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 and its synthetic analogues are known to affect many leukocyte functions, in some cases by binding to specific cell surface receptors coupled to adenylate cyclase. In this study, adenosine receptors were demonstrated on normal rabbit alveolar macrophages by examining specific binding of tritiated 5-N-ethylcarboxamide adenosine (NECA) to intact cells. Scatchard analysis suggested a single class of approximately 33,000 binding sites per cell and an estimated Kd of 0.46 mumol/L. Competitive inhibition of tritiated NECA binding was demonstrated for 2-chloroadenosine (2-CA; Ki = 3.68 mumol/L) and L-phenylisopropyl adenosine (L-PIA; Ki greater than 100 mumol/L), a rank order of binding affinities indicative of an A2 receptor. Theophylline and isobutyl methylxanthine had Kis of 368 and 27.6 mumol/L, respectively. For functional correlation, NECA was found to be 10-fold more potent than L-PIA in stimulating an increase in intracellular cyclic adenosine monophosphate. In addition, macrophages were cultured for 24 hours with NECA, 2-CA, or L-PIA to determine whether these analogues modulated expression of either cell-associated procoagulant activity or elaboration of plasminogen activator. Procoagulant activity was suppressed by as much as 62% (P less than 0.05); the rank order of potency and blockade of the effect with theophylline suggest that suppression of procoagulant activity occurred primarily by stimulation of A2 receptors. By contrast, these analogues stimulated production and release of plasminogen activator by 30% (P less than 0.05), but this effect had none of the features of an A2-mediated mechanism. Macrophages were cotreated with nitrobenzylthioinosine (10 mumol/L) and adenosine deaminase (2 U/ml) to allow adenosine accumulation exclusively within the cell.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptors on rabbit alveolar macrophages: binding characteristics and effects on cellular function. 303 32

In isolated segments of guinea-pig ileum, amrinone (0.3 mM-0.3 M) caused a transient contraction followed by a concentration-dependent relaxation. Theophylline (0.1-0.5 mM) mimicked the effects of amrinone but apparently inhibited relaxation induced by the latter. However the total decrease of muscle tension measured in preparations exposed to amrinone before and after theophylline treatment was quantitatively comparable. Dipyridamole (0.1 microM) potentiated the relaxing effect of amrinone. The stimulatory response of the ileum to high concentrations of adenosine (10-50 mM) was abolished by amrinone. In preparations treated with adenosine deaminase (10 U/ml) the basal tone was decreased and both amrinone and theophylline were ineffective. In rat ileum, amrinone exerted a marked relaxing effect that was abolished by adenosine deaminase. Thus amrinone appears to cause relaxation of intestinal smooth muscle from different species by hindering the stimulatory effect of endogenous adenosine. The possible intracellular localization of the amrinone-adenosine interaction site is discussed.
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PMID:Possible role of adenosine in the relaxant effect of amrinone on guinea-pig ileum. 361 Nov 43

1-Methylisoguanosine, a novel purine isolated from the sponge Tedania digitata (Schmidt) selectively inhibited contractions produced by nerve stimulation in the guinea-pig ileum but was without effect on contractions produced by acetylcholine or histamine. The ED50 for inhibition of nicotine responses or responses to submaximal transmural stimulation was 1.1 mumoles/l. The inhibition of nerve-mediated contractions appeared to be due to inhibition of transmitter release from nerve endings in the ileum, as has been suggested for the action of adenosine. Theophylline antagonized the action of 1-methylisoguanosine and overall the results suggest that 1-methyl-isoguanosine acts at an adenosine receptor in the guinea-pig ileum, but is approximately ten times more potent than adenosine itself. A series of related purines which were resistant to the action of adenosine deaminase were also tested for their effect on the nerve-mediated contractions of guinea-pig ileum and the results compared with the in vivo effect on muscle relaxation in mice. All active purines tested produced results qualitatively similar to those of 1-methylisoguanosine itself.
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PMID:Inhibition of nerve-mediated contractions in isolated guinea-pig ileum by 1-methylisoguanosine, a novel purine from a sponge. 625 32

The inhibitory effects of adenosine, ATP, 5'-adenylyl methylene diphosphonate (beta, gamma-meATP) and adenosine 5'-alpha, beta-methylene triphosphonate (alpha, beta-meATP) were compared on the cholinergic twitch responses to transmural stimulation of the guinea-pig ileum. Adenosine, ATP and beta, gamma-meATP reduced the twitch responses in a concentration dependent manner. Theophylline antagonized and dipyridamole potentiated the inhibitory responses to adenosine, ATP and beta, gamma-meATP. Inhibitory responses to alpha, beta-meATP were usually preceded by an enhancement in twitch height. Contractions of the unstimulated ileum to alpha, beta-meATP were blocked by atropine and tetrodotoxin while those elicited by ATP were unaffected, which suggests that the initial excitatory effects of alpha, beta-meATP may be due to its ability to release ACh from cholinergic nerve terminals. Use of high pressure liquid chromatography and bioluminescence assay techniques demonstrated the ability of the tissue to degrade ATP and beta, gamma-meATP and, at a much slower rate, alpha, beta-meATP. Inhibitory responses to ATP, AMP and beta, gamma-meATP were reduced by adenosine deaminase, which also abolished responses to adenosine. 5'-AMP deaminase abolished responses to AMP and adenosine, and reduced those to ATP and beta, gamma-meATP. The results suggest that the inhibitory effect of ATP on cholinergic neurotransmission is due to its rapid breakdown to AMP or adenosine, which act on prejunctional P1-purinoceptors.
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PMID:Evidence for the presence of P1-purinoceptors on cholinergic nerve terminals in the guinea-pig ileum. 627 50

Serosal addition of adenosine after inhibition of adenosine deaminase with deoxycoformycin increases short-circuit current (Isc) and tissue conductance of isolated epithelia of rabbit descending colon. In the presence of Cl this increase in Isc results from a reversal of electrically neutral Cl absorption to rheogenic Cl secretion. When Cl is absent the stimulating effect of adenosine on Isc is reduced to one-third and appears to be brought about by HCO3 secretion. Under all conditions active Na transport remains unaltered. Adenosine-induced electrolyte secretion is markedly decreased by serosal addition of furosemide and depends on the presence of Na on the serosal side of the tissue. The stoichiometry of the interaction of Na and Cl with the basolateral Cl entry mechanism appears to be 1:1. Under Na-free conditions adenosine elicits a current transient which is carried by Cl ions and which is not inhibited by furosemide. Hence this current transient seems to be brought about by rheogenic apical Cl efflux. All these findings suggest that the conductive step in transepithelial Cl secretion resides in the apical membrane. Hyperpolarization of the Na-transporting cells by luminal addition of amiloride does not enhance electrolyte secretion. The site of action of adenosine is the extracellular surface of the basolateral membrane, because (a) luminal addition of adenosine is ineffective, (b) nitrobenzylmercaptopurineriboside, a blocker of cellular nucleoside uptake, augments the effect of serosal adenosine, and (c) the intracellular metabolites of adenosine do not mediate the effect. From the rank-order of potency of adenosine and its analogues 5'-N-ethylcarboxamide adenosine and N6-cyclohexyladenosine it is concluded that the adenosine receptors involved in electrolyte secretion are of the Ra subtype. Theophylline partially inhibits the secretory effect. The intracellular mediator of adenosine appears to be cyclic AMP and/or cyclic GMP, since the tissue levels of both compounds are rapidly elevated after addition of adenosine and both cyclic AMP and cyclic 8-bromo-GMP are able to mimic the adenosine action.
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PMID:Stimulation of electrolyte secretion in rabbit colon by adenosine. 669 90

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

The possible role of brain adenosine in acute ethanol-induced alteration in glucose utilization in the whole brain, as well as in the specific brain areas (cerebellum and brain stem), was investigated. Mice were killed 20-min postethanol, and the fresh tissue slices (300 microns) of brain and/or specific brain areas were incubated for 100 min in a 5.5 mM glucose medium in Warburg flasks using [6-(14)C]glucose as a tracer. Trapped 14CO2 was counted to estimate glucose utilization. Ethanol (2 g/kg, i.p.) markedly increased the glucose utilization in whole brain and in both motor areas of brain. Theophylline (50 mg/kg, i.p.), an adenosine antagonist, significantly reduced ethanol-induced increase in glucose utilization in whole brain, as well as in brain areas. However, adenosine agonist N6-cyclohexyladenosine (CHA; 0.1 mg/kg, i.p.) on the contrary, significantly accentuated ethanol-induced increase in glucose utilization in these tissues that was nearly completely blocked by theophylline pretreatment. Theophylline alone did not produce any significant change in glucose utilization, whereas CHA alone (in vivo and in vitro) significantly increased glucose utilization, as well as ethanol-induced increase in glucose utilization in an additive manner. Relevant supportive data were obtained by experiments in which adenosine deaminase (ADA), p-sulfophenyltheophylline (8-SPT), and CHA were administered in vitro to the slice preparations. Both ADA and 8-SPT were effective in almost completely blocking the ethanol-induced increase in glucose utilization, whereas CHA further enhanced the ethanol-induced increase in glucose utilization in an additive manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible central adenosinergic modulation of ethanol-induced alterations in [14C]glucose utilization in mice. 757 8

Freshly drawn blood samples from seven female and seven male healthy donors were used. Arginine8-vasopressin (AVP) effects on platelet aggregation and serotonin (5-HT) release were examined in adenosine-depleted platelet-rich plasma (PRP) and PRP containing normal amounts of plasma adenosine. No significant differences in the plasma adenosine levels were noted between female (208 +/- 90 nM) and male (239 +/- 85 nM) subjects, but significant differences in AVP-induced platelet aggregation and 5-HT release were noted between female and male subjects. In adenosine-depleted PRP, platelets from most female donors could be aggregated irreversibly at low levels of AVP (18 mU/ml, or 42 nM), whereas platelets from most male donors responded poorly and caused only reversible aggregation at much higher AVP levels (108-720 mU/ml PRP or 252-1,680 nM). In contrast, in PRP containing normal amounts of adenosine, AVP response to induce platelet aggregation was much weaker, demonstrating that adenosine acts as a natural modulator of AVP actions. Theophylline and a relatively selective A2 antagonist DMPX (3,7-dimethyl-1-propargylxanthine) attenuate the plasma adenosine effects causing potentiation in AVP activity on platelet aggregation. These studies suggest that agents that can increase plasma adenosine levels (e.g., inhibitors of nucleoside transport and adenosine deaminase), or adenosine receptor antagonists, may have potential therapeutic uses in modulation of AVP actions in the body. Furthermore, the human platelet serves as a suitable pharmacologic model to study interactions between biologically produced adenosine and AVP.
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PMID:Modulation of vasopressin actions on human platelets by plasma adenosine and theophylline: gender differences. 833 6

Theophylline at low doses (10 mg/kg/day p.o.) under long-term conditions (for 16 consecutive days) increased the adenosine deaminase (ADA) activity in spleen and thymus of adult male albino rats without changing its hepatic ADA activity. Treatment with high doses (20 mg/kg/day p.o.) under similar conditions, on the other hand, decreased the splenic and hepatic ADA activity and increased the thymic ADA activity. This induction of thymic ADA activity, however, was significantly less than that observed with low doses of theophylline. The plasma corticosterone level was increased without changing its adrenal level under similar conditions. This study, thus, indicates that long-term theophylline treatment may potentiate or suppress the immune response, depending on the dose, through the tissue (liver/spleen/thymus)-specific modulation of ADA activity and plasma corticosterone status.
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PMID:Theophylline-induced changes in mammalian adenosine deaminase activity and corticosterone status: possible relation to immune response. 920 66

This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism. A selective adenosine A2 receptor agonist (CGS-21680, 1 microM) exhibited the most efficient potency for decreasing neutrophil apoptosis for 16 h from 63+/-5 to 19+/-4% (P < 0.001); it exerted poor and adverse effects on eosinophil survival. A selective protein kinase A inhibitor KT-5720 (10 microM) reversed the capacity of dibutyryl cAMP but not CGS-21680 to induce an inhibitory effect on neutrophil apoptosis, suggesting that occupancy of adenosine A2 receptors inhibit neutrophil apoptosis by a cAMP-independent mechanism. Theophylline derivatives show the following pattern of potency for inducing neutrophil apoptosis competing with CGS-21680: 8-phenyltheophylline = 8-p-sulfophenyltheophylline > theophylline >> enprofylline. This pattern is consistent with the affinity established for A2A receptors. Theophylline demonstrated an additive effect to that of anti-Fas antibody (CH11, 1 microg/mL) in inducing neutrophil apoptosis, but not to that of adenosine deaminase or KF-17837 (a selective A2 receptor antagonist; 1 microM), suggesting conflicting effects on the receptor antagonism. These findings suggest that theophylline has an immunomodulatory action on neutrophil apoptosis via a mechanism of A2A antagonism.
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PMID:Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. 1077 Feb 86


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