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)

Adenosine is an endogenous neuromodulator with depressant effects on CNS neurons. Adenosine agonists produce biphasic effects on activity, decreases in operant response rate, and anticonvulsant effects. These effects are similar to some of the behavioral effects of ethanol. In addition, it has recently been shown that relative sensitivities to some of the behavioral effects of ethanol and purinergic drugs are similar in inbred strains of mice. These findings have prompted the speculation that ethanol's behavioral effects may be mediated by an agonist action on adenosine-receptive neurons. The present study provided a direct test of this hypothesis with respect to the discriminative stimulus properties of ethanol. In this study, neither the A1 receptor agonist N6-cyclohexyladenosine nor the A2 receptor agonist N6-ethylcarboxamide adenosine produced significant generalization to the ethanol stimulus. In addition, neither the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)-adenine nor the adenosine uptake inhibitor dipyridamole were able to enhance the level of ethanol-appropriate responding seen after a low dose of ethanol. Both caffeine and 8-phenyltheophylline partially but significantly antagonized the stimulus properties of ethanol. However, the doses required to achieve these effects were much higher than those needed to block adenosine receptors. These findings strongly suggest that the discriminative stimulus properties of ethanol are not mediated through an agonist action on adenosine-receptive neurons.
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PMID:Endogenous adenosine-receptive systems do not mediate the discriminative stimulus properties of ethanol. 382 98

Whole-blood cultures of human lymphocytes were exposed in the G2-phase to caffeine and to 4 inhibitors of DNA synthesis, hydroxyurea (HU), 2'-deoxyadenosine (dAdo), 1-beta-D-arabinofuranosylcytosine (araC) and aphidicolin (Aph), either individually or in pairs resulting in 10 different possible combinations. Since dAdo is rapidly deaminated in whole-blood cultures, all treatments involving dAdo were carried out in the presence of an inhibitor of the enzyme adenosine deaminase (ADA). The G2-treatments were carried out on 3 different types of culture, (1) cultures that had not previously been exposed to any mutagenic treatment, (2) cultures that had been irradiated with 0.4 Gy of X-rays 3.5 h before harvesting, and (3) cultures that had been exposed for 2 h to 4 X 10(-5) M thiotepa (TT) in G0 immediately before stimulation with phytohaemagglutinin. The aim of the study was to find out in which combinations the inhibitors enhanced synergistically the frequencies of spontaneous and induced chromatid aberrations. In all 3 types of experiment, synergistic effects were observed with most of the 10 combinations, those involving HU being particularly effective. A very strong synergistic enhancement was also obtained when dAdo was combined with Aph.
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PMID:Synergistic enhancement of the frequency of chromatid aberrations in cultured human lymphocytes by combinations of inhibitors of DNA repair. 392 42

A new adenosine analogue, (-)-iodo-N6-phydroxyphenylisopropyladenosine [(-)-IHPIA], has been developed for radioligand binding studies of Ri adenosine receptors. In addition, the effects of (-)IHPIA on adenosine-mediated responses of rat fat cells have been characterized. (-)IHPIA is slightly less potent at Ri adenosine receptors than (-)N6-phenylisopropyladenosine [(-)PIA] as assessed by adenylate cyclase and lipolysis studies. (-)IHPIA inhibited basal adenylate cyclase activity with an IC50 of 60 nmol/l compared to an IC50 of 16.3 nmol/l for (-)PIA. (-)PIA and (-)IHPIA inhibited adenosine deaminase-stimulated lipolysis of intact rat fat cells with an IC50 of 0.55 and 3.6 nmol/l. The potency of (-)N6-phydroxyphenylisopropyladenosine [(-)HPIA] was intermediate. (-)HPIA has been labelled with carrier-free Na[125I] to very high specific activity (2,175 Ci/mmol) and used as agonist radioligand in binding studies of Ri adenosine receptors. The binding of (-)[125I]HPIA was saturable, reversible and stereospecific. Saturation analysis revealed two affinity states with dissociation constants (KD) of 0.7 and 7.6 nmol/l and maximal number of binding sites (Bmax) of 0.94 and 0.95 pmol/mg protein. The rate constant of association, k1, was 3.7 X 10(8) l X mol-1 X min-1. Binding was slowly reversible with a t1/2 of 88 min. In competition experiments specific binding was most potently inhibited by (-)PIA, N6-cyclohexyladenosine (CHA), (-)HPIA and (-)IHPIA, followed by 5'-N-ethylcarboxamidoadenosine (NECA) and 2-chloroadenosine. 1,3-Diethyl-8-phenylxanthine (DPX) and 8-phenyltheophylline were the most potent adenosine antagonists with Ki-values of 67 and 83 nmol/l, whereas the methylxanthines 3-isobutyl-1-methylxanthine, theophylline and caffeine had Ki-values between 1 and 21 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Labelling of Ri adenosine receptors in rat fat cell membranes with (-)-[125iodo]N6-hydroxyphenylisopropyladenosine. 608 4

Adenosine and its analogs depress the firing of neurons in various brain regions. The primary mode of action of adenosine in exerting this action appears to be the depression of calcium entry, thus decreasing presynaptic neurotransmitter release. Adenosine uptake inhibitors and adenosine deaminase inhibitors potentiate the depressant actions of adenosine. Caffeine and theophylline, methylxanthines, antagonize these actions. Adenosine is therefore likely to be released and to exert an ongoing modulation of the neuron excitability in the intact brain. Adenosine uptake by nerve terminals appears to be important in regulating the extracellular concentration of adenosine and thus of adenosine's action. A number of groups of centrally active sedative, anxiolytic and anticonvulsant drugs inhibit adenosine uptake by brain synaptosomal preparations. It is proposed that these agents exert their sedative effects by inhibiting adenosine uptake and thus potentiating depressant actions by locally released adenosine on neuronal activity.
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PMID:Adenosine mediates sedative action of various centrally active drugs. 613 Apr 65

Rats ingesting high doses of caffeine reproduce the self-destructive behaviour observed in the Lesch-Nyhan syndrome. This syndrome includes a deficit in hypoxanthine-guanine phosphoribosyltransferase. We have observed, however, that the activity of hypoxanthine-guanine phosphoribosyltransferase increases in direct proportion to the concentration of caffeine found in rat brain. It appears, therefore, that the caffeine model is not a true model for the Lesch-Nyhan syndrome, or alternatively, that the deficit in hypoxanthine-guanine phosphoribosyltransferase is coincidental and not a main key to the multifarious aspects of the syndrome, particularly the self-mutilation. The possibility that levels of dopamine are increased in the caffeine model are discussed as a basis for the destructive behaviour. We have found also that ingestion of large amounts of caffeine increases the activities in rat brain of adenosine deaminase, purine nucleoside phosphorylase, aspartate carbamoyl-transferase, dihydroorotase, and dihydroorotate oxidase.
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PMID:Lesch-Nyhan syndrome, caffeine model: increase of purine and pyrimidine enzymes in rat brain. 614 65

Methylxanthines, such as caffeine and theophylline, potentiate the rotation behaviour induced by dopamine receptor agonists in rats with unilateral lesions of the nigro-striatal pathway. In the present study we have examined the possibility that interaction with central adenosine mechanisms could influence rotation behaviour. Under in vitro conditions adenosine and N6-phenylisopropyl-adenosine (PIA) stimulate cyclic AMP accumulation. This effect was enhanced by the phosphodiesterase inhibitor rolipram, but blocked by alkylxanthines such as caffeine, theophylline and, particularly, 8-phenyl-theophylline. Rotation behaviour induced by apomorphine (0.05 mg/kg), was inhibited by PIA and rolipram and by a low dose of the adenosine deaminase inhibitor EHNA (2 mg/kg). By contrast, theophylline and 8-phenyl-theophylline caused a potentiation. The former drug stimulated rotation behaviour per se, while the latter did not. 8-Phenyl-theophylline entered the brain poorly and its concentration in brain it was less than 1/10 of theophylline. It is concluded that theophylline does not potentiate rotation behaviour secondarily to inhibition of phosphodiesterase. Antagonism of endogenous adenosine may partly explain the effect of methylxanthines. Possibly, some as yet unknown mechanism may also contribute to the effects of xanthine-derivatives on rotation behaviour.
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PMID:On the mechanism by which methylxanthines enhance apomorphine-induced rotation behaviour in the rat. 663 4

Administered intracisternally, adenosine (ADO), 2-chloroadenosine (CADO), adenosine-5'-cyclopropylcarboxamide (ACC) and adenosine-5'-ethylcarboxamide (AEC) caused dose-related increases in hot plate reaction times in mice. The rank order of potency was AEC=ACC greater than CADO greater than ADO and ACC exerted demonstrable effects with doses as low as 10 ng/mouse. ADO itself was more potent than AMP, ADP, ATP and several other related compounds of interest. Theophylline, caffeine and 8-phenyltheophylline antagonized the antinocisponsive effect of CADO or ACC. Papaverine (an adenosine uptake blocker) and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA: an adenosine deaminase inhibitor) potentiated the effect of ADO. EHNA did not potentiate the action of CADO in this procedure. The antinocisponsive effect of CADO was not antagonized by a host of neurally active agents including naloxone, clonidine and RO 20-1724. Time course studies indicated that the antinocisponsive effect of ADO was transient with the peak effect occurring 5 min after injection and disappearing by 60 min, whereas the effect of CADO persisted for at least 90 min. Intracisternally administered CADO also caused a pronounced hypothermia, loss of muscle tone and was active in the mouse writhing test. Taken together, these data demonstrate that purine exert potent in vivo behavioral effects and are consonant with the existence of a central purinergic P1-receptor which is amenable to selective pharmacological manipulation.
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PMID:In vivo behavioral assessment of central nervous system purinergic receptors. 689 75

Adenosine and ATP depressed resting O2 uptake in frog sartorius. This action was blocked by low levels of caffeine and by 8-phenyltheophylline. It was mimicked by a polymer of adenosine. Adenosine also decreased radioactive calcium uptake in muscles. Potassium and magnesium content were increased while sodium and calcium content were decreased by adenosine. Adenosine did not decrease oxygen uptake in muscles from frogs sacrificed in winter months. However, adenosine deaminase, which inactivates adenosine by removing the amino group, increased oxygen uptake, calcium content and lactate release of these muscles. Our results suggest that adenosine reduces resting metabolism, possibly through reducing passive leaks of electrolytes.
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PMID:Effect of adenosine on oxygen uptake and electrolyte content of frog sartorius muscle. 697 47

The vasodilatory effect of adenosine and some related compounds were studied in subcutaneous adipose tissue in situ. The effects of three drugs that inhibit adenosine elimination; two adenosine uptake blockers, dipyridamole and dilazep, the adenosine deaminase inhibitor, EHNA, were also studied. Plasma levels of adenosine were simultaneously determined by HPLC. Adenosine was a potent vasodilator and 2- and 6-substituted analogues were even more potent. Tissue blood flow was linearly related to the venous plasma concentrations of adenosine. An elevation of adenosine in plasma from 0.25 to 0.5 Mu M enhanced blood flow by approximately 50%. A further increase to 1 mu M was associated with a doubling of adipose tissue blood flow. Adenosine also increased the vascular conductance and the capillary filtration coefficient, indicating that is is active on all sections of the vascular bed. Theophylline and caffeine (30- 100 mu M in arterial plasma) antagonized the vasodilatory effect of exogenous adenosine, abolished vasodilation due to EHNA+dipyridamole and reduced resting blood flow. The results suggest that adenosine plays a physiological role in regulating adipose tissue blood flow.
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PMID:Role of adenosine in adipose tissue circulation. 729 98

Field and intracellular potentials were recorded from CA1 pyramidal stratum in submerged slices (at 33 degrees). During "normal" oxygenation (95% O2 + 5% CO2), tonic depression of population spikes and field excitatory postsynaptic potentials by endogenous adenosine was demonstrated by (i) the marked enhancement by the adenosine antagonists 8-(p-sulfophenyl)theophylline (10 microM) and caffeine (0.2 mM), (ii) depression by the transport blocker dipyridamole (5 microM), and (iii) enhancement by exogenous adenosine deaminase (all tested by bath application). Thus, adenosine deaminase (0.5 units/ml) reduced by 10.7 +/- 3.0% (S.E.) the half-maximal stimulus intensity (for population spikes). The effects of adenosine deaminase were prevented by the specific inhibitor, deoxycoformycin (30 microM). In intracellular recordings, excitatory postsynaptic potentials were enhanced in a comparable manner by adenosine deaminase. By contrast, neither deoxycoformycin (5 and 30 microM) nor erythro-9-(2-hydroxy-3-nonyl)adenine (another adenosine deaminase inhibitor; 10 and 50 microM) had significant effects on population spikes. Superfusion with anoxic medium (saturated with 95% N2 + 5% CO2) for 2-3 min suppressed population spikes reversibly, by a mechanism involving adenosine, because 8-(p-sulfophenyl)theophylline (10 microM) and caffeine (0.2 mM) delayed the onset of anoxic block and accelerated the subsequent recovery, and the recovery was much slower or incomplete in the presence of dipyramidole (0.5 microM). However, the anoxic suppression of population spikes was not affected by deoxycoformycin (30 microM) or erythro-9-(2-hydroxy-3-nonyl)adenine (10 microM); the corresponding 50% postanoxic recovery times were also unchanged (e.g. 4.0 +/- 0.2 min for controls and 4.1 +/- 0.3 min in deoxycoformycin).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endogenous adenosine deaminase does not modulate synaptic transmission in rat hippocampal slices under normoxic or hypoxic conditions. 789 60


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