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)

Methotrexate, a folate antagonist, is a potent antiinflammatory agent when used weekly in low concentrations. We examined the hypothesis that the antiphlogistic effects of methotrexate result from its capacity to promote intracellular accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) that, under conditions of cell injury, increases local adenosine release. We now present the first evidence to establish this mechanism of action in an in vivo model of inflammation, the murine air pouch model. Mice were injected intraperitoneally with either methotrexate or saline for 3-4 wk during induction of air pouches. Pharmacologically relevant doses of methotrexate increased splenocyte AICAR content, raised adenosine concentrations in exudates from carrageenan-inflamed air pouches, and markedly inhibited leukocyte accumulation in inflamed air pouches. The methotrexate-mediated reduction in leukocyte accumulation was partially reversed by injection of adenosine deaminase (ADA) into the air pouch, completely reversed by a specific adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), but not affected by an adenosine A1 receptor antagonist, 8-cyclopentyl-dipropylxanthine. Neither ADA nor DMPX affected leukocyte accumulation in the inflamed pouches of animals treated with either saline or the potent antiinflammatory steroid dexamethasone. These results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites.
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PMID:The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. 825 24

Intracellular recordings were performed on hippocampal CA3 neurons in vitro to investigate the inhibitory tonus generated by endogenously produced adenosine in this brain region. Bath application of the highly selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine at concentrations up to 100 nM induced both spontaneous and stimulus-evoked epileptiform burst discharges. Once induced, the 1,3-dipropyl-8-cyclopentylxanthine-evoked epileptiform activity was apparently irreversible even after prolonged superfusion with drug-free solution. The blockade of glutamatergic excitatory synaptic transmission by preincubation of the slices with the amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM), but not with the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid (50 microM), prevented the induction of epileptiform activity by 1,3-dipropyl-8-cyclopentylxanthine. The generation of the burst discharges was independent of the membrane potential, and the amplitude of the slow component of the paroxysmal depolarization shift increased with hyperpolarization, indicating that the 1,3-dipropyl-8-cyclopentylxanthine-induced bursts were synaptically mediated events. Recordings from tetrodotoxin-treated CA3 neurons revealed a strong postsynaptic component of endogenous adenosinergic inhibition. Both 1,3-dipropyl-8-cyclopentylxanthine and the adenosine-degrading enzyme adenosine deaminase produced an apparently irreversible depolarization of the membrane potential by about 20 mV. Sometimes, this depolarization attained the threshold for the generation of putative calcium spikes, but no potential changes resembling paroxysmal depolarization shift-like events were observed. At the concentrations used in electrophysiological experiments (30-100 nM), 1,3-dipropyl-8-cyclopentylxanthine displayed only a negligible inhibitory action on total cyclic nucleotide phosphodiesterase activity measured by means of a radiochemical assay in a homogenate of the rat cerebral cortex. Furthermore, even high concentrations of the selective phosphodiesterase inhibitor rolipram (10 microM), which displays no affinity to adenosine receptors, did not mimic the electrophysiological actions of 1,3-dipropyl-8-cyclopentylxanthine, thus excluding the possibility that the effects of the A1 receptor antagonist on neuronal discharge behavior can be ascribed to an inhibition of phosphodiesterases. The present data demonstrate that endogenously released adenosine exerts a vigorous control on the excitability of hippocampal CA3 neurons on both the pre- and postsynaptic sites. The long-lasting disinhibition following a transient suppression of adenosinergic inhibition strongly suggests that, besides its well-known short-term effects on neuronal activity, adenosine might also contribute to the long-term control of hippocampal excitability.
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PMID:Disinhibition of hippocampal CA3 neurons induced by suppression of an adenosine A1 receptor-mediated inhibitory tonus: pre- and postsynaptic components. 830 25

The drug (2-amino-4,5-dimethyl-3-thienyl)-[3(trifluoromethyl)-phenyl]methanone (PD 81,723) has been shown to enhance allosterically A1 adenosine receptor binding in brain membranes. The objective of this study was to determine the specificity and selectivity (A1 versus A2) of PD 81,723 as an enhancer of the negative dromotropic effect of exogenous adenosine in guinea pig isolated and in situ hearts. In isolated hearts, PD 81,723 alone produced only a small stimulus to His bundle (S-H) interval prolongation of 1.5 to 4 msec, which was completely reversed by the A1 adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase. PD 81,723 (5 microM) significantly decreased the EC50 value of adenosine for prolongation of the S-H interval from 6.7 +/- 0.6 to 4.4 +/- 0.5 microM. The potentiation of the negative dromotropic effect of adenosine by PD 81,723 was dose dependent, i.e., 5 and 10 microM PD 81,723 enhanced the maximal S-H interval prolongation caused by 3 microM adenosine by 207% and 609%, respectively. In contrast, the same concentration of PD 81,723 had no effect on either the S-H interval prolongation caused by carbachol or MgCl2 or the coronary vasodilatory effect of adenosine. In in situ hearts, PD (2 mumol/kg i.v.) alone caused only a small but not significant negative dromotropic effect, increasing the atrium to His interval from 58 +/- 2 to 61 +/- 1 msec. However, the same dose of PD 81,723 caused a significant leftward and upward shift of the adenosine dose-response curve for inducing atrium to His bundle interval prolongation and increased the degree of atrioventricular block caused by adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective potentiation by an A1 adenosine receptor enhancer of the negative dromotropic action of adenosine in the guinea pig heart. 835 94

The pharmacological and biochemical profile of N6-cyclopentyl-9-methyladenine (N-0840) was elucidated in vitro and in vivo. In radioligand binding assays, N-0840 had 14- to 400-fold greater affinity for A1 than A2 adenosine receptors and did not inhibit radioligand binding to alpha-1, alpha-2, beta, 5-hydroxytryptamine 1a, muscarinic, D1 or D2 receptors at concentrations < or = 10,000 nM. In guinea pig tissues, N-0840 competitively antagonized A1 receptor-mediated, 5'-N-ethylcarboxamidoadenosine-induced negative inotropism (paced left atria, KB = 0.83 microM), chronotropism (spontaneously beating right atria, KB = 0.91 microM) and dromotropism (Langendorff heart; KB = 0.72 microM). However, at concentrations up to 100 microM, N-0840 did not antagonize A2 adenosine receptor-mediated, 5'-N-ethylcarboxamidoadenosine-induced relaxations of the guinea pig aorta. N-0840 was a poor inhibitor of total cyclic nucleotide phosphodiesterase activity and of adenosine uptake (IC50 > 200 microM), and it did not inhibit adenosine deaminase activity. In anesthetized rats, N-0840 selectively antagonized A1 adenosine receptor-mediated bradycardia, but generally failed to affect A2 adenosine receptor-mediated vasodilation in the in situ perfused hindquarters (A2/A1 selectivity: > or = 33-fold). The duration of action of N-0840 ranged from 1 min (after 3 mumol/kg i.v.) to 8 hr (after 100 mumol/kg p.o.). N-0840 (< or = 100 mumol/kg i.v.; < or = 1,000 mumol/kg p.o.) had little or no effect on blood pressure or heart rate and produced no adverse drug reactions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro and in vivo pharmacological characterization of N6-cyclopentyl-9-methyladenine (N-0840): a selective, orally active A1 adenosine receptor antagonist. 838 36

Adenosine is one agent under investigation as a therapeutic intervention of myocardial stunning. Adenosine caused numerous effects on the cardiovascular system through its interaction with A1 and A2 receptors. We investigated adenosine A1 receptor mediated mechanisms of cardiac protection in the stunned rat myocardium. Previous studies showed that both adenosine and R-phenylisopropyladenosine (PIA), an A1 receptor agonist, prolonged the time to onset of ischemic contracture in ischemic isolated rat hearts. Phenylaminoadenosine, an A2 receptor agonist, did not have any effect, while receptor antagonists blocked adenosine and PIA action. Direct attenuation of the effects of myocardial stunning was observed by altering levels of interstitial fluid adenosine. Our laboratory has shown that administration of erythro-9(2-hydroxy-3-nonyl) adenine (EHNA; an adenosine deaminase inhibitor) to dogs subjected to left anterior descending coronary artery (LAD) occlusion followed by reperfusion results in dramatic increases in ischemic levels of interstitial fluid adenosine and postischemic myocardial function. Using a similar model in dogs, we have shown that exogenous intracoronary adenosine (50 micrograms/kg per min) augmented postischemic recovery of function, as assessed by significant enhancement (p < 0.01) of systolic wall thickness (7.0 +/- 3.0 pretreatment vs -5.7 +/- 1.7 controls). These data support the role for an adenosine A1 receptor mediated mechanism for protection against myocardial stunning.
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PMID:Adenosine and the stunned heart. 846 27

Twenty-six beagles of either sex, weighing 10.4 +/- 0.3 kg, were used to investigate the role of adenosine in the genesis of ventricular arrhythmias during systemic hypoxia. After instrumentation dogs were randomly assigned to one of four treatment groups: 14 dogs were pretreated before hypoxia with adenosine deaminase (n = 7, group I) or its vehicle (n = 7, group II) while 12 other dogs were pretreated with the A1 selective adenosine receptor antagonist BW A1433U (n = 6, group III) or its vehicle (n = 6, group IV). Each dog was exposed to a 3-min period of hypoxic ventilation [3% O2-5% CO2-92% N2; PO2 in arterial blood 96 +/- 3 Torr (before hypoxia), 21 +/- 1 Torr (during hypoxia)]. The percentages of ventricular ectopic beats (19) experienced in the four groups after 3 min of hypoxia were 21 +/- 10% (group I, P < 0.05 relative to group II), 50 +/- 2% (group II), 15 +/- 8% (group III, P < 0.05 relative to group IV), and 42 +/- 7% (group IV). Ventricular bigeminy, the most prominent arrhythmia seen in this study, was significantly reduced by adenosine deaminase and BW A1433U. No significant differences in other monitored cardiovascular variables were seen between adenosine deaminase and BW A1433U treatment groups and their corresponding vehicles. These findings implicate endogenous adenosine as an arrhythmogenic mediator during hypoxia and point to a mechanism involving the A1 adenosine receptor.
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PMID:Adenosine deaminase and BW A1433U attenuate hypoxia-induced ventricular ectopy. 851 67

The effect of the adenosine A1 receptor activation on calcitonin secretion was studied in medullary thyroid carcinoma cells of the rat (rMTC 6-23). Calcitonin was determined by radioimmunoassay, intracellular cAMP by protein binding assay, intracellular calcium in fura-2 loaded single cells using microspectrofluorimetry, and calcium channel activity by patch clamp technique. The adenosine A1 receptor analogue N-6 phenylisopropyl-adenosine (PIA) (10(-10)-10(-6) M) inhibits dose-dependently glucagon (10(-7) M) and rGRH (10(-7) M) stimulated cAMP formation and calcitonin secretion. These effects were partly abolished by pretreatment with pertussis toxin (PT) (100 ng/ml). PIA (10(-10)-10(-6) M) also suppressed extracellular calcium-stimulated calcitonin secretion, rises in intracellular calcium, and calcium channel currents. PT (100 ng/ml) pretreatment again partly abolished this inhibitory effect. The addition to the medium of adenosine deaminase (0.4 U/ml) stimulated calcitonin secretion. Our results suggest that in calcitonin-secreting cells A1 receptors couple to adenylate cyclase and calcium channels via PT-sensitive G proteins and thus inhibit calcitonin secretion. Adenosine seems to act as an autocrine/paracrine factor in calcitonin-secreting cells.
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PMID:Adenosine A1-receptors inhibit cAMP and Ca2+ mediated calcitonin secretion in C-cells. 855 39

Adenosine deaminase (ADA) is not only a cytosolic enzyme but can be found as an ecto-enzyme. At the plasma membrane, an adenosine deaminase binding protein (CD26, also known as dipeptidylpeptidase IV) has been identified but the functional role of this ADA/CD26 complex is unclear. Here by confocal microscopy, affinity chromatography and coprecipitation experiments we show that A1 adenosine receptor (A1R) is a second ecto-ADA binding protein. Binding of ADA to A1R increased its affinity for the ligand thus suggesting that ADA was needed for an effective coupling between A1R and heterotrimeric G proteins. This was confirmed by the fact that ASA, independently of its catalytic behaviour, enhanced the ligand-induced second messenger production via A1R. These findings demonstrate that, apart from the cleavage of adenosine, a further role of ecto-adenosine deaminase on the cell surface is to facilitate the signal transduction via A1R.
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PMID:Adenosine deaminase affects ligand-induced signalling by interacting with cell surface adenosine receptors. 860 28

Spinal administration of adenosine analogs and an adenosine kinase inhibitor produces antinociception in thermal threshold tests. In the present study, we determined the effects of N6-cyclohexyladenosine (adenosine A1 receptor selective), 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethyl-carboxamidoadeno sine (CGS-21680) (adenosine A2A receptor selective), and 5'-N-ethylcarboxamidoadenosine (NECA) (non-selective), on formalin induced nociceptive responses (flinching/lifting and licking/biting) using two concentrations of formalin (2% and 5%). We also examined the antinociceptive effects of 5'-amino-5'-deoxyadenosine, an adenosine kinase inhibitor, and deoxycoformycin, an adenosine deaminase inhibitor, under these conditions. Adenosine A1 receptor agonists, but not the A2A selective agent, produced significant antinociception, as did 5'-amino-5'-deoxyadenosine, but not deoxycoformycin. The extent of antinociception produced was greater with the lower stimulus intensity. The effects of NECA and 5'-amino-5'-deoxyadenosine were inhibited by caffeine, indicating the involvement of cell surface adenosine receptors in their actions. We conclude (a) that the adenosine A1, but not the A2A, receptor is involved in spinally mediated antinociception, (b) that adenosine kinase is more important than adenosine deaminase in regulating endogenous adenosine levels in the spinal cord, and (c) that stimulus intensity is an important determinant of the efficacy of purines in the spinal cord.
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PMID:Antinociception by adenosine analogs and an adenosine kinase inhibitor: dependence on formalin concentration. 860 54

We previously reported that adenosine A1 receptor activation protects against the cardiodepressant effects of hydrogen peroxide in isolated rat hearts. The present study examined whether a transient ischemic period of 5 min duration, which preconditions the heart against ischemic and reperfusion-induced dysfunction, can bestow protection against 30-min exposure to hydrogen peroxide in isolated rat hearts. Transient ischemia on its own failed to alter the cardiac response to hydrogen peroxide. However, when transient ischemia was carried out in the presence of the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thioguanosine and the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-nonyl)adenine, a significant attenuation of the hydrogen peroxide-induced loss in contractility was evident and this was associated with significant preservation of tissue glycogen content. The protective effect of the transient ischemia/drug combination on both functional changes and glycogen levels was abolished by the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine as well as by glibenclamide, a blocker of the ATP-sensitive potassium channel (KATP). To further assess the role of glycogen in the protection against hydrogen peroxide, we compared the effects of the adenosine A1 agonist N6-cyclopentyl adenosine (CPA) and insulin. While both treatments protected against hydrogen peroxide the effect of insulin was superior to any other treatment. Moreover, while all protective modalities preserved glycogen stores after hydrogen peroxide treatment, the protection afforded by insulin was also associated with significantly elevated glycogen levels prior to hydrogen peroxide administration. No protection by either CPA or insulin was evident in the absence of exogenous glucose. Taken together, our results demonstrate that a brief period of ischemia with concomitant administration of agents which increase interstitial adenosine levels protects against hydrogen peroxide toxicity. The effect is mediated by activation of adenosine A1 receptors and is linked to KATP stimulation. Moreover, our results are strongly suggestive of an important role of glycogen preservation in bestowing protective effects against hydrogen peroxide cardiotoxicity.
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PMID:Transient ischemia in the presence of an adenosine deaminase plus a nucleoside transport inhibitor confers protection against contractile depression produced by hydrogen peroxide. Possible role of glycogen. 876 52


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