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)

cGMP enhances cAMP accumulation in platelets via cGMP-inhibited phosphodiesterase (PDE3) [Maurice and Haslam (1990) Mol. Pharmacol. 37, 671-681]. However, cGMP might also limit cAMP accumulation by activating cGMP-stimulated phosphodiesterase (PDE2). We therefore evaluated the role of PDE2 in human platelets by using erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) to inhibit this enzyme selectively. IC50 values for the inhibition of platelet PDE2 by EHNA, with 10 microM cAMP as substrate in the absence and in the presence of 1 microM cGMP, were 15 and 3 microM respectively. Changes in platelet cyclic [3H]nucleotides were measured after prelabelling with [3H]adenine and [3H]guanine. Nitroprusside (NP) caused concentration-dependent increases in [3H]cGMP and a biphasic increase in [3H]cAMP, which was maximal at 10 microM (49+/-6%) and smaller at 100 microM (32+/-6%) (means+/-S.E.). In the presence of EHNA (20 microM), which had no effects alone, NP caused much larger increases in platelet [3H]cAMP (125+/-14% at 100 microM). EHNA also enhanced [3H]cGMP accumulation at high NP concentrations. In accord with these results, EHNA markedly potentiated the inhibition of thrombin-induced platelet aggregation by NP. The roles of cAMP and cGMP in this effect were investigated by using 2', 5'-dideoxyadenosine to inhibit adenylate cyclase. This compound decreased the accumulation of [3H]cAMP but not that of [3H]cGMP, and diminished the inhibition of platelet aggregation by NP with EHNA. We conclude that much of the effect of NP with EHNA is mediated by cAMP. Lixazinone (1 microM), a selective inhibitor of PDE3, increased platelet [3H]cAMP by 177+/-15%. This increase in [3H]cAMP was markedly inhibited by NP; EHNA blocked this effect of NP. Parallel studies showed that NP suppressed the inhibition of platelet aggregation by lixazinone. EHNA enhanced the large increases in [3H]cAMP seen with 20 nM prostacyclin (PGI2), but had no effect with 1 nM PGI2. NP and 1 nM PGI2 acted synergistically to increase [3H]cAMP, an effect attributable to the inhibition of PDE3 by cGMP; EHNA greatly potentiated this synergism. In contrast, NP decreased the [3H]cAMP accumulation seen with 20 nM PGI2, an effect that was blocked by EHNA. The results show that, provided that cGMP is present, PDE2 plays a major role in the hydrolysis of low cAMP concentrations and restricts any increases in cAMP concentration and decreases in platelet aggregation caused by the inhibition of PDE3. At high cAMP, PDE2 plays the major role in cAMP breakdown, whether cGMP is present or not.
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PMID:Activation of cGMP-stimulated phosphodiesterase by nitroprusside limits cAMP accumulation in human platelets: effects on platelet aggregation. 916 26

Several 6-aryl-5-oxygenated substituted pyridazinones have been synthesized and evaluated in vitro for inhibition of platelet aggregation induced by adenosine 5'-diphosphate (ADP), thrombin and collagen. All the tested compounds (except 8 and 9) inhibited platelet aggregation in a dose-dependent manner. The IC50 of the most active substance, compound 2b, was around 60 microM against ADP and collagen as inducers. The inhibition of platelet aggregation caused by test compounds was dependent on the level of oxidation of the function at the 5-position, with the order of IC50 values being R-OH (2a, b, 5) < R-CHO (6, 7) < < R-COOH (8, 9). None of the tested compounds increased the intracellular levels of cAMP, indicating a lack of inhibitory activity on cAMP phosphodiesterase (PDE III) in intact cells. These results suggest that the group present at the 5 position of 6-aryl-5-substituted pyridazinones determines the platelet aggregation-inhibitory activity, and that a mechanism other than PDE inhibition is responsible for this effect.
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PMID:Pyridazines. XIII. Synthesis of 6-aryl-5-oxygenated substituted-3(2H)-pyridazinones and evaluation as platelet aggregation inhibitors. 924 48

Duvernoy's secretion from representatives of the colubrid genus Boiga has been shown by other workers: (1) to contain an alpha-bungarotoxin-like component (Blanding's tree snake, Boiga blandingi); (2) to exhibit acetylcholine receptor binding activity (the brown tree snake, Boiga irregularis); and (3) to react strongly (B. blandingi and the mangrove snake, Boiga dendrophila) with antisera raised against elapid venoms. The present study provides the first evidence for the presence of acetylcholinesterase, a common elapid enzyme, in the Duvernoy's secretion of B. dendrophila and B. blandingi at levels of 122 +/- 7 and 0.36 +/- 0.02 International Enzyme Units, respectively. Constants for inhibition by eserine were 1.25 x 10(-7) M and 2.79 x 10(-7) M, respectively. The Duvernoy's secretion of B. dendrophila exhibited significant phospholipase and haemolytic activities, whereas phosphodiesterase was only weakly present and no thrombin-like activity was observed.
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PMID:Enzymatic properties of the Duvernoy's secretion of Blanding's tree snake (Boiga blandingi) and of the mangrove snake (Boiga dendrophila). 924 13

The effect on human platelets of 2-(1-piperazinyl)-4H-pyrido[1,2-a]pyrimi din-4-one (AP155) was tested in vitro by measuring cyclic adenosine monophosphate (cAMP) level, cytosolic Ca++, [(125I)]fibrinogen binding as well as aggregation induced by several agonists. AP155 dose-dependently inhibited aggregation both in platelet rich plasma (PRP) and in washed platelets (WP), exerting its maximal power in the presence of collagen, ADP and platelet activating factor (PAF). It specifically inhibited the activity of cAMP high affinity phosphodiesterase (PDE), resulting in a sufficient increase in cAMP levels to activate cAMP-dependent protein kinase. AP155 was able to inhibit aggregation, the increase in cytosolic Ca++ induced by thrombin, and fibrinogen binding to ADP or thrombin-stimulated platelets. Thus, this new pyridopyrimidine derivative exerts its antiplatelet activity by increasing cAMP intracellular concentration.
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PMID:Effect of 2-(1-piperazinyl)-4H-pyrido[1,2-a]pyrimidin-4-one (AP155) on human platelets in vitro. 926 19

In the present study the "in vitro" influence of 3-(1-piperazinyl)-1H-pyrimido[1,2-a]quinolin-1-one (AQ11) and 2-(piperazinyl)-4H-pyrimido[2,1-a]isoquinolin-4-one (IQ3b) on human platelet aggregation, cAMP elevation, cytosolic calcium and fibrinogen binding has been investigated. Both drugs inhibited platelet aggregation in a concentration-dependent manner. In PRP AQ11 was slightly more active than IQ3b when aggregation was induced by ADP, collagen, A23187 or PMA, whereas in washed platelets challenged by thrombin, IQ3b was more effective than AQ11. Both compounds produced increase in cAMP intracellular level being the effect potentiated by the adenylate cyclase activator iloprost and IQ3b was more powerful than AQ11. Moreover IQ3b was more effective in inhibiting cAMP in high affinity phosphodiesterase (IC50 values: IQ3b 11 +/- 5 microM; AQ11 43 +/- 8 microM) and calcium elevation (IC50 values: IQ3b 9 +/- 4 microM; AQ11 32 +/- 6 microM). These compounds also inhibited fibrinogen binding in platelets challenged by ADP or thrombin. The results suggest that these new potent agents inhibit platelet phosphodiesterase activity causing an elevation in cAMP levels sufficient to inhibit calcium rise and fibrinogen binding. This mechanism can be responsible for the ability of the compounds to prevent platelet aggregation.
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PMID:Mechanism of action of two new pyrimidoquinoline and isoquinoline derivatives in human platelets. 930 22

The effect of PCA-4230, a new dihydropyridine derivative with a potent antithrombotic activity, on cyclic nucleotide phosphodiesterase in platelets was studied. PCA-4230 inhibited (54%) cyclic GMP hydrolytic activity of a platelet cytosolic fraction, whereas it did not affect that of cyclic AMP. Results suggested that PCA-4230 inhibited a cyclic GMP-dependent phosphodiesterase, known as cGB PDE or type V, on a purified enzyme from rabbit platelets by a non-competitive-uncompetitive type inhibition. In addition, PCA-4230 potentiated the increase in both cyclic GMP and cyclic AMP levels evoked by sodium nitroprusside. Furthermore, PCA-4230 and forskolin caused a synergistic effect in cyclic AMP, and also potentiated the phosphorylation of 50 kDa and 22 kDa proteins, reported as substrates of cyclic GMP- and cyclic AMP-dependent protein kinases that are related to the inhibition of platelet functions. Finally, PCA-4230 also potentiated the forskolin- and sodium nitroprusside-inhibited serotonin release evoked by thrombin, probably related to the increased cyclic nucleotide level.
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PMID:Involvement of cyclic GMP in the mode of action of a new antithrombotic agent PCA-4230; inhibition of the platelet cyclic GMP dependent phosphodiesterase. 933 Apr 37

Endothelial cell contraction plays a pivotal role in vascular leakage. It increases the extravasation of fluid and macromolecules from the lumen into the interstitium. This is also true for bronchial edema. Previous studies have indicated that an elevation of intracellular adenosine-3',5'-cyclic monophosphate (cAMP) or guanosine-3',5'-cyclic monophosphate (cGMP), respectively, can counteract this vascular leakage by improving the endothelial barrier function in analogy to the relaxation of smooth muscle cells. To investigate the potential antiedemateous effects of ularitide acetate (CAS 115966-23-9), isoproterenol hemisulfate (CAS 6078-56-4), sodium nitroprusside (CAS 13755-38-9, SNP), aminophylline (CAS 317-34-0), and combinations of these compounds, their effects on thrombin-induced macromolecular permeability raise in relation to cGMP- or cAMP-levels, respectively, in a model of human umbilical vein endothelial cells (HUVECs) were examined. Ularitide acetate, isoproterenol hemisulfate, and SNP all increased the amount of cyclic nucleotides and decreased the raise in permeability in the following order of potency: isoproterenol hemisulfate > ularitide acetate > SNP. Aminophylline raised both cGMP- and cAMP-levels in a weaker amount and was not able to decrease the thrombin-induced permeability raise on its own. By way of contrast, preincubation of HUVECs with aminophylline resulted in a more than additive potentiation of the cGMP-levels and the permeability lowering induced by ularitide-acetate. These in vitro-data indicate that ularitide-acetate, especially in combination with phosphodiesterase (PDE) inhibitors, could probably have beneficial effects in bronchial permeability edema.
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PMID:Comparison of the effects of ularitide acetate and other bronchorelaxing substances on the thrombin-induced permeability raise of human endothelial cell monolayers. 955 82

The effect of compounds increasing intracellular adenosine 3':5'-cyclic monophosphate [cAMP]i levels (prostacyclin, isoproterenol, forskolin, cholera toxin), and of the cAMP analogs 8-bromo-cAMP and dibutyryl-cAMP, on the regulated secretion (acute release) of tissue-type plasminogen activator (tPA) and von Willebrand factor (vWF) was studied in cultured human umbilical vein endothelial cells (HUVEC). Prostacyclin, isoproterenol and forskolin, which increased [cAMP]i in HUVEC, and the cell-permeant cAMP analog 8-bromo-cAMP induced dose- and time-dependent secretion of tPA and vWF. The extent of vWF and tPA release correlated with [cAMP]i, and was increased by the phosphodiesterase inhibitor isobutylmethylxanthine. In contrast to thrombin, the cAMP-elevating agents did not increase the intracellular calcium concentration [Ca2+]i in HUVEC. At submaximal concentrations, the effects of thrombin and prostacyclin were additive. Our results show that an increase in [cAMP]i resulted in regulated secretion (acute release) of tPA and vWF from HUVEC, without the concomitant increase in [Ca2+]i which is, in HUVEC, essential for thrombin-induced regulated secretion to occur. cAMP-induced secretion represents a novel mechanism for causing regulated secretion of tPA and vWF from endothelial cells.
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PMID:Adenosine 3':5'-cyclic monophosphate induces regulated secretion of tissue-type plasminogen activator and von Willebrand factor from cultured human endothelial cells. 956 4

The antiplatelet activity of (6-[(3-methylene-2-oxo-5-phenyl-5-tetrahydrofuranyl)methoxy]quinol inone) (CCT-62) was determined in vitro in rabbit platelets. CCT-62 inhibited rabbit platelet aggregation and ATP release caused by thrombin (0.1 U/ml), platelet-activating factor (2 ng/ml), collagen (10 microg/ml), arachidonic acid (100 microM), and 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha (1 microM) in a concentration-dependent manner. The IC50 values for platelet aggregation were 18.4 +/- 4.5, 10.1 +/- 1.6, 3.0 +/- 0.9, 1.5 +/- 0.3 and 1.0 +/- 0.3 microM, respectively. In addition, CCT-62 disaggregated the clumped platelets caused by these aggregation inducers. It also inhibited phosphoinositide breakdown and intracellular calcium elevation induced by the above platelet aggregation inducers. CCT-62 increased intracellular cyclic AMP and cyclic GMP levels in a concentration- and time-dependent manner. Furthermore, it potentiated cyclic AMP formation caused by prostaglandin E1 but not that caused by 3-isobutyl-1-methylxanthine. CCT-62 did not affect adenylate or guanylate cyclase but inhibited cyclic AMP- and cyclic GMP-phosphodiesterase activities. The antiplatelet effect of CCT-62 was reversed by a protein kinase A inhibitor, N-[2-(P-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89). This data clearly indicated that CCT-62 is an inhibitor of phosphodiesterases and that its antiplatelet effect is mainly mediated by elevation of cyclic AMP levels.
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PMID:Cyclic AMP and cyclic GMP phosphodiesterase inhibition by an antiplatelet agent, 6-[(3-methylene-2-oxo-5-phenyl-5-tetrahydrofuranyl)methoxy)quinol inone (CCT-62). 966 3

Platelet inhibition significantly reduces the risk of cardiovascular mortality and morbidity. However, current antiplatelet therapies have limitations, and more efficacious agents are needed. E5510 is a novel compound that has multiple platelet inhibitory effects in in vitro studies. We compared the in vivo, pharmacodynamic effects of maximal antiplatelet doses of E5510 (20 mg) with 300 mg aspirin in a placebo-controlled, triple crossover trial in nine healthy volunteers. Collagen-induced platelet aggregation and serum thromboxane B2 (TxB2) were similarly inhibited by both compounds in the first 12 h but showed recovery at 24 h in the E5510 group only (p < 0.05). Thrombin and U46619-induced platelet aggregation, as well as basal and prostaglandin E2 (PGE2)-stimulated platelet cyclic adenosine monophosphate (cAMP) levels were unchanged after ingestion of either agent. E5510 and aspirin reduced systemic thromboxane formation without affecting prostacyclin biosynthesis. Neither E5510 nor aspirin inhibited the excretion of 8-epi PGF2alpha and 5,6-DHET, two indices of cyclooxygenase-independent arachidonate metabolism. In conclusion, (a) E55 10 in vivo most likely induces a reversible inhibition of cyclooxygenase, without affecting thromboxane synthetase, phosphodiesterase, thrombin, or thromboxane receptor-mediated signaling; (b) single doses of aspirin or E5510 affect thromboxane/prostacyclin profiles favorably, supporting their use in acute coronary syndromes. This study outlines a comprehensive and minimally invasive approach for the assessment of the in vivo mechanism of action of novel antiplatelet agents.
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PMID:A randomized, placebo-controlled, crossover study of E5510 and aspirin in healthy volunteers. 989 Mar 91


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