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)

Inhibition of neutrophil-myocyte adhesion and adhesion-dependent myocyte injury by adenosine was evaluated using isolated TNF-alpha-activated canine cells. Adenosine inhibited adhesion of activated neutrophils to cardiac myocytes with an IC50 of 11 +/- 4 nM. Inhibition of neutrophil adhesion (92 +/-3% by 100 nM adenosine) led to inhibition of myocyte injury (by 90 +/- 6%, as assessed by dye exclusion). Inhibition of cell adhesion by adenosine was blocked by the A2 antagonist, 1,3-dimethyl-1-propylxanthine, but not by the A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine. Moreover, the A2 agonist, CGS21680 (2-[4-(2-carboxymethyl)phenethylamino]-5'-N-ethylcarboxamido adenosine), but not the A1 agonist, N6-cyclopentyladenosine, mimicked adenosine in preventing cell adhesion. These observations implicate the A2 receptor in the mechanism of inhibition of cell adhesion. pretreatment and washing of neutrophils, but not cardiac myocytes, with adenosine or CGS21680 led to inhibition of adhesion, suggesting that the neutrophil A2 receptor is the target of adenosine's action. In contrast, inhibition of cell adhesion by adenosine was poteniated by 8-cyclopentyl-1,3-dipropylxanthine (IC50 = 4 +/- 1 nM) and attenuated by N6-cyclopentyladenosine, suggesting that occupancy of A1 receptors can conversely increase cell adhesion. Neutrophil-myocyte adhesion was inhibited by acadesine (IC50 = 12 +/- 2 microM) also via an adenosine-dependent mechanism because it was blocked by 1,3-dimethyl-1-propylxanthine or adenosine deaminase, an enzyme that degrades any adenosine that is formed. Acadesine-induced inhibition if cell adhesion (83 +/- 4% by 100 microM) resulted in inhibition of myocyte injury (by 76 +/- 6%). Other adenosine-regulating agents, including the acadesine analogue, GP531 (5-amino-1 beta-D-(5-benzylamino-5-deoxyribofuranosyl) imidazole-4-carboxamide), and inhibitors of adenosine transport and intracellular metabolism also inhibited cell adhesion. These results indicate that exogenous or endogenous adenosine can inhibit neutrophil-myocyte adhesion and injury in cells activated with TNF-alpha by an A2-mediated mechanism. Although the predominant activity of adenosine is to attenuate cell adhesion, stimulation of A1 receptors has the opposite effect, i.e., to augment adhesive interactions.
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PMID:Adenosine activates A2 receptors to inhibit neutrophil adhesion and injury to isolated cardiac myocytes. 765 Mar 88

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

5-Aminoimidazole-4-carboxamide riboside (AICA riboside; Acadesine) activates AMP-activated protein kinase (AMPK) in intact cells, and is reported to exert protective effects in the mammalian CNS. In rat cerebrocortical brain slices, AMPK was activated by metabolic stress (ischaemia > hypoxia > aglycaemia) and AICA riboside (0.1-10 mm). Activation of AMPK by AICA riboside was greatly attenuated by inhibitors of equilibrative nucleoside transport. AICA riboside also depressed excitatory synaptic transmission in area CA1 of the rat hippocampus, which was prevented by an adenosine A1 receptor antagonist and reversed by application of adenosine deaminase. However, AICA riboside was neither a substrate for adenosine deaminase nor an agonist at adenosine receptors. We conclude that metabolic stress and AICA riboside both stimulate AMPK activity in mammalian brain, but that AICA riboside has an additional effect, i.e. competition with adenosine for uptake by the nucleoside transporter. This results in an increase in extracellular adenosine and subsequent activation of adenosine receptors. Neuroprotection by AICA riboside could be mediated by this mechanism as well as, or instead of, by AMPK activation. Caution should therefore be exercised in ascribing an effect of AICA riboside to AMPK activation, especially in systems where inhibition of adenosine re-uptake has physiological consequences.
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PMID:AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus. 1500 83