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)

We investigated the effect of adenosine A1 receptors on the release of acetylcholine (ACh) and GABA, and on the intracellular calcium concentration ([Ca2+]i) response in cultured chick amacrine-like neurons, stimulated by KCl depolarization. The KCl-induced release of [3H]ACh, but not the release of [14C]GABA, was potentiated when adenosine A1 receptor activation was prevented by perfusing the cells with adenosine deaminase (ADA) or with 1,3-dipropyl-8-cycloentylxanthine (DPCPX). The changes in the [Ca2+]i induced by KCl depolarization, measured in neurite segments of single cultured cells, were also modulated by endogenous adenosine, acting on adenosine A1 receptors. Our results show that adenosine A1 receptors inhibit Ca2+ entry coupled to ACh release, but not to the release of GABA, suggesting that the synaptic vesicles containing each neurotransmitter are located in different zones of the neurites, containing different VSCC and/or different densities of adenosine A1 receptors.
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PMID:Adenosine A1 receptors inhibit Ca2+ channels coupled to the release of ACh, but not of GABA, in cultured retina cells. 1066 90

1. We investigated how manipulations of the degree of activation of adenosine A(1) and A(2A) receptors influences the action of the neuropeptide, calcitonin gene-related peptide (CGRP) on synaptic transmission in hippocampal slices. Field excitatory post-synaptic potentials (EPSPs) from the CA1 area were recorded. 2. When applied alone, CGRP (1 - 30 nM) was without effect on field EPSPs. However, CGRP (10 - 30 nM) significantly increased the field EPSP slope when applied to hippocampal slices in the presence of the A(1) receptor antagonist, 1,3-dipropyl-8-cyclopenthyl xanthine (DPCPX, 10 nM), or in the presence of the A(2A) adenosine receptor agonist CGS 21680 (10 nM). 3. The A(2A) receptor antagonist, ZM 241385 (10 nM) as well as adenosine deaminase (ADA, 2 U ml(-1)), prevented the enhancement of field EPSP slope caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this effect of CGRP requires the concomitant activation of A(2A) adenosine receptors by endogenous adenosine. 4. The protein kinase-A inhibitors, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 10 microM) and adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS, 50 microM), as well as the inhibitor of ATP-sensitive potassium (K(ATP)) channels, glibenclamide (30 microM), prevented the facilitation of synaptic transmission caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this effect of CGRP involves both K(ATP) channels and protein kinase-A. 5. It is concluded that the ability of CGRP to facilitate synaptic transmission in the CA1 area of the hippocampus is under tight control by adenosine, with tonic A(1) receptor activation by endogenous adenosine 'braking' the action of CGRP, and the A(2A) receptors triggering this action.
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PMID:Tonic activation of A(2A) adenosine receptors unmasks, and of A(1) receptors prevents, a facilitatory action of calcitonin gene-related peptide in the rat hippocampus. 1069 45

Dependent on the number of phosphate residues, diadenosine polyphosphates (APnP) exert divergent inotropic effects in the human heart. We studied the inotropic effects of the smallest member of this family, diadenosine monophosphate (AP1A). Force of contraction was measured in an isometric setup in isolated electrically driven (0.5 Hz) preparations from human atria. AP1A exerted a concentration-dependent negative inotropic effect. The IC50 value was 20.2 microM and the IC50 value was 3.1 microM (n = 5-8). At 100 microM AP1A, force of contraction declined to 50% of the predrug value after 2.5 +/- 0.5 min of incubation (n = 8). AP1A antagonized the positive inotropic effect of the beta-adrenoceptor agonist isoprenaline (10 nM). For 100 microM AP1A, the time to 50% of the predrug force in the presence of isoprenaline amounted to 2.3 +/- 0.2 min (n = 5). The positive inotropic and lusitropic effects of isoprenaline were antagonized by AP1A. The direct (AP1A alone) and indirect (AP1A in the presence of isoprenaline) negative inotropic effects of AP1A were blocked by the A1-adenosine receptor antagonist 1,3-dipropyl-cyclopentyl-xanthine (DPCPX, 0.3 microM). The inotropic effect of AP1A was not blocked by adenosine deaminase. In conclusion, AP1A exerts indirect and direct negative inotropic effects in the human heart through A1-adenosine receptors. These effects might protect the heart against excessive beta-adrenergic stimulation.
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PMID:Inotropic effects of diadenosine monophosphate (AP1A) in isolated human cardiac preparations. 1083 21

The extracellular "cAMP-adenosine pathway" refers to the local production of adenosine mediated by cAMP egress into the extracellular space, conversion of cAMP to AMP by ectophosphodiesterase, and the metabolism of AMP to adenosine by ecto-5'-nucleotidase. The goal of this study was to assess whether the cAMP-adenosine pathway limits cardiac fibroblast growth. Studies were conducted in ventricular cardiac fibroblasts maintained in 3-dimensional cultures. Addition of exogenous cAMP to cardiac fibroblasts increased extracellular levels of AMP, adenosine, and inosine in a concentration-dependent and time-dependent manner. This effect was attenuated by blockade of total phosphodiesterase activity (3-isobutyl-1-methylxanthine), ectophosphodiesterase activity (high concentration of 1, 3-dipropyl-8-p-sulfophenylxanthine), or ecto-5'-nucleotidase (alpha, beta-methylene-adenosine-5'-diphosphate). Treatment with exogenous cAMP inhibited cell growth as assessed by DNA synthesis ((3)H-thymidine incorporation), cell proliferation (cell counts), and protein synthesis ((3)H-leucine incorporation). Antagonism of A(2) (KF17837) or A(1)/A(2) (low concentration of 1, 3-dipropyl-8-p-sulfophenylxanthine), but not A(1) (8-cyclopentyl-1, 3-dipropylxanthine), adenosine receptors blocked the growth-inhibitory effects of exogenous cAMP, but not the growth inhibitory effects of 8-bromo-cAMP (stable cAMP analogue). The growth-inhibitory effects of exogenous cAMP were enhanced by the combined inhibition of adenosine deaminase [erythro-9-(2-hydroxy-3-nonyl) adenine] and adenosine kinase (iodotubercidin). In conclusion, the extracellular cAMP-adenosine pathway exists in cardiac fibroblasts and attenuates cell growth. Pharmacological augmentation of this pathway could abate pathological cardiac remodeling in heart disease.
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PMID:Cardiac fibroblasts express the cAMP-adenosine pathway. 1098 61

Superfusion of rat hippocampal slices with ATP induces a form of facilitation that has been poorly characterised. The present study has confirmed that at low concentrations of ATP (10 microM or less), an initial depression of evoked potential size is followed by a rebound facilitation which is not reproduced by alphabeta-methyleneATP, betagamma-methyleneATP, or the dinucleotide P1,P6-diadenosine hexaphosphate. The post-ATP facilitation could be prevented by the adenosine A1 receptor antagonists 8-phenyltheophylline or 1,3-dipropyl-8-cyclopentyltheophylline (50 nM), or superfusion of adenosine deaminase. The adenosine A2A receptor antagonist 8-(chlorostyryl)-caffeine did not affect the inhibition but prevented the post-ATP facilitation. The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid prevented the establishment of post-ATP facilitation. The post-ATP facilitation was also blocked by suramin at a concentration (50 microM) that does not block glutamate receptors. Suramin prevented the induction but not the maintenance phase of the post-ATP facilitation. The repeated induction of post-ATP facilitation by bursts of electrical stimulation designed to saturate the normal mechanisms of long-term potentiation prevented the induction of post-ATP facilitation. However, repeated applications of ATP to achieve saturation of its receptor did not prevent the subsequent induction of electrically evoked long-term potentiation. It is concluded that ATP can induce a form of synaptic facilitation which resembles only partially that induced by electrical stimulation and which may require the simultaneous activation of P1 and P2 receptors.
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PMID:Characterisation of ATP-induced facilitation of transmission in rat hippocampus. 1110 29

Renal sodium handling is important for regulating BP, and renal dopamine and adenosine play an important role in renal sodium handling, however the interaction of these hormones in the kidney was not clarified. In in vivo experiments, adenosine significantly increased water and sodium excretion by 50% compared with vehicle when infused into the left renal artery, accompanied by an increase in urinary dopamine excretion in the left kidney. Neither water-sodium excretion nor dopamine excretion changed in the vehicle-infused kidney. Aromatic L-amino acid decarboxylase activity in the left kidney was significantly higher than that in the noninfused right kidney. The increase in water-sodium excretion induced by adenosine was significantly inhibited by SCH23390, a selective D1 receptor antagonist. In in vitro experiments, porcine renal proximal tubular cells were incubated with 250 microM L-dopa and N(6)-cyclohexyladenosine, an adenosine type 1 receptor agonist, after treatment with adenosine deaminase. N(6)-cyclohexyladenosine significantly increased dopamine formation at a concentration of 10(-9) to 10(-7) M, and this was completely inhibited by 1,3-dipropyl-8-cyclopentylxanthin, an adenosine A1 antagonist. These results show that renal dopamine synthesis is stimulated by adenosine through the activation of aromatic L-amino acid decarboxylase and suggest that adenosine leads to an increase in renal dopamine and natriuresis.
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PMID:Adenosine activates aromatic L-amino acid decarboxylase activity in the kidney and increases dopamine. 1113 47

We compared the modulation of synaptic transmission by adenosine A(1) receptors in the hippocampus of aged (24 months) and young adult rats (6 weeks). The adenosine A(1) receptor agonist, N(6)-cyclopentyladenosine, was less potent (P:<0.05) to inhibit synaptic transmission in aged (EC(50)=53 nM) than young adult (EC(50)=14 nM) hippocampal slices, these effects being prevented by the A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). In contrast with the lower effect of the A(1) receptor agonist, it was observed that blockade of A(1) receptors with DPCPX (50 nM), or removal of endogenous extracellular adenosine with adenosine deaminase (2 u ml(-1)), caused a more pronounced disinhibition of synaptic transmission in aged rats. Also consistent with a more intense A(1) receptor-mediated inhibitory tonus by endogenous adenosine in aged rats was the finding that to fully prevent the depression of synaptic transmission induced by 3 min hypoxia, a higher concentration of DPCPX was required in slices from aged (100 nM) than from young (50 nM) rats. It is concluded that in hippocampal slices of aged rats the efficiency of A(1) receptors to modulate synaptic transmission is reduced, but this may be compensated by an enhanced inhibitory tonus by endogenous adenosine.
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PMID:Modification of adenosine modulation of synaptic transmission in the hippocampus of aged rats. 1113 40

Adenosine inhibits growth of cardiac fibroblasts; however, the adenosine receptor subtype that mediates this antimitogenic effect remains undefined. Therefore, the goals of this study were to determine which adenosine receptor subtype mediates the antimitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat left ventricular cardiac fibroblasts, PDGF-BB (25 ng/mL) stimulated DNA synthesis ((3)H-thymidine incorporation), cellular proliferation (cell number), collagen synthesis ((3)H-proline incorporation), and MAP kinase activity. The adenosine receptor agonists 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, but not N(6)-cyclopentyladenosine, 4-aminobenzyl-5'-N-methylcarboxamidoadenosine, or CGS21680, inhibited the growth effects of PDGF-BB, an agonist profile consistent with an A(2B) receptor-mediated effect. The adenosine receptor antagonists KF17837 and 1,3-dipropyl-8-p-sulfophenylxanthine, but not 8-cyclopentyl-1,3-dipropylxanthine, blocked the growth-inhibitory effects of 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, an antagonist profile consistent with an A(2) receptor-mediated effect. Antisense, but not sense or scrambled, oligonucleotides to the A(2B) receptor stimulated basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis. Moreover, the growth-inhibitory effects of 2-chloroadenosine, 5'-N-methylcarboxamidoadenosine, and erythro-9-(2-hydroxy-3-nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminase and adenosine kinase, respectively) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A(2B) receptor. Our findings strongly support the hypothesis that adenosine causes inhibition of CF growth by activating A(2B) receptors coupled to inhibition of MAP kinase activity. Thus, A(2B) receptors may play a critical role in regulating cardiac remodeling associated with CF proliferation. Pharmacologic or molecular biological activation of A(2B) receptors may prevent cardiac remodeling associated with hypertension, myocardial infarction, and myocardial reperfusion injury after ischemia.
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PMID:A(2b) receptors mediate the antimitogenic effects of adenosine in cardiac fibroblasts. 1123 Mar 62

Our previous studies show that cardiac fibroblasts express the extracellular "cAMP-adenosine pathway," that is, the generation of adenosine from extracelluar cAMP. The goal of this study was to assess whether activation of the cAMP-adenosine pathway by stimulation of endogenous cAMP synthesis regulates cardiac fibroblast growth. Cardiac fibroblasts in 3D cultures were used as the model system. Treatment of cardiac fibroblasts with forskolin, isoproterenol, or norepinephrine increased cAMP production and extracellular levels of adenosine, and these effects were prevented by inhibition of adenylyl cyclase (2',5'-dideoxyadenosine). Treatment with forskolin, isoproterenol, or norepinephrine for 24 hours inhibited DNA synthesis ((3)H-thymidine incorporation), and this effect was enhanced by combined inhibition of adenosine deaminase (erythro-9-[2-hydroxy-3-nonyl] adenine) plus adenosine kinase (iodotubercidin). Inhibition of adenylyl cyclase or adenosine receptors (1,3-dipropyl-8-p-sulfophenylxanthine or KF17837) prevented the effects of forskolin, isoproterenol, and norepinephrine on DNA synthesis. Forskolin also inhibited protein synthesis ((3)H-leucine incorporation) and cell proliferation, and these effects were blocked by adenosine receptor antagonism. Treatment of cardiac fibroblasts with norepinephrine for >48 hours but not <48 hours increased DNA synthesis, protein synthesis, and cell number. However, blockade of adenylyl cyclase or antagonism of adenosine receptors caused norepinephrine to induce proliferation in <48 hours. Our findings indicate that the endogenous cAMP-adenosine pathway regulates cardiac fibroblast growth.
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PMID:Endogenous cyclic AMP-adenosine pathway regulates cardiac fibroblast growth. 1130 9

1. It is well established that presynaptic adenosine A1-receptor activation inhibits acetylcholine (ACh) release in the guinea-pig ileum. The present study extends this observation and examines a possible role for endogenous adenosine in modulating cholinergic nerve function. 2. The actions of the adenosine uptake blocker, dipyridamole, the adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine (EHNA) and the A1-receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) were examined on electrically evoked neurogenic, cholinergic twitch contractions of the guinea-pig ileum. Some additional studies measuring [3H]-ACh release were also performed. 3. Adenosine and the selective A1-receptor agonist, 2-chloroadenosine (2-CA), inhibited electrically evoked contractions and, in the case of 2-CA, [3H]-ACh release. The actions were antagonized by DPCPX. At low concentrations, dipyridamole and EHNA enhanced the effect of adenosine causing a leftward shift of the concentration-response curve. In contrast, inhibition induced by 2-CA was unaffected by either dipyridamole or EHNA. 4. When applied alone at higher concentrations, EHNA and dipyridamole produced a concentration-dependent suppression of cholinergic neurotransmission. In both cases, the effect could be reversed by DPCPX. At the same concentration, DPCPX alone produced a small but consistent increase in twitch height and [3H]-ACh release. 5. The data confirm the existence of inhibitory presynaptic adenosine A1-receptors modulating cholinergic nerve function in the guinea-pig ileum and suggests that these receptors can be activated by endogenous adenosine released either as adenosine itself or as an ATP metabolite.
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PMID:Activation of presynaptic A1-receptors by endogenous adenosine inhibits acetylcholine release in the guinea-pig ileum. 1142 76


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