI of 6.05 and in two minor components with pI of 6.2 and 6.4. Proteinase II hydrolyzed Leu-beta-NA, Arg-beta-NA and Ala-beta-NA but did not hydrolyze beta-naphthylamides of dicarboxylic acids and Gly-Phe-beta-Na. This proteinase split BANA and histone and very slowly split azocasein and collagen. Proteinase II was found to have a molecular weight of 30 000 and a pI of 6.8-6.9. Proteinase I inactivated fructose-1.6-diphosphate aldolase, partly inactivated glucose-6-phosphatase dehydrogenase and caused activation of phosphodiesterase of cyclic nucleotides. Proteinase II had no effect on the activity of the above enzymes. A comparison of proteinase I and II with enzymes described in literature demonstrated that the former was cathepsin L, while the latter was cathepsin H from spleen.
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PMID:[Characteristics of two thiol proteinases from spleen active in neutral media]. 675 12

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

Anti-aggregating activity of 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG 626) was tested using rabbit platelets in vitro. EG-626 alone, when added before, prevented platelet aggregation induced by ADP, as did PGI2, papaverine and dipyridamole. Spontaneous disaggregation was also accelerated when EG-626 was added after the maximal aggregation induced by ADP. EG-626 alone also inhibited platelet aggregation induced by collagen and arachidonic acid. ID50s of these agents in ADP-induced aggregation were 7-9 nM for PGI2, 223 microM for EG-626, 266 microM for papaverine and 957 microM for dipyridamole. When EG-626 was used in combination with PGI2, a threshold dose (50 microM) of EG-626 potentiated the antiaggregation effect of subthreshold dose (3 nM) of PGI2 upto 100% inhibition in collagen-induced platelet aggregation. The marked potentiating effect of EG-626 was accompanied by an accumulation of cyclic AMP in the platelets. These effects might be due to inhibition of phosphodiesterase. Papaverine and dipyridamole, other phosphodiesterase inhibitors, also potentiated the anti-aggregating activity of PGI2. The activity of papaverine, however, was one eighth of EG-626 and that of dipyridamole was much less. The most effective combination of PGI2 and EG-626 to induce 50% inhibition was obtained with 20% of ID50 of each agent, whereas that of PGI2 and papaverine or dipyridamole was 39 or 41%, respectively.
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PMID:Potentiation of anti-aggregating activity of PGI2 by 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG-626) in rabbit platelets in vitro. 699 30


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