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)

The effect of forskolin (FSK) on [3H]-acetylcholine release ([3H]-ACh) from the phrenic motor nerve terminals, and its modification by adenosine deaminase (ADA), by the A2-adenosine receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamide adenosine (CGS 21680C), by the A1-adenosine receptor agonist R-N6-phenylisopropyl adenosine (R-PIA), by the A2-antagonist N-(2-(dimethylamino)-ethyl)-N-methyl-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3 -dipropyl-1H-purine-8-yl)-benzene sulphonamide (PD 115,199), and by the A1-antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) were studied on the rat phrenic-hemidiaphragm preparation. It is concluded that the excitatory effect of FSK on evoked [3H]-ACh release depends on tonic A2-adenosine receptor activation.
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PMID:Facilitation of [3H]-ACh release by forskolin depends on A2-adenosine receptor activation. 846 31

In the present study the effect of adenosine and adenosine analogues on rabbit isolated cavernosal smooth muscle has been evaluated in comparison with the effect of acetylcholine and electrical field stimulation. In the presence of guanethidine and indomethacin, acetylcholine and electrical field stimulation relaxed the rabbit corpus cavernosum, which was precontracted with phenylephrine. The nitric oxide synthesis inhibitor, N omega-nitro-L-arginine-methylester (L-NAME), greatly reduced the relaxation induced by electrical stimulation and completely abolished the relaxant effect of acetylcholine. A concentration-dependent relaxation of the rabbit corpus cavernosum was produced by adenosine; this effect was not modified by L-NAME, but was reduced by adenosine deaminase. On the other hand, the adenosine-induced relaxation was potentiated by the inhibitor of adenosine deaminase, erythro-9-(2-hydroxy-3-nonyl)adenine and by the adenosine uptake inhibitor dipyridamole. Moreover, the effect of adenosine was antagonized by the unspecific adenosine receptor antagonist 8-phenyltheophylline. The receptor subtypes involved in cavernosal relaxation were characterized by using selective receptor antagonists: 1,3-dipropyl-8-cyclopentylxanthine, a blocker of A, receptors, did not modify adenosine-induced relaxation. This effect was, however, antagonized by the A2-receptor antagonist CGS15943. A relaxant effect was also obtained with nanomolar concentrations of two synthetic adenosine analogues, the preferential A2 receptor agonist 5'-N-ethylcarboxamidoadenosine and the A2a selective agonist CGS21680. These results demonstrated that adenosine has potent relaxant activity on the corpus cavernosum, acting through a mechanism different from the nitric oxide pathway, and that receptors involved in the effect of adenosine belong to the A2a subtype.
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PMID:The potent relaxant effect of adenosine in rabbit corpora cavernosa is nitric oxide independent and mediated by A2 receptors. 853 48

We hypothesized that adenosine, known to be release from inflammatory sites, could lessen the potentially damaging activity of neutrophils (PMN) primed by tumor necrosis factor-alpha (TNF alpha) at sites of infection. We investigated the effect of adenosine on PMN primed with cell-free medium from mononuclear leukocytes (MNL) that had been treated with lipopolysaccharide (LPS) yielding a conditioned medium rich in TNF alpha and on PMN primed with recombinant human TNF alpha (rhTNF alpha). LPS (10 ng/mL) minimally primed PMN, but LPS-MNL-conditioned medium increased PMN chemiluminescence in response to f-Met-Leu-Phe (fMLP) 1242% compared with unprimed PMN. LPS-MNL-conditioned medium contained adenosine (approximately 30 nM). Converting the adenosine in the LPS-MNL-conditioned medium to inosine with adenosine deaminase (ADA) or blocking adenosine binding to PMN with the adenosine receptor antagonist 1,3-dipropyl-8-(phenyl-p-acrylate)-xanthine (BW A1433U) resulted in a near doubling of chemiluminescence. The LPS-MNL-conditioned medium contained TNF alpha (836 pg/mL; approximately 1 U/mL). Recombinant human TNF alpha (1 U/mL) primed PMN for a 1033% increase in chemiluminescence. Added adenosine decreased rhTNF alpha-primed PMN chemiluminescence (IC50 approximately 100 nM), and adenosine (100 nM) decreased both superoxide and myeloperoxidase release from rhTNF alpha-primed fMLP-stimulated PMN. The activity of adenosine was counteracted by ADA and BW A1433U, and the modulating effect of adenosine was on the primed response rather than on priming per se. Thus, physiological concentrations of adenosine reduce the effects of recombinant human TNF alpha and native human TNF alpha (released from LPS-treated MNL) on PMN activity. Endogenous adenosine may preclude or minimize damage to infected tissue by damping the TNF alpha-primed PMN oxidative response.
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PMID:Adenosine modulation of tumor necrosis factor-alpha-induced neutrophil activation. 861 64

The actions of adenosine, adenosine deaminase, the adenosine uptake blocker, S-(p-nitrobenzyl)-6-thioinosine, and of the adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine, on electrically evoked [3H]acetylcholine release were investigated in rat phrenic nerve-hemidiaphragm preparations. Adenosine deaminase (0.25-2.5 U/ml) increased [3H]acetylcholine release. S-(p-Nitrobenzyl)-6-thioinosine (3-30 microM) and erythro-9(2-hydroxy-3-nonyl)adenine (25 nM-50 microM) caused biphasic effects on [3H]acetylcholine release: at low concentrations S-(p-nitrobenzyl)-6-thiomosine (5 microM) and erythro-9(2-hydroxy-3-nonyl)adeNine (50 nM) decreased [3H]acetylcholine release, and at concentrations higher than 10 microM S-(p-nitrobenzyl)-6-thioinosine and 0.5 microM for erythro-9(2-hydroxy-3-nonyl)adenine facilitated [3H]acetylcholine release. Both S-(p-nitrobenzyl)-6-thioinosine-induced inhibition and facilitation of [3H]acetylcholine release resulted from extracellular endogenous adenosine accumulation, because they were blocked after inactivation of endogenous adenosine with adenosine deaminase (0.5 U/ml). The inhibitory actions of both S-(p-nitrobenzyl)-6-thioinosine (5 microM) and erythro-9(2-hydroxy-3-nonyl)adenine (50 nM) were antagonized by the A1 adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (2.5 nM), whereas the blockade of A2a adenosine receptors with PD 115,199 (25 nM) prevented the facilitatory effects of S-(p-nitrobenzyl)-6-thioinosine (30 microM) and erythro-9(2-hydroxy-3-nonyl)adenine (50 microM). The adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine (25 nM), potentiated the effect of S-(p-nitrobenzyl)-6-thioinosine (3-30 microM), and this adenosine uptake blocker, when applied at a concentration (3 microM) that by itself was devoid of effect, potentiated both the inhibitory (25 nM) and excitatory (0.5 microM) effects of erythro-9(2-hydroxy-3-nonyl)adenine, on evoked [3H]acetylcholine release. Exogenously applied adenosine (10-500 microM) had biphasic effects similar to those of S-(p-nitrobenzyl)-6-thioinosine and erythro-9(2-hydroxy-3-nonyl)adenine. Adenosine (30 microM) reduction of evoked [3H]acetylcholine release was prevented after pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (2.5 nM); when applied at high concentrations (100-500 microM), adenosine consistently increased evoked [3H]acetylcholine release in a PD 115,199 (25 nM)-sensitive manner. It is concluded that both uptake and deamination are effective in removing extracellular endogenous adenosine that tonically activates both inhibitory (A1) and excitatory (A2a) adenosine receptors, regulating the A1/A2a adenosine receptors' activation balance.
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PMID:Adenosine uptake and deamination regulate tonic A2a receptor facilitation of evoked [3H]acetylcholine release from the rat motor nerve terminals. 878 32

1. In the present work, we investigated the action of adenosine originating from extracellular catabolism of adenine nucleotides, in two preparations where synaptic transmission is modulated by both inhibitory A1 and excitatory A(2a)-adenosine receptors, the rat hippocampal Schaffer fibres/CA1 pyramid synapses and the rat innervated hemidiaphragm. 2. Endogenous adenosine tonically inhibited synaptic transmission, since 0.5-2 u ml-1 of adenosine deaminase increased both the population spike amplitude (30 +/- 4%) and field excitatory post-synaptic potential (f.e.p.s.p.) slope (27 +/- 4%) recorded from hippocampal slices and the evoked [3H]-acetylcholine ([3H]-ACh) release from the motor nerve terminals (25 +/- 2%). 3. alpha, beta-Methylene adenosine diphosphate (AOPCP) in concentrations (100-200 microM) that almost completely inhibited the formation of adenosine from the extracellular catabolism of AMP, decreased population spike amplitude by 39 +/- 5% and f.e.p.s.p. slope by 32 +/- 3% in hippocampal slices and [3H]-ACh release from motor nerve terminals by 27 +/- 3%. 4. Addition of exogenous 5'-nucleotidase (5 u ml-1) prevented the inhibitory effect of AOPCP on population spike amplitude and f.e.p.s.p. slope by 43-57%, whereas the P2 antagonist, suramin (100 microM), did not modify the effect of AOPCP. 5. In both preparations, the effect of AOPCP resulted from prevention of adenosine formation since it was no longer evident when accumulation of extracellular adenosine was hindered by adenosine deaminase (0.5-2 u ml-1). The inhibitory effect of AOPCP was still evident when A1 receptors were blocked by 1,3-dipropyl-8-cyclopentylxanthine (2.5-5 nM), but was abolished by the A2 antagonist, 3,7-dimethyl-1-propargylxanthine (10 microM). 6. These results suggest that adenosine originating from catabolism of released adenine nucleotides preferentially activates excitatory A2 receptors in hippocampal CAI pyramid synapses and in phrenic motor nerve endings.
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PMID:Preferential activation of excitatory adenosine receptors at rat hippocampal and neuromuscular synapses by adenosine formed from released adenine nucleotides. 888 6

In this study we determined whether cAMP is metabolized to adenosine in vascular smooth muscle cells and whether cAMP-derived adenosine modulates vascular smooth muscle cell growth. Confluent smooth muscle cells were exposed to cAMP (0.01 to 30 mumol/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol/L; an inhibitor of both extracellular and intracellular phosphodiesterase), alpha, beta-methyleneadenosine 5'-diphosphate (AMP-CP, 100 mumol/L; an ecto-5'-nucleotidase inhibitor), and 1,3-dipropyl-8-p-sulfophenyl-xanthine (DPSPX, 100 mumol/L; a xanthine that can inhibit extracellular phosphodiesterase) for 0 to 60 minutes. Medium was then sampled and assayed for AMP, adenosine, and inosine. cAMP increased the amount of AMP, adenosine, and inosine in the medium in a time- and concentration-dependent manner. The conversion of cAMP to adenosine and inosine was inhibited by blockade of phosphodiesterase with IBMX, of ecto-phosphodiesterase with DPSPX, and of ecto-5'-nucleotidase with AMP-CP. To evaluate the physiological relevance of cAMP-derived adenosine in vascular smooth muscle cell proliferation, we studied the inhibitory effects of cAMP (10(-4) mol/L) and 8-bromo-cAMP (10(-4) mol/L) on fetal calf serum-induced DNA synthesis ([3H]thymidine incorporation) in the presence and absence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, an inhibitor of adenosine deaminase), dipyridamole (a blocker of adenosine transport), KF17837 (a selective A2 adenosine receptor antagonist), and DPSPX (a nonselective adenosine receptor antagonist). cAMP inhibited DNA synthesis, and both EHNA and dipyridamole enhanced this effect. Both KF17837 and DPSPX significantly reduced the inhibitory effects of cAMP on DNA synthesis; however, they did not reduce the inhibitory effects of 8-bromo-cAMP on DNA synthesis. These results indicate that vascular smooth muscle cells metabolize cAMP to adenosine via the sequential action of ecto-phosphodiesterase and ecto-5'-nucleotidase and provide the first evidence that cAMP-derived adenosine can inhibit vascular smooth muscle cell growth. Hence, this cAMP-adenosine pathway may importantly contribute to the regulation of vascular biology.
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PMID:Cyclic AMP-adenosine pathway inhibits vascular smooth muscle cell growth. 890 21

We describe how endogenous adenosine can prevent the induction of homosynaptic long-term depression (LTD) in the CA1 region of slices of adult rat hippocampus. Neither of two consecutive periods of prolonged low frequency stimulation (LFS; 1 Hz, 900 stimuli) of the Schaffer collateral-commissural fibres resulted in the induction of LTD in the CA1 region of hippocampal slices from adult (8-30 week) animals. However, in the presence of adenosine deaminase or the selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentyl-xanthine (DPCPX), LTD was induced by each of the first and second of two periods of LFS. The first period of LFS did not, but the second period of LFS did, induce LTD in the presence of DPCPX and the NMDA receptor antagonist, D-2-amino-5-phosphonopentanoate (AP5). The present results show that A1 receptor activation by endogenous adenosine can prevent the induction of LTD in the adult hippocampus.
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PMID:A role for adenosine in the regulation of long-term depression in the adult rat hippocampus in vitro. 914 2

The concentration of endogenous adenosine in the cerebrospinal fluid increased 2-3-fold of the original level in the area of rat superior colliculus after the intraperitoneal administration of an adenosine deaminase inhibitor, EHNA (erythro-9-(2-hydroxy-3-nonyl)adenosine, 10 mg/kg). Potentials evoked in the superior colliculus by optic tract stimulation were also facilitated by 120-160% of their initial amplitudes. A selective A1 adenosine receptor antagonist, DPCPX (8-cyclopentyl-1,3-dipropylxanthine), failed to reduce such EHNA-induced facilitation. However, a selective A2A adenosine receptor antagonist, KF17837 (8(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine) completely eliminated the facilitatory effects of EHNA. Northern blot analysis demonstrated abundant expression of A1 adenosine receptor mRNA in the superior colliculus. RT-PCR analysis was able to detect the concomitant expression of A2A adenosine receptor mRNA, but at levels lower than one-tenth of the striatal expression. In the superior colliculus, A2A adenosine receptors function predominantly on the facilitatory effects of adenosine, irrespective of the ubiquitous expression of A1 adenosine receptors.
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PMID:Endogenous adenosine facilitates neurotransmission via A2A adenosine receptors in the rat superior colliculus in vivo. 920 Jul 56

Identification of A1 adenosine receptors (A1Rs) in a tumor cell line derived from rat pituitary (GH4 cells) was performed by ligand binding and immunological experiments. Subsequently, the involvement of A1Rs in the regulation of calcium conductance was studied in these cells. The agonist N6-(R)-(2-phenylisopropyl)adenosine (R-PIA) did not modify the intracellular calcium basal levels, whereas it inhibited the increase produced by 15 mM KCl depolarization. The antagonist 1,3-dipropyl-8-cyclopentylxanthine led to the opening of voltage-dependent cell surface calcium channels in the absence of exogenous KCl. The channels were of the L type because the effect was abolished by calciseptine and by verapamil. These results suggest that endogenous adenosine exerts a tonic inhibitory effect on calcium transport. This was confirmed by the high adenosine concentration found in cell supernatants (up to 1 microM) and by the calcium mobilization produced by exogenously added adenosine deaminase. In depolarizing conditions, the calcium peak in the presence of adenosine deaminase was reduced when cells were preincubated with R-PIA, thus suggesting that A1R activation regulates the intensity of depolarization. These results demonstrate that adenosine is an important regulator of the physiological state of pituitary tumor cells by modulating, in an autocrine manner, the activity of L-type voltage-dependent calcium channels.
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PMID:Regulation of L-type calcium channels in GH4 cells via A1 adenosine receptors. 937 88

ATP analogs substituted in the gamma-phosphorus (ATPgammaS, beta, gamma-imido-ATP, and beta,gamma-methylene-ATP) were used to probe the involvement of P2 receptors in the modulation of synaptic transmission in the hippocampus, because their extracellular catabolism was virtually not detected in CA1 slices. ATP and gamma-substituted analogs were equipotent to inhibit synaptic transmission in CA1 pyramid synapses (IC50 of 17-22 microM). The inhibitory effect of ATP and gamma-phosphorus-substituted ATP analogs (30 microM) was not modified by the P2 receptor antagonist suramin (100 microM), was inhibited by 42-49% by the ecto-5'-nucleotidase inhibitor and alpha,beta-methylene ADP (100 microM), was inhibited by 74-85% by 2 U/ml adenosine deaminase (which converts adenosine into its inactive metabolite-inosine), and was nearly prevented by the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10 nM). Stronger support for the involvement of extracellular adenosine formation as a main requirement for the inhibitory effect of ATP and gamma-substituted ATP analogs was the observation that an inhibitor of adenosine uptake, dipyridamole (20 microM), potentiated by 92-124% the inhibitory effect of ATP and gamma-substituted ATP analogs (10 microM), a potentiation similar to that obtained for 10 microM adenosine (113%). Thus, the present results indicate that inhibition by extracellular ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ecto-nucleotidases and channeling of the generated adenosine to adenosine A1 receptors.
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PMID:Inhibition by ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ecto-nucleotidases into adenosine and channeling to adenosine A1 receptors. 948 85


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