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)

This study was conducted to elucidate the role of S-adenosyl-L-homocysteine (SAH) hydrolase, 5'-nucleotidase and adenosine kinase in the production and removal of adenosine in the isolated guinea pig heart during normoxic (95% O2) and hypoxic (30% O2) perfusion. Using an adenosine kinase inhibitor (5'-amino-5'-deoxy-adenosine; 50 microM) and an adenosine deaminase inhibitor (EHNA; 5 microM) the total steady-state production rate of adenosine in the heart was estimated to be greater than 1.2 nmol.min-1 per g wet wt., during normoxia. Most (95%) of the SAH-derived adenosine is salvaged by adenosine kinase action. The rate of adenosine phosphorylation increased 3-fold when isolated hearts were perfused with hypoxic medium, suggesting that adenosine kinase is not substrate-saturated under normoxic conditions. The steady-state production of adenosine was also estimated during hypoxia (5.9 nmol-min-1 per g wet wt.) and compared with previously determined transmethylation rate during hypoxia (1.12 nmol.min-1 x g wet wt.). In an attempt to assess the in-vivo activity of cytosolic 5'-nucleotidase, the 5'-AMP pool was labelled by perfusing the isolated hearts with tricyclic nucleoside (TCN) which became phosphorylated (TCN-P). The release rate of both adenosine and TCN in the post-labelling phase was increased by hypoxic perfusion, suggesting that the increased rate of 5'-AMP hydrolysis may be due to increased availability of substrate, as well as activation of 5'-nucleotidase. Our findings suggest that during normoxic perfusion a significant amount of adenosine is derived from an apparently oxygen-independent mechanism (cellular transmethylation) whereas during hypoxic perfusion hydrolysis of adenine nucleotides to adenosine prevails.
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PMID:Adenosine metabolism in the guinea pig heart: the role of cytosolic S-adenosyl-L-homocysteine hydrolase, 5'-nucleotidase and adenosine kinase. 829 79

When human umbilical vein endothelial cells were prelabeled with [14C]-adenine and then exposed to xanthine oxidase (40 mU/ml) and hypoxanthine (100 microM) for 4 h, cellular adenine nucleotides were depleted (18 +/- 3% of total radioactivity vs. 61 +/- 10% in controls), nucleotides appeared in the culture medium (8 +/- 3% vs. 4 +/- 3%) together with the catabolic products inosine, hypoxanthine, and uric acid (74 +/- 4% vs. 35 +/- 11%). In the presence of H2O2 (100 microM) for 30 min, cellular nucleotides were depleted (46 +/- 25%) and catabolic products appeared in the medium (40 +/- 26%), but radioactive nucleotides in the medium were unaltered. In the presence of an inhibitor of ecto-5'-nucleotidase [alpha, beta-methylene-adenosine 5'-diphosphate (ADP), 0.5 mM], exposure to xanthine oxidase and hypoxanthine resulted in the appearance of three times more nucleotides in the culture medium than in the absence of the inhibitor, but there was no change in medium nucleotides after H2O2 exposure. In the presence of an inhibitor of adenosine deaminase (2-deoxycoformycin, 2 microM), both exposures caused an accumulation of adenosine in the medium, calculated to represent a minimum of 25% of nucleotide catabolism. We conclude that exposure to both a superoxide-generating system (hypoxanthine plus xanthine oxidase) and H2O2 induce catabolism of adenine nucleotides, which mainly takes place through adenosine 5'-monophosphate (AMP) deaminase. However, superoxide but not H2O2 also causes membrane damage and leakage of nucleotides into the medium.
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PMID:Mechanisms of adenine nucleotide depletion from endothelial cells exposed to reactive oxygen metabolites. 838 Nov 5

Adenosine is recognised as an important regulator of myocardial function and coronary vascular tone in the ischaemic myocardium. It is produced by the enzymatic dephosphorylation of 5'-AMP by 5'-nucleotidase and the hydrolysis of SAH by SAH-hydrolase. 5'-Nucleotidase is thought to contribute to adenosine production aside from the accumulation of 5'-AMP in the ischaemic myocardium, while the hydrolysis of SAH plays a major role in adenosine production in the normoxic myocardium. 5'-Nucleotidase activity is reported to increase adenosine production through accumulation of ATP, ADP, H+, Mg2+ and inorganic phosphate during ischaemia. In addition, we have found that alpha 1 adrenergic receptors, activated in ischaemic hearts, increase both 5'-nucleotidase activity and adenosine production. Inactivation of adenosine deaminase and adenosine kinase may also contribute to adenosine production. On the other hand, the major role of endogenous adenosine is to increase coronary blood flow. This adenosine induced coronary vasodilatation is amplified by alpha 2 adrenoceptor stimulation. Adenosine induced vasodilatation is also enhanced by increasing H+ and opening ATP sensitive K+ channels, which occurs in the ischaemic myocardium. However, coronary vasodilatation is not the only effect of adenosine in the ischaemic myocardium. Stimulation of adenosine A2 receptors coupled to Gs proteins attenuates both free radical generation by activated leucocytes and aggregation of platelets. Adenosine A1 receptor activation coupled to G(i) proteins attenuates beta adrenoceptor mediated increases in myocardial contractility, Ca2+ influx into myocytes, and noradrenaline release from the presynaptic nerves. Any or all of these effects may attenuate ischaemic and reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of adenosine and its interaction with alpha adrenoceptor activity in ischaemic and reperfusion injury of the myocardium. 838 27

2',3'-dideoxyadenosine (ddAdo) and 2',3'-dideoxyinosine (ddIno) are potent and selective inhibitors of the replication of the human immunodeficiency virus type 1 (HIV1) in several cell culture systems. Equipotent in terms of antiviral activity, both compounds selectively inhibit the reverse transcription of HIV-1 by virtue of their conversion into ddATP. In human lymphoid cells ddAdo is converted to the active metabolite, ddATP, but it also undergoes rapid deamination, via adenosine deaminase, to form ddIno. ddIno, like ddAdo, gives rise to dideoxynucleotides of the dideoxy-adenylate series (ddAMP, ddADP and ddATP), as well as to IMP and to adenylate ribonucleotides. With the main object of blocking the deamination of ddAdo, we studied its anti-HIV-1 activity in the presence of different adenosine deaminase inhibitors, namely Coformycin (CF), 9-(erythro-2-hydroxy-3-nonyl) adenine (EHNA) and some deaza-EHNA derivatives. In contrast with reports on 2'-deoxycoformycin (Cooney et al., 1987), the adenosine deaminase inhibitors tested by us showed a significant increase in the antiviral activity of ddAdo, but not of ddIno. Enhancement was obtained with EHNA and CF concentrations up to 250 and > 12,500 times lower than their respective maximum non toxic doses. In combination with EHNA or CF, ddAdo could be used at concentrations up to ten times lower than those required to obtain the same degree of inhibition when ddAdo (or ddIno) was used alone. The use of EHNA or CF in combination with ddAdo at concentrations that inhibit the multiplication of HIV-1, allowed uninfected cells to maintain their normal multiplication rates. In fact, in combination experiments, cytotoxic effects were evident only with doses of EHNA, or CF and ddAdo 10 to 100 or more times higher than those required to inhibit HIV-1 significantly. The in vivo implications of these results for anti-HIV chemotherapy are discussed.
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PMID:Enhancement of the anti-HIV-1 activity of ddAdo by coformycin, EHNA and deaza-EHNA derivatives. 859 Mar 88

Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was shown to reverse the hypoxic pressor response (HPR) in the isolated, blood-perfused rat lung model. EHNA, an adenosine deaminase inhibitor, showed reversal of the HPR in a dose-dependent manner (EC50 = 129 +/- 30 microM). We found that the reversal of HPR by EHNA was not mediated by the adenosine receptors because the EHNA effect was not blocked by the adenosine receptor antagonist, 8-p-sulfophenyl-theophylline (67 microM; n = 6). Pretreatment with a cy-clic-3',5'-adenosine monophosphate (cAMP)-dependent protein kinase inhibitor, Rp-adenosine-3',5'-cyclic monophosphorothioate (0.5 mM; n = 4), blocked EHNA reversal of the HPR. As an alternative mechanism of action, EHNA inhibition of cyclic nucleotide phosphodiesterase(s) isozymes was studied in endothelium intact and denuded pulmonary arteries. Using anion-exchange chromatography the cyclic nucleotide phosphodiesterase (PDE) separated into predominantly PDE families 2 and a mixture of 3 and 4. DEAE fractions showing cAMP hydrolysis activated by 5 microM cyclic-3',5'-guanosine monophosphate (cGMP) had a Km for cAMP of 6.3 microM and an apparent Kact for cGMP of 1.4 microM. EHNA was shown to inhibit PDE2 competitively. In intact vessels, the IC50 for EHNA was 3.3 microM using 0.03 microM [3H]-cAMP substrate assayed in the presence of 2 microM cGMP and in denuded vessels 3.7 microM at 0.03 microM [3H]-cAMP substrate in the presence of 5 microM cGMP. Fractions in which cAMP hydrolysis was inhibited or not affected by 5 microM cGMP (PDE3 and 4, respectively) showed an IC50 of > 200 microM for EHNA. We conclude that reversal of the hypoxic pressor response by EHNA in the isolated, perfused rat lung model occurs with a mechanism involving in part inhibition of smooth muscle PDE2.
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PMID:Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic-3',5'-guanosine monophosphate-stimulated phosphodiesterase to reverse hypoxic pulmonary vasoconstriction in the perfused rat lung. 863 46

Monophosphoryl lipid A (MLA), a derivative of the minimal substructure of lipopolysaccharide (lipid A) possesses immunomodulatory activity of the parent lipid A yet enjoys reduced toxicity. It has previously been reported that pretreatment with MLA reduces myocardial infarct size and stunning in dogs following ischemia and reperfusion. The aim of this study was to evaluate the ability of monophosphoryl lipid A (MLA) to preserve global cardiac function and peripheral hemodynamics in a rabbit model of prolonged regional ischemia (90 min), and reperfusion (6 h). An evaluation of potential mechanisms by which MLA may preserve cardiac function was also undertaken. Single dose pretreatment with MLA (35 micrograms/kg i.v.) 24 h prior to ischemia resulted in significant improvement in left ventricular developed pressure, dP/dt, rate-pressure product and mean arterial pressure during reperfusion (P < 0.05 v control). Although in this model of prolonged ischemia MLA pretreatment did not reduce infarct size (54.5 +/- 11.4% in control v 63.3 +/- 8.3% in MLA, P = N.S.), evaluation of myocardial adenylate and adenosine catabolite pools at the end of ischemia indicated a preservation of ATP and ADP and a decreased production of downstream adenosine catabolites including inosine, xanthine and uric acid. Adenosine kinase, but not 5'-nucleotidase (5'-NTase) or adenosine deaminase activity determined following reperfusion was 76% and 60% higher (P < 0.05) in non-risk and post-ischemic myocardium of MLA pretreated rabbits compared with controls. Although there was a trend toward lower tissue myeloperoxidase activity in post-ischemic myocardium from treated rabbits, the results were not significantly different from control animals. These results suggest that a 24-h pretreatment with MLA, without further treatment during ischemia or reperfusion was associated with: (1) preservation of global myocardial function during reperfusion; (2) preservation of myocardial high energy adenylates and reduced formation of adenosine catabolites during ischemia; (3) elevated myocardial adenosine kinase activity. Increased recycling of adenosine to phosphorylated nucleotides may result from MLA's affect on adenosine kinase, which could explain the drugs effect on adenylate and adenosine metabolite pools.
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PMID:Preservation of global cardiac function in the rabbit following protracted ischemia/reperfusion using monophosphoryl lipid A (MLA). 874 27

1. Previous studies have shown that the rat duodenum contains P1 and P2Y purinoceptors via which it relaxes to adenosine and adenosine 5'-triphosphate (ATP) respectively. It has also been shown to contract to uridine 5'-triphosphate (UTP) and adenosine 5'-O-(3-thiotriphosphate) (ATP-gamma-S), and based on their differential inhibition by the P2 antagonist suramin it has been suggested that they act via two separate receptors. In addition, the rat duodenum has been shown to dephosphorylate ATP rapidly via ectonucleotidases and adenosine deaminase. In this study the responses of two preparations from the rat duodenum, the longitudinal muscle and the muscularis mucosae, were investigated using a series of nucleotides and suramin. 2. 2-Methylthioadenosine 5'-triphosphate (2-MeSATP), ATP, ATP-gamma-S and adenosine 5'-alpha,beta-methylene-triphosphonate (AMPCPP) each relaxed the longitudinal muscle, with an agonist potency order of 2-MeSATP > ATP = ATP-gamma-S > AMPCPP, while UTP and uridine 5'-diphosphate (UDP) were not observed to elicit relaxation. This indicates the presence of a relaxant P2Y-purinoceptor on the longitudinal muscle. The longitudinal muscle did not contract to any of the agonists at concentrations of 300 microM, apart from ATP-gamma-S which caused very weak contractions. 3. ATP-gamma-S, adenosine 5'-methylenediphosphonate (AMPCP), AMPCPP, ATP, UTP, adenosine 5'-diphosphate (ADP), UDP and 2-MeSATP each contracted the muscularis mucosae with an agonist potency order of ATP-gamma-S > or = AMPCP > or = AMPCPP = ATP = UTP = ADP = UDP >> 2-MeSATP, although maximal responses were not obtained at concentrations of 300 microM. The muscularis mucosae did not relax to any of the agonists at concentrations of 300 microM. 4. Suramin (1 mM) inhibited relaxations induced by ATP on the longitudinal muscle, shifting the relaxation concentration-response curve to the right. This further supports the presence of a P2Y-purinoceptor on this muscle layer. Suramin (1 mM) inhibited contractions induced by AMPCPP, but not those induced by ATP, UTP or ATP-gamma-S, in the muscularis mucosae. Desensitization of the muscularis mucosae was seen with AMPCPP, but not with UTP or ATP-gamma-S, and no cross-desensitization between AMPCPP and UTP or ATP-gamma-S was observed. This suggests there are two receptors which mediate contraction on the rat duodenum muscularis mucosae, one suramin-sensitive and the other suramin-insensitive. 5. ATP was rapidly degraded by the muscularis mucosae to ADP, adenosine 5'-monophosphate (AMP) and inosine, with no adenosine being detected. A similar rate of degradation was seen for UTP with UDP, uridine 5'-monophosphate (UMP) and uridine being formed and for 2-MeSATP with 2-methylthioadenosine 5'-diphosphate (2-MeSADP), 2-methylthioadenosine 5'-monophosphate (2-MeSAMP) and 2-methylthioadenosine being formed. AMPCPP and ATP-gamma-S were both degraded more slowly, AMPCPP being degraded to AMPCP, and ATP-gamma-S to ADP, AMP and inosine. Suramin (1 mM), did not significantly affect the rate and pattern of degradation of these nucleotides, apart from AMPCPP which was degraded slightly more slowly in the presence of suramin. 6. These results show that there is a P2Y-purinoceptor which mediates relaxation in the rat duodenum longitudinal muscle. They also show that there is a contraction-mediating suramin-sensitive receptor on the rat duodenum muscularis mucosae which is desensitized by AMPCPP, and thus is probably of the P2X subtype. In addition, there is a contraction-mediating suramin-insensitive receptor on the rat duodenum muscularis mucosae which is not desensitized by UTP or ATP-gamma-S, and at which ATP and UTP show equal potency, and is thus probably of the P2U subtype. In addition, the rat duodenum muscularis mucosae contains ectonucleotidases and adenosine deaminase, which rapidly degrade nucleotides, although the inhibition by suramin of this deg
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PMID:Responses of the longitudinal muscle and the muscularis mucosae of the rat duodenum to adenine and uracil nucleotides. 885 97

The effect of cyclic adenosine 3',5'-monophosphate (cAMP) on epileptiform activity in rat hippocampal slices was investigated. Bath-applied cAMP reversibly decreased the frequency of extracellularly recorded discharges in the CA3 subfield induced by bethanechol- or theophylline-containing solutions. Because cAMP was presumed to be relatively membrane impermeant, we developed and tested the hypothesis that this cAMP-mediated effect occurred extracellularly through the catabolic conversion of cAMP to 5'-AMP and, in turn, to adenosine, a known inhibitory neuromodulator. Three predictions derived from this catabolic hypothesis were tested. First, blockers of the enzymes involved were predicted to antagonize this effect of cAMP. In contrast, the coapplication of a cAMP-phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), or a 5'-nucleotidase inhibitor, adenosine 5'-[alpha, beta-methylene] diphosphate (AMP-CP), enhanced the cAMP-induced suppressive effect. Second, the nonhydrolyzable cAMP analogs, dibutyryl- and 8-bromo-cAMP, were predicted to be ineffective. Low concentrations (5-40 microM) of these two derivatives, however, also suppressed bethanechol-induced discharges, while, at a higher concentration (100 microM), both analogs increased discharge frequencies. Third, enzymatic catabolism of adenosine was predicted to antagonize cAMP's effect, but coapplying adenosine deaminase (10 U/mL) did not diminish this action. Because these data did not support the catabolic hypothesis, other, as yet undefined, mechanisms must be responsible for the discharge-suppressant effect of cAMP.
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PMID:Suppression of drug-induced epileptiform discharges by cyclic AMP in rat hippocampus. 933 68

The objective of the present study was to establish the optimal combination of inhibitors of adenosine metabolism and nucleotide precursors resulting in long-term increase in endogenous adenosine concentration without adverse metabolic consequences in non-ischemic cardiomyocytes and endothelial cells. Cardiomyocytes and endothelial cells were isolated after collagenase digestion of the rat heart. Freshly isolated cardiac myocytes or cultured endothelial cells were incubated for up to 8 h with no inhibitors or substrates or with various combinations of adenosine deaminase inhibitor: 5 micron M erythro-9(2-hydroxy-3-nonyl)adenine (EHNA), adenosine kinase inhibitors: 10 micro M 5'-iodotubercidin (ITu) or 10 micro M 5'-aminoadenosine (AA) and nucleotide precursors: 100 micro M adenine, 2.5 mm ribose and 5 mm inorganic phosphate. Nucleotide, nucleoside and base concentrations were evaluated at the end of the incubation by HPLC in cardiomyocyte or endothelial cells extracts and in incubation media. Adenosine content in cardiomyocyte suspension was enhanced after 3 h incubation in the presence of ITu+EHNA as compared to EHNA alone (2.8+/-0.2 v 0.9+/-0.2 nmol/mg protein, respectively). ATP decreased from an initial value of 22.7+/-0.7 nmol/mg protein to 18.9+/-0.7 in the presence of ITu+EHNA, while ATP was maintained at 21.8+/-0.7 nmol/mg protein with EHNA. With adenine+ITu+EHNA, the changes were similar to those observed with ITu+EHNA. However, with ribose+adenine+ITu+EHNA, ATP increased to 25. 8+/-1.2 nmol/mg protein and adenosine concentration was elevated to 3.9+/-0.3 nmol/mg protein. Similar results were observed if AA was used instead of ITu to inhibit adenosine kinase. All the changes were maintained after 8 h of incubation. Adenosine content was increased in endothelial cells incubated with ITu+EHNA to 3.1+/-0.4 nmol/mg protein as compared to 1.1+/-0.2 nmol/mg protein with EHNA alone after 3 h, while ATP decreased (18.1+/-1.1 v 22.0+/-1.4 nmol/mg protein with EHNA+ITu or EHNA, respectively). In the presence of adenine+ITu+EHNA, adenosine content increased after 3 h to 6.5+/-0.9 nmol/mg protein while ATP was elevated to 26.1+/-0.8 nmol/mg protein. Additional presence of ribose was without effect. No changes in adenylate energy charge were observed in cardiomyocytes or endothelium under any conditions studied. Inhibition of adenosine kinase and adenosine deaminase caused a decrease in ATP together with increased adenosine content both in endothelial cells and cardiomyocytes. However, the addition of adenine (endothelial cells) or adenine with ribose (cardiomyocytes) together with inhibitors of adenosine metabolism protected cells from ATP depletion and further increased adenosine concentration.
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PMID:Adenine/ribose supply increases adenosine production and protects ATP pool in adenosine kinase-inhibited cardiac cells. 951 42

1. When perfused with a medium containing no added magnesium and 4-aminopyridine (4AP) (50 microM) hippocampal slices generated epileptiform bursts of an interictal nature. We have shown in a previous study that adenosine 5'-triphosphate (ATP) depressed epileptiform activity and that this effect was blocked by the adenosine A1 receptor antagonist cyclopentyltheophylline but was not affected by adenosine deaminase. This implied that ATP might act indirectly at P1 receptors or at a xanthine-sensitive P2 receptor. The aim of the present study was to investigate further the action of ATP on epileptiform activity. 2. ATP can be metabolized by ecto-nucleotidases to adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) and adenosine, respectively. Each of these metabolites can activate receptors in its own right: P2 receptors for ADP and P1 receptors for AMP and adenosine. 3. We now show that both AMP and ATP (50 microM) significantly decrease epileptiform discharge rate in a rapid and reversible manner. 5'Adenylic acid deaminase (AMP deaminase, AMPase) (0.2 u ml(-1)), when perfused alone did not significantly alter the discharge rate over the 10 min superfusion period used for drug application. When perfused concurrently with AMP (50 microM), AMP deaminase prevented the depressant effect of AMP on discharge rate. 4. AMP deaminase, at a concentration of 0.2 u ml(-1) which annulled the effect of AMP (50 microM), prevented the inhibitory activity of ATP (50 microM). A higher concentration of ATP (200 microM) depressed the frequency of spontaneous bursts to approximately 30% control and this response was also prevented by AMP deaminase. 5. Superfusion of the slices with 5'-nucleotidase also prevented the inhibitory activity of ATP on epileptiform discharges. 6. The results suggest that AMP mediates the inhibitory effects of ATP on epileptiform activity, a conclusion which can explain the earlier finding that cyclopentyltheophylline but not adenosine deaminase inhibited the effect of ATP. A corollary to this is that, when examining the pharmacology of ATP, care must be taken to inactivate AMP with AMP deaminase, as well as adenosine with adenosine deaminase, before a direct action of ATP on P1 receptors can be postulated. Failure to do so may have led to erroneous conclusions in some previous studies of nucleotide activity on nucleotide receptors.
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PMID:Adenosine monophosphate as a mediator of ATP effects at P1 purinoceptors. 969 Aug 76


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