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:3.5.4.17 (adenosine deaminase)
5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Although secretin and vasoactive intestinal peptide (VIP) stimulate production of the second-messenger substance cyclic AMP and exert a positive inotropic action on rat ventricle in vitro, a direct action of these peptides on cardiomyocytes has not been established. In contrast to hearts of other mammalian species, which possess VIP-preferring receptors, rat heart is unique in that the existence of a "relatively nonselective receptor" at which both secretin and VIP may bind has been proposed. We wished to define the receptor(s) for secretin and VIP present on rat ventricular cardiomyocytes using a homogeneous suspension of viable cells. With adenosine deaminase 5 U/ml and the phosphodiesterase (PDE) inhibitor isobutyl methylxanthine (IBMX) 1 mM, both secretin and VIP increased intracellular levels of cyclic AMP maximally and concentration dependently after 5 min: EC50 values were 8 and 58 nM, respectively. At maximally effective concentrations, secretin 1 microM increased intracellular levels of cyclic AMP fourfold above basal levels, whereas a 1.6-fold increase was induced by VIP 10 microM. Maximum changes in cell length (dL) of isolated cardiomyocytes during electrically stimulated (0.5 Hz) contractions were determined in the presence of adenosine deaminase 2.5 U/ml. Under these conditions, both secretin and VIP produced a concentration-dependent positive contractile response that became maximal 5 min after addition of the peptide. Secretin 50 nM increased the amplitude of cellular contractions maximally to a value 37% greater than that obtained without peptide. VIP 20 nM increased the amplitude of cellular contractions maximally to a value 19% greater than that obtained without peptide. The EC50 values were 470 and 700 pM for VIP and secretin, respectively. The selective antagonist at VIP-preferring receptors, 4-Cl DPhe-6 Leu-17 VIP 10 microM did not antagonise the actions of VIP. In the presence of the selective antagonist at receptors for secretin, secretin 7-27 > or = 10 microM, the concentration dependence of the effect of secretin on accumulation of cellular cyclic AMP and contractile amplitude displayed a rightward parallel shift: the pA2 value for secretin 7-27 was 4.96. Secretin 7-27 also induced a rightward parallel shift of the concentration dependence of the actions of VIP. VIP 10 microM was additive with low concentrations of secretin (< 10 nM) in stimulating production of cyclic AMP but antagonised this response at higher concentrations of secretin (> 10 nM). Similarly, VIP 2 and 20 nM enhanced the contractile response to low concentrations of secretin (< 1 nM), but antagonised the response at higher concentrations of secretin (> 1 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Secretin and vasoactive intestinal peptide are potent stimulants of cellular contraction and accumulation of cyclic AMP in rat ventricular cardiomyocytes. 752 89

Recently, an inhibitor of adenosine deaminase, erythro-9-(2-hydroxyl-3-nonyl)adenine (EHNA), was shown to selectively block the activity of purified cGMP-stimulated phosphodiesterase (PDE) (cGS-PDE, or PDE2) in human and porcine heart [J. Mol. Cell. Cardiol. 24 (Suppl. V):102 (1992)]. Because cGS-PDE was found to mediate the cGMP-induced inhibition of L-type Ca2+ current (Ica) in frog ventricular cells, we tested the effects of EHNA in this preparation. Ica was measured using the whole-cell patch-clamp technique and a perfusing pipette. EHNA (0.3-30 microM) had no significant effect on either basal Ica or isoprenaline (1 nM)- or cAMP (10 microM)-elevated Ica. However, EHNA dose-dependently (IC50 approximately 3 microM) reversed the inhibitory effect of cGMP on cAMP-stimulated Ica. EHNA (30 microM) also blocked the inhibitory effect of NO donors, such as sodium nitroprusside (1 mM) and 3-morpholinosydnonimine (30 microM), on isoprenaline-stimulated Ica. In addition, EHNA dose-dependently (IC50 approximately 4-5 microM) inhibited the cGMP-induced stimulation of PDE activity in frog ventricle particulate fraction, as well as purified soluble cGS-PDE. However, EHNA (up to 30 microM) did not modify the activities of three other purified soluble PDE isoforms. Moreover, EHNA did not change the Ka (40 nM) for cGMP activation of cGS-PDE, which suggests that EHNA does not inhibit cGS-PDE by displacing cGMP from the allosteric regulator site. Because adenosine did not mimic the effects of EHNA on Ica or PDE activity, it is unlikely that the effects of EHNA are due to adenosine deaminase inhibition. We conclude that EHNA acts primarily to inhibit cGS-PDE in intact cardiac myocytes. This compound should be useful in evaluating the physiological role of cGS-PDE in various tissues.
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PMID:Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic GMP-stimulated phosphodiesterase in isolated cardiac myocytes. 762 66


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