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)

EG626 (oxagrelate), a specific inhibitor of cyclic AMP phosphodiesterase, produced in vitro a concentration-dependent inhibition of platelet aggregation induced by collagen and ADP in human platelets. When adenosine was added to the platelet rich plasma (PRP) in the presence of a threshold concentration of EG626, the potency of adenosine in inhibiting platelet aggregation was markedly potentiated. This potentiating effect of EG626 proved to be synergistic, but not additive and was accompanied by a marked accumulation of cyclic AMP in the platelets. The antiaggregating and cyclic AMP increasing activities of adenosine were little affected by S-(p-nitrobenzyl)-6-thioguanosine (6TG), an uptake inhibitor of adenosine, or 2'-deoxycoformycin, an inhibitor of adenosine deaminase. The incorporation of adenosine into platelets was abolished by 6TG. These observations indicate that incorporation of adenosine into platelets is not required for inhibition of aggregation or an increase in cyclic AMP and that the site of action of adenosine is probably extracellular. It also appears that the synergistic action by EG626 is not the result of an inhibition of adenosine uptake and/or adenosine deaminase. This speculation is supported in part by the finding that EG626 also potentiates the antiaggregating activity of 2-chloroadenosine. Antiaggregating activity of prostaglandin E1, an activator of adenylate cyclase, was markedly potentiated in combination with EG626. Dibutyryl cyclic AMP showed a time-dependent inhibition of the platelet aggregation, and the inhibitory action was markedly potentiated by EG626. Qualitatively similar results were obtained with another phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). All these data suggest that the synergistic potentiation of the antiaggregating activity of adenosine by EG626 might be due to the synergistic accumulation of cyclic AMP in the platelets. This action is mediated through activation of adenylate cyclase by adenosine in combination with the inhibition of cyclic AMP phosphodiesterase by EG626.
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PMID:Potentiation of antiaggregating activity of adenosine by a phosphodiesterase inhibitor, EG626 (oxagrelate), in human platelets in vitro. 620 94

Previous work in our laboratory led us to postulate that N2a cells release adenosine into growth medium, where it acts at the extracellular adenosine receptors to modulate the sensitivity of the cells to the cyclic AMP-elevating effect of adenosine [Green, RD, J Pharmacol Exp Ther 201:610, 1977]. We have now devised a high-performance liquid chromatographic (HPLC) procedure capable of quantitating the concentrations of adenosine in cells and tissue culture media. Growth media of N2a cells and a variant of N2a cells deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRT-) contain 10-20 nM adenosine, while that of a variant deficient in adenosine kinase (AK-) is elevated severalfold. It appears that the concentration of adenosine in growth media is determined by both the rate at which it is released by cells into the medium and the rate at which it is metabolized by adenosine deaminase present in the serum in the growth medium. Both N2a and AK- cells release considerable amounts of adenosine into serum-free medium (SFM) over a short period. Adenosine release is greater from AK- cells and is accelerated by erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), a potent adenosine deaminase inhibitor. This accelerated release is retarded by dipyridamole and homocysteine. Surprisingly, dipyridamole and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20 1724), a potent phosphodiesterase inhibitor, stimulate basal adenosine release from N2a but not from AK- cells. It remains to be determined if this is due to an effect of these compounds on adenosine kinase. These results give further support for the hypothesis that adenosine in growth medium modulates the sensitivity of the cells to the cyclic AMP-elevating affect of adenosine, and furthermore they suggest that adenosine in growth media may tonically stimulate adenylate cyclase and affect processes controlled by the cyclic AMP:cyclic AMP-dependent protein kinase system.
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PMID:Release of adenosine by C1300 neuroblastoma cells in tissue culture. 626 30

Several 2- or/and 8-substituted adenosine derivatives were tested for their ability to inhibit the adenosine deaminase activity in hog heart and Ca++, calmodulin-dependent phosphodiesterase activity in hog brain. Among these derivatives, 2-piperidyladenosine competitively inhibited not only the adenosine deaminase activity but also the phosphodiesterase activity. Further substitution of this compound with a bulky group at 8-position, 2-piperidyl-8-(8-aminooctylamino)-adenosine, abolished its ability to inhibit the adenosine deaminase activity, but progressively increased in the ability to inhibit the phosphodiasterase activity. On the other hand, 8-monosubstituted adenosine derivatives did not inhibit the adenosine deaminase activity.
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PMID:Inhibition by 2- or/and 8-substituted adenosine derivatives of adenosine deaminase and calmodulin-dependent phosphodiesterase. 626 79

1. Hydrolyzing activities on cAMP were investigated in E. coli B cells incubated in the presence or absence of 10(-5) M spermine, spermidine or putrescine. 2. Bacterial cells incubated in the presence of each of the investigated polyamines show an increase in the PDE (phosphodiesterase) activities already evident after 3 min of incubation, reaching the maximum between 5 and 10 min. disappearing between 15 and 25 min. 3. The stimulating effect is higher in the presence of lower (10(-6) M) substrate concentration (high affinity PDE activities). 4. Kinetic analyses carried out for the "high affinity" PDE activity, indicate that spermidine and putrescine are the most effective on increasing both the Vmax or the apparent Km. 5. Kinetic analysis carried out for the "low affinity" PDE activity, indicate that putrescine is the most active on increasing either the Vmax or the apparent Km and that spermine and spermidine have both quantitatively and qualitatively comparable effects. 6. Analyses, by TLC, of the products of the hydrolytic activities on cyclic AMP (5'-adenosine monophosphate (5'-AMP), adenosine, inosine) indicate that the incubation in the presence of each of three polyamines, results in an increase also of the 5' nucleotidase and adenosine deaminase activity.
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PMID:Hydrolyzing activities on cAMP in E. coli B cells incubated in the presence of polyamines. 627 51

The effects of S-adenosylhomocysteine and S-adenosylmethionine on some purine- and pyrimidine-metabolizing systems have been examined. Both compounds were capable of acting as relatively good inhibitors of adenosine deaminase, nucleoside phosphorylase, and adenylate deaminase activities but as relatively poor inhibitors of myokinase and nucleoside monophosphate kinase. The inhibitory effects were freely reversible. 5'-Nucleotidase, orotidine 5'- phosphate, and phosphodiesterase were unaffected. Nucleoside phosphorylase was competitively inhibited by both compounds, whereas mixed inhibitory effects occurred with adenosine deaminase.
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PMID:The effects of S-adenosylhomocysteine and S-adenosylmethionine on some purine- and pyrimidine-metabolizing systems. 629 1

The adenosine deaminase (ADA) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), at low concentrations (less than 10 microM), enhances the inhibitory activity of adenosine against lymphocyte-mediated cytolysis (LMC) without itself being inhibitory. At higher concentrations, EHNA alone is inhibitory to LMC with an IC50 of 160 microM. This inhibition is reversible upon washout, appears to affect an early stage of the lytic process, and does not appear to involve changes in basal levels of cyclic AMP (cAMP), ribonucleoside 5'-triphosphate pool sizes, S-adenosylhomocysteine levels, or protein carboxymethylation. EHNA does enhance the cAMP response of cytolytic lymphocytes (CL) to activators of adenylate cyclase such as prostaglandin E1. EHNA inhibits lymphocyte high-affinity cAMP phosphodiesterase at immunosuppressive levels, exhibiting hyperbolic mixed-type inhibition (Ki = 83 microM, alpha = 0.47, beta = 0.18). Whereas inhibition of intralymphocytic ADA is complete at low concentrations (less than 25 microM) of EHNA, inhibition of LMC and intralymphocytic cAMP phosphodiesterase increases linearly with EHNA concentration to at least 200 microM. The presence of 200 microM EHNA during the centrifugation of mixtures of CL and EL4 leukemia target cells leads to increased CL cAMP levels. 2'-Deoxycoformycin, a more potent ADA inhibitor than EHNA, is not inhibitory to LMC and shows none of these cAMP-related effects. These results suggest that CL-target cell contact stimulates adenylate cyclase in the CL and that EHNA inhibits LMC due to its enhancement of this target cell-stimulated elevation of cAMP.
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PMID:Inhibition of lymphocyte-mediated cytolysis and cyclic AMP phosphodiesterase by erythro-9-(2-hydroxy-3-nonyl)adenine. 629 34

The present study was designed to clarify the reason why rat platelets obtained from arterial blood show a less marked aggregation than those obtained from venous blood, and to investigate the contribution of the vessel wall to this phenomenon. Incubation of arterial or venous platelet-rich plasma (PRP) with papaverine, a phosphodiesterase blocker, resulted in a more marked inhibition of the aggregation parameters for arterial than for venous PRP, indicating that a cAMP-dependent mechanism is involved. Incubation of PRP in vitro with adenosine deaminase did not significantly modify aggregation. Rats treated in vivo with different doses of acetylsalicylic acid or of tranylcypromine, two cyclo-oxygenase inhibitors, abolished the aggregation differences between arterial and venous PRP. It is suggested that this difference in platelet behavior may be due to a mechanism dependent on a PGI2-like, probably cAMP-related activity in which the heart and/or the lungs may play an important role.
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PMID:What's provoking different aggregation between arterial and venous platelets in the rat? 644 10

Methylxanthines, such as caffeine and theophylline, potentiate the rotation behaviour induced by dopamine receptor agonists in rats with unilateral lesions of the nigro-striatal pathway. In the present study we have examined the possibility that interaction with central adenosine mechanisms could influence rotation behaviour. Under in vitro conditions adenosine and N6-phenylisopropyl-adenosine (PIA) stimulate cyclic AMP accumulation. This effect was enhanced by the phosphodiesterase inhibitor rolipram, but blocked by alkylxanthines such as caffeine, theophylline and, particularly, 8-phenyl-theophylline. Rotation behaviour induced by apomorphine (0.05 mg/kg), was inhibited by PIA and rolipram and by a low dose of the adenosine deaminase inhibitor EHNA (2 mg/kg). By contrast, theophylline and 8-phenyl-theophylline caused a potentiation. The former drug stimulated rotation behaviour per se, while the latter did not. 8-Phenyl-theophylline entered the brain poorly and its concentration in brain it was less than 1/10 of theophylline. It is concluded that theophylline does not potentiate rotation behaviour secondarily to inhibition of phosphodiesterase. Antagonism of endogenous adenosine may partly explain the effect of methylxanthines. Possibly, some as yet unknown mechanism may also contribute to the effects of xanthine-derivatives on rotation behaviour.
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PMID:On the mechanism by which methylxanthines enhance apomorphine-induced rotation behaviour in the rat. 663 4

Eight 5'-(steroid-21-phosphoryl)-9-(beta-D-arabinofuranosyl)-adenines (IV-XI) have been prepared and evaluated against L1210 lymphoid leukemia in culture. These include the 9-(beta-D-arabinofuranosyl)adenine conjugates of hydrocortisone (IV), cortisone (V), corticosterone (VI), cortexolone (VII), 11-deoxycorticosterone (VIII), prednisolone (IX), prednisone (X), and dexamethasone (XI). Conjugates IV, IX, X, and XI inhibited the in vitro growth of L1210 lymphoid leukemia cells by 50% (ED50) at a concentration of 2.3-7.8 microM, while 9-(beta-D-arabinofuranosyl)adenine (vidarabine, I) and its 5'-monophosphate (II) each showed ED50 value of 30 microM. All of the conjugates were enzymatically hydrolyzed to the corresponding steroid and II, the latter undergoing further hydrolysis to I, by phosphodiesterase I, 5'-nucleotidase, and acid phosphatase. However, these conjugates were resistant to hydrolysis by alkaline phosphatase and adenosine deaminase.
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PMID:Nucleoside conjugates V: Synthesis and biological activity of 9-(beta-D-arabinofuranosyl)adenine conjugates of corticosteroids. 670 3

The pharmacology and cellular mechanism by which metabotropic glutamate receptor (mGluR) activation modulates cAMP formation was studied in cross-chopped hippocampal slices from neonatal (7 day old) rats. The selective mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), and other non-selective mGluR agonists produced concentration-related stimulation of basal cAMP formation in this tissue. The relative agonist potency order was 1S,3R-ACPD = quisqualate > ibotenate >> 1R,3S-ACPD. 1S,3R-ACPD stimulated cAMP accumulation was antagonized in a stereoselective manner by L-2-amino-3-phosphonopropionate (L-AP3), but not by higher chain homologues such as L-2-amino-4-phosphonobutyrate (L-AP4) and 2-amino-5-phosphonopentanoate (AP5). 1S,3R-ACPD-enhanced cAMP formation was greatly inhibited by incubation with adenosine deaminase. In the adult rat hippocampus, 1S,3R-ACPD did not appreciably increase basal cAMP, but inhibited forskolin-stimulated cAMP formation, and this effect was observed with or without adenosine deaminase. In the presence of the adenosine receptor antagonist and cAMP phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX), 1S,3R-ACPD did not enhance cAMP formation in the neonatal hippocampus, but inhibited forskolin-stimulated cAMP (like in the adult tissue). These results demonstrate that mGluRs that increase cAMP in the neonatal hippocampus have a unique pharmacology when compared to mGluRs that decrease cAMP accumulation and increase phosphoinositide hydrolysis. 1S,3R-ACPD stimulation of cAMP in the neonatal rat hippocampal slice involves potentiation of responses to endogenous adenosine. Negatively coupled cAMP linked mGluRs are also present in the neonatal tissue, but are masked by the predominance of the positively coupled mGluR cAMP response.
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PMID:Metabotropic glutamate receptor modulation of cAMP accumulation in the neonatal rat hippocampus. 751 34


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