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:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Adenosine is known to stimulate capillary outgrowth and endothelial cell proliferation, but the underlying mechanism has not been identified. In order to identify the receptor subtype involved, the effects of adenosine receptor agonists and antagonists on human umbilical vein endothelial cell (HUVEC) proliferation were investigated. 2. Raising intracellular adenosine levels by use of the adenosine transport inhibitor, 4-nitrobenzylthioinosine (NBMPR) did not affect cell growth. This observation suggests that stimulation of an extracellular adenosine receptor generates the mitogenic signal. 3. In the presence of adenosine deaminase (ADA), which was used to remove adenosine present in the culture medium, the adenosine receptor agonists N-ethylcarboxamidoadenosine (NECA, non-selective) and CGS21680 (A2A-receptor-selective) stimulated [3H]-thymidine incorporation with a half-maximum effect at about 10 nM, while N6-cyclopentyladenosine (CPA, A1-selective) was about 100 fold less potent. The adenosine receptor antagonist, xanthine amine congener (XAC) produced a concentration-dependent decrease in endothelial cell proliferation with a half-maximum effect at about 10 nM. Hence, stimulation of an endothelial A2A-adenosine receptor seems responsible for the mitogenic signal. 4. In the presence of ADA, isoprenaline is also able to stimulate [3H]-thymidine incorporation with a half maximal effect of about 3 nM, an effect, which is reversed by the highly beta 2-selective antagonist, ICI 118,551. In the absence of ADA, isoprenaline exerts only a minor stimulatory effect. Combination of A2A adenosine and beta 2-adrenoceptor agonists did not further enhance [3H]-thymidine incorporation when compared to the sole addition of each agonist. We therefore conclude that both receptors stimulate endothelial cell proliferation via a common signal transduction pathway. 5. Both receptors are coupled to stimulation of adenylyl cyclase via the stimulatory G protein G8.However, direct activation of downstream effectors in the cyclic AMP-signalling cascade (G8 with cholera toxin, adenylyl cyclase with forskolin, protein kinase A with 8Br-cyclic AMP) not only failed to mimic the action of receptor-activation, but even reduced cell proliferation.6. Similarly, pertussis toxin-treatment which inactivated the Gi 2 protein present in HUVEC and thus inhibited cell proliferation per se, did not impair the ability of A2A-receptor agonists to stimulate cell proliferation. This suggests that the A2A-adenosine and beta2-adrenoceptor-mediated stimulation of endothelial cell proliferation occurs via a mechanism that is independent of G8 and Gi.
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PMID:Stimulation of human umbilical vein endothelial cell proliferation by A2-adenosine and beta 2-adrenoceptors. 759 25

Adenosine 3',5'-cyclic monophosphate (cAMP), accumulated in the presence of adenosine, was measured in medullary portions of mouse thick ascending limbs of Henle's loop, suspended either in classic extracellular buffer or in the presence of added NaCl. Under control conditions (140 mmol/l NaCl), adenosine (< 10(-5) mol/l) and N6-cyclohexyladenosine, an A1 adenosine receptor agonist, inhibit the cAMP accumulation induced by arginine vasopressin (AVP). On the other hand, high concentrations of adenosine and CGS-21680, an A2 adenosine receptor agonist, stimulate cAMP formation. Addition of NaCl (+300 mmol/l) to extracellular buffer stimulates the release of endogenous adenosine. It also enhances A2 receptor-induced cAMP accumulation but suppresses A1 receptor-mediated inhibition of adenylyl cyclase. This hypertonic NaCl medium also potentiates the stimulatory action of AVP on adenylyl cyclase. The modifications of tubular responses to both AVP and A1 and A2 agonists, brought about by hypertonic NaCl, were all inhibited by adenosine deaminase, thereby demonstrating the involvement of endogenous adenosine. Adenosine, the release and the effects of which are modulated by hypertonic NaCl, thus appears to act as an endogenous physiological modulator of kidney medulla function.
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PMID:Hypertonic NaCl enhances adenosine release and hormonal cAMP production in mouse thick ascending limb. 763 23

A comparison of the effects of various phosphodiesterase (PDE) inhibitors upon cellular cAMP levels was undertaken in human neuroblastoma SH-SY5Y cells. When inhibitors such as rolipram and Ro 20 1724 (selective for the low Km cAMP-specific PDE) were used, cAMP levels were seen to rise dramatically under basal (< or = 60 fold) or forskolin-stimulated (< or = 200 fold) conditions. However, the non-selective PDE inhibitor isobutylmethylxanthine (IBMX) was 7-18% as effective as these other agents even at 1 mM. The poor efficacy of IBMX was not attributable to concomitant increases in cGMP, to alterations in cAMP egress or to a lack of sensitivity of the cellular PDEs to IBMX inhibition. In additivity experiments, IBMX potently and rapidly reduced cAMP that had accumulated after rolipram treatment. The fact that the agonist 2-chloroadenosine can enhance cAMP accumulation in these cells, and that cAMP elevated by rolipram or forskolin can be reduced by adenosine deaminase and theophylline suggest that cell-derived adenosine enhances cAMP in these cells in an autocrine fashion. Since IBMX is an adenosine receptor antagonist, it is suggested that its blockade of endogenous adenosine effects is at least partly responsible for its poor response when compared to other PDE inhibitors which are weaker adenosine receptor antagonists. These results forewarn against assuming that similar levels of cAMP accumulate after application of PDE inhibitors in these cells.
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PMID:Comparison of the effect of isobutylmethylxanthine and phosphodiesterase-selective inhibitors on cAMP levels in SH-SY5Y neuroblastoma cells. 768 30

The excitatory amino acid (EAA), L-cysteine sulfinic acid (L-CSA), elicited a dose-dependent increase in cAMP accumulation in adult rat hippocampus that was not blocked by ionotropic glutamate receptor antagonists. Therefore, the possibility was examined that L-CSA activates the (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD)-sensitive metabotropic glutamate receptor (mGluR) that increases cAMP by potentiating responses elicited by adenosine or other agonists of receptors coupled to adenylate cyclase via Gs. Like 1S,3R-ACPD, L-CSA induced a cAMP response that was inhibited by the adenosine receptor antagonist, 8-para-sulfyltheophylline, and by adenosine deaminase. In contrast to the 1S,3R-ACPD-induced cAMP response, the L-CSA-induced response was not potentiated by the adenosine uptake inhibitor, dipyridamole. Taken together with the previous finding that L-CSA does not potentiate cAMP responses elicited by agonists of receptors that activate Gs, these data suggest that L-CSA increases cAMP accumulation by activating a metabotropic EAA receptor that is different from the 1S,3R-ACPD-sensitive mGluR associated with potentiation of cAMP responses.
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PMID:An L-cysteine sulfinic acid-sensitive metabotropic receptor mediates increased cAMP accumulation in hippocampal slices. 773 95

In two groups of Saffan-anaesthetized, spontaneously breathing rats we have attempted to identify the peripheral influences of adenosine in mediating the responses evoked by hypoxia by using an adenosine receptor antagonist, 8-sulphophenyltheophylline (8-SPT, 20 mg kg-1 i.v., Group 1) and adenosine deaminase (ADA, 500 units in 0.04 ml infused into the tail artery for 10 min, Group 2); neither of these drugs crosses the blood-brain barrier. Recordings were made of respiration, heart rate, arterial pressure, blood flow and vascular conductance in the femoral artery, with ankle ligated (FBF and FVC, respectively) and in the carotid artery with all branches except the internal carotid ligated (CBF and CVC, respectively, Group 1 only) in order to indicate responses in skeletal muscle and cerebral vasculature. Hypoxia (breathing 8 or 10% O2 for 10 min) evoked an increase followed by a secondary decrease in respiration, tachycardia followed by secondary bradycardia, a fall in arterial pressure, an increase in FVC and CVC and an increase, followed by a decrease, in CBF. Neither 8-SPT nor ADA had any significant effect on the secondary decrease in respiration. The secondary bradycardia was unaffected by 8-SPT, but abolished by ADA. Both drugs reduced the fall in arterial pressure and the increase in FVC; 8-SPT had no significant effect on the increase in CVC, but CBF no longer fell with arterial pressure. We propose that adenosine contributes to the hypoxia-induced fall in arterial pressure by causing vasodilatation in skeletal muscle and possibly by causing bradycardia by a direct action on the heart; other evidence suggests that adenosine contributes to the secondary decrease in respiration by acting on central respiratory neurones. The possibility that the fall in arterial pressure and the secondary falls in CBF, respiration and heart rate, can become interdependent in a positive feedback manner is discussed.
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PMID:Differentiation of the peripherally mediated from the centrally mediated influences of adenosine in the rat during systemic hypoxia. 781 67

1. An eye-cup preparation in anaesthetized rabbits was used to examine opioid modulation of acetylcholine (ACh) release from cholinergic neurones in the retina. 2. The mu-opioid receptor agonist, [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO), when applied locally to the retina at concentrations between 1-30 microM significantly increased the light-evoked release of ACh. The effect of DAMGO was completely blocked by the selective mu-receptor antagonist CTOP but the kappa-receptor antagonist nor-binaltorphimine (norBNI) did not affect the action of DAMGO on ACh release indicating that the opioid produced its effect by activation of mu-receptors (the rabbit retina has negligible delta-receptors). 3. Blockade with bicuculline and strychnine of GABAergic and glycinergic inputs to the cholinergic neurones did not affect the action of DAMGO on ACh release. Also DAMGO did not reduce the potassium-evoked release of either GABA or glycine from rat isolated retinas. 4. Exposure of the rabbit retina to a combination of an A1-adenosine receptor antagonist, 8-cyclopentyl-1,3 dipropylxanthine (DPCPX), and adenosine deaminase did not affect the enhancing action of DAMGO on the light-evoked release of ACh. 5. When the retina in the rabbit eye-cup was exposed to kainate, the release of ACh was increased by approximately three times the resting release. In the presence of DAMGO the kainate-evoked release of ACh was enhanced by 44%. 6. These experiments show that activation of mu-opioid receptors by DAMGO increases the release of ACh elicited by physiological stimulation (flickering light). Since we could find no evidence thatDAMGO reduces inhibitory inputs to the cholinergic neurones, it seems that the enhancing action ofDAMGO on the light-evoked release of ACh involves a direct excitatory effect rather than disinhibition.This conclusion is supported by the enhancing action of DAMGO on the kainate-evoked release of ACh because kainate is thought to act directly on the cholinergic neurones.
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PMID:Enhancement of retinal acetylcholine release by DAMGO: possibly a direct opioid receptor-mediated excitatory effect. 785 68

The retina is an area of the central nervous system that possesses intrinsic cholinergic neurones which release acetylcholine (ACh) in response to stimulation with flickering light. Using an eye-cup preparation in anaesthetized rabbits we found that when the retina was exposed to the P2-purinoceptor antagonist, PPADS, the light-evoked release of ACh was strikingly increased (by over 40%). In contrast, ATP reduced the light-evoked release of ACh by 20%. The inhibitory effect of ATP was not due to its catabolism to adenosine because it was not affected by the A1-adenosine receptor antagonist, DPCPX, in combination with adenosine deaminase. The actions of both ATP and PPADS were completely blocked by strychnine. We conclude that during physiological stimulation of the retina with light, ATP is co-released with ACh and partially inhibits ACh release by activating (with ACh) an inhibitory glycinergic feedback loop.
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PMID:Modulation by endogenous ATP of the light-evoked release of ACh from retinal cholinergic neurones. 788 57

Inhibition of platelet aggregation by acadesine was evaluated both in vitro and ex vivo in human whole blood using impedance aggregometry, as well as in vivo in a canine model of platelet-dependent cyclic coronary flow reductions. In vitro, incubation of acadesine in whole blood inhibited ADP-induced platelet aggregation by 50% at 240 +/- 60 microM. Inhibition of platelet aggregation was time dependent and was prevented by the adenosine kinase inhibitor, 5'-deoxy 5-iodotubercidin, which blocked conversion of acadesine to its 5'-monophosphate, ZMP, and by adenosine deaminase. Acadesine elevated platelet cAMP in whole blood, which was also prevented by adenosine deaminase. In contrast, acadesine had no effect on ADP-induced platelet aggregation or platelet cAMP levels in platelet-rich plasma, but inhibition of aggregation was restored when isolated erythrocytes were incubated with acadesine before reconstitution with platelet-rich plasma. Acadesine (100 mg/kg i.v.) administered to human subjects also inhibited platelet aggregation ex vivo in whole blood. In the canine Folts model of platelet thrombosis, acadesine (0.5 mg/kg per min, i.v.) abolished coronary flow reductions, and this activity was prevented by pretreatment with the adenosine receptor antagonist, 8-sulphophenyltheophylline. These results demonstrate that acadesine exhibits antiplatelet activity in vitro, ex vivo, and in vivo through an adenosine-dependent mechanism. Moreover, the in vitro studies indicate that inhibition of platelet aggregation requires the presence of erythrocytes and metabolism of acadesine to acadesine monophosphate (ZMP).
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PMID:Adenosine-mediated inhibition of platelet aggregation by acadesine. A novel antithrombotic mechanism in vitro and in vivo. 792 29

The pH dependency of the binding of ligands to adenosine A2a receptors in rat striatal membranes was examined. For those agonists sensitive to adenosine deaminase a solubilised membrane preparation was used. A two- to fourfold increase in affinity was observed for CGS-21680, 5'-N-ethylcarboxamidoadenosine, adenosine, 3'-deoxyadenosine, 5'-deoxyadenosine, inosine, and N6-methoxypurine riboside on lowering the ambient pH from 7.0 to 5.5. In contrast, no such pH dependency was observed with 2'-deoxyadenosine, although 2'-methoxyadenosine binding was pH dependent. This effect on the affinity of CGS-21680 was reduced by diethylpyrocarbonate and restored by hydroxylamine and implied a pK value of 7.0 for the histidine residue involved. No such dependence was observed with cyclopentyltheophylline or dimethylpropargylxanthine. It is concluded that one of the histidines conserved in the adenosine receptor binding site acts as a hydrogen bond donor to the oxygen of the 2'-hydroxyl group of adenosine agonists.
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PMID:Role of histidine residues in the adenosine A2a receptor ligand binding site. 793

Adenosine induced by hypoxia exerts various effects via different types of receptors. Recently, hypoxia was shown to be a strong inducer of vascular endothelial growth factor, a secreted endothelial cell specific mitogen. In this report, we studied on effects of adenosine on inducibility of VEGF and possible mediation of hypoxia for its induction in U-937 cells. Hypoxia induced expression of VEGF mRNA with an early peak at 1 hour. 5'-N-ethylcarboxamidoadenosine, an adenosine analog, strongly induced VEGF mRNA, which was inhibited by 3,7-dimethyl-1-propargylxanthine (DMPX), an A2-antagonist. The hypoxic induction was inhibited by adenosine deaminase, 7-(beta-hydroxyethyl)theophylline, a non-selective adenosine receptor antagonist and DMPX. These results suggest that the hypoxic induction of VEGF mRNA is mediated by adenosine via A2-receptor in U-937 cells.
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PMID:Adenosine as an endogenous mediator of hypoxia for induction of vascular endothelial growth factor mRNA in U-937 cells. 794 78


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