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)

The loss of the catabolic products of adenosine triphosphate in the form of purine nucleosides and oxypurines during ischemia and subsequent reperfusion may limit adenine nucleotide regeneration. This study compared the effects of infusion of inhibitors of the major reactions involved in the degradation of adenosine triphosphate to inosine on the postischemic recovery of high energy phosphate and myocardial function. Inhibitors of adenylate kinase, 5'nucleotidase, adenosine translocase and adenosine deaminase were studied. Following 30 minutes of ischemia, only hearts infused with alpha, beta, methylene adenosine diphosphate (5' nucleotidase inhibitor) recovered significantly better ventricular function than control (p less than 0.05), but all hearts had increased adenosine triphosphate regeneration (p less than 0.05). The formation and washout of greater than 30% of the total adenine pool metabolites was not prevented by any drug. Nevertheless all manipulations of adenine metabolism resulted in recruitment of high energy phosphate during preischemic infusion.
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PMID:The influence of inhibitors of the ATP degradative pathway on recovery of function and high energy phosphate after transient ischemia in the rat heart. 302 47

The loss of the catabolic products of adenosine triphosphate in the form of purine nucleosides and oxypurines during ischemia and subsequent reperfusion may limit adenine nucleotide regeneration. This study compared the effects of infusion of inhibitors of the major reactions involved in the degradation of adenosine triphosphate to inosine on the postischemic recovery of high energy phosphate and myocardial function. Isolated rat hearts were made totally ischemic after a 5-min infusion of p1,p5-diadenosine pentaphosphate, alpha, beta-methylene adenosine diphosphate, nitrobenzyl-6-thioinosine, or erythro-9-(2-hydroxy-3-nonyl) adenine, which are inhibitors of adenylate kinase, 5'-nucleotidase, adenosine translocase, and adenosine deaminase, respectively. Following 30 min of ischemia, only hearts infused with alpha, beta-methylene adenosine diphosphate recovered significantly better ventricular function than did the control (P less than 0.05), but all hearts had increased adenosine triphosphate and creatine phosphate regeneration (P less than 0.05). The formation and washout of greater than 30% of the total adenine pool metabolites were not prevented by any drug. Nevertheless all manipulations of adenine metabolism resulted in recruitment of high energy phosphate during preischemic infusion which may have potential benefits in elective ischemic arrest.
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PMID:Influence of inhibitors of ATP catabolism on myocardial recovery after ischemia. 304 Nov 5

Two main candidates, adenosine 5'-triphosphate (ATP) and vasoactive intestinal peptide (VIP), have been proposed as inhibitory transmitters at neuromuscular junctions in the gut. We have used a photoaffinity analogue of ATP, 3'-O-(4-benzoyl)benzoyl ATP or BzATP, that binds covalently to ATP receptors and inactivates them in the presence of light and a specific high-affinity VIP antiserum in order to examine the contributions of ATP and VIP to neurally induced relaxation in circular smooth muscle of the gastric fundus of the guinea pig. VIP and ATP caused dose-dependent relaxation; the effect of ATP was equal to that of its stable isostere, alpha, beta-methylene ATP, and was resistant to degradation by adenosine deaminase, indicating interaction of ATP with purinergic P2-receptors. Relaxation induced by VIP was selectively inhibited by VIP antiserum (final dilution 1:120), while that induced by ATP was selectively inhibited by photoactivated BzATP. Relaxation induced by electrical field (i.e., neural) stimulation was inhibited by VIP antiserum only; photoactivated BzATP had no effect. Inhibition of neurally induced relaxation ranged from 86% (P less than 0.01) at the lowest frequencies to 34% (P less than 0.01) at the highest frequencies. Maximal field stimulation caused an 11-fold increase in VIP release from intramural neurons. The results strongly favor VIP as the neural mediator of gastric relaxation.
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PMID:Vasoactive intestinal peptide as a neural mediator of gastric relaxation. 396 63

In the transversely cut rat hippocampus, adenosine caused a dose-dependent increase in the accumulation of [3H]cyclic AMP from [3H]ATP. Adenosine breakdown products were inactive. AMP was somewhat less effective than adenosine, and its effect could be partially, but not completely, abolished by alpha, beta-methylene-ADP and GMP, which inhibited its metabolism by 5'-nucleotidase. The effect of adenosine was unaffected by inhibitors of adenosine deaminase, but enhanced by several inhibitors of adenosine uptake. Some analogues of adenosine, including N6-phenylisopropyladenosine (PIA), 2-chloroadenosine and adenosine 5'-ethylcarboxamide (NECA), were more active than adenosine, whereas others such as 2-deoxyadenosine and 9-(tetrahydro-2-furyl)adenine (SQ 22536) actually inhibited the response. The effect of PIA was highly stereospecific. The action of adenosine was inhibited by several alkylxanthines, the most potent of which was 8-phenyltheophylline. [3H]Cyclohexyladenosine (CHA) bound specifically to cell membranes from the rat hippocampus. The extent of binding was similar to that found in other cortical areas. The relative potency of some adenosine analogues and alkylxanthines to displace labelled CHA was essentially similar to their potency as effectors of the cyclic AMP system. Adenosine contributed to the cyclic AMP-elevating effect of alpha-adrenoceptor-stimulating drugs and several amino acids, but not to that seen with isoprenaline. The cyclic AMP increase seen following depolarization was only partially adenosine-dependent. The present results demonstrate that the rat hippocampus contains adenosine receptors mediating cyclic AMP accumulation and that these receptors have similar characteristics to those mediating pyramidal cell depression. Adenosine-induced cyclic AMP accumulation may be used as a biochemical correlate to electrophysiology and as a convenient parameter to assess the influence of drugs on adenosine mechanisms in the rat hippocampus.
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PMID:Adenosine receptors mediating cyclic AMP production in the rat hippocampus. 612 48

In an attempt to further define the site of myocardial adenosine formation, isolated guinea pig hearts were perfused with potent inhibitors of 5'-nucleotidase [alpha, beta-methylene adenosine 5'-diphosphate (AOPCP)] and of nucleoside transport [4-nitrobenzyl thioinosine (NBMPR)]. AOPCP (50 microM) inhibited the activity of cardiac ecto-5'-nucleotidase by 85% but did not influence the release of adenosine, inosine, and hypoxanthine formed at an accelerated rate by the heart during hypoxic perfusion (30% O2). In contrast, NBMPR (5 microM) diminished the hypoxia-induced release of adenosine and its degradatives and greatly potentiated the increase of myocardial tissue levels of respective purine compounds. Studies carried out with 5'-deoxyadenosine, an adenosine derivative that is not metabolized, indicate NBMPR to inhibit both uptake and release of adenosine in the isolated heart and in human erythrocytes. Cell fractionation studies on guinea pig ventricular muscle revealed that 5'-nucleotidase, though mainly associated with the membrane fraction, is also found in the cardiac cytosol (200,000-g supernatant), exhibiting a different substrate specificity. Furthermore, S-adenosylhomocysteine hydrolase as well as adenosine kinase and adenosine deaminase proved to be exclusively present in the cytosolic fraction. Our findings suggest that in the hypoxic heart a) ecto-5'-nucleotidase most likely is not involved in the formation of adenosine, b) release of adenosine from the heart requires adenosine to be transported across the sarcolemma membrane, and c) adenosine is predominantly formed intracellularly, a process involving cytosolic 5'-nucleotidase and/or S-adenosylhomocysteine hydrolase.
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PMID:Different sites of adenosine formation in the heart. 626 1

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

The role of adenosine in postcontraction hyperemia (PCH) following sustained, maximal isometric contractions was studied in free-flowing dog gracilis muscles. The hemodynamic responses to contraction were examined in the presence and absence of dipyridamole (an adenosine transport inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, an adenosine deaminase inhibitor), or alpha, beta-methyleneadenosine-5'-diphosphate (AOPCP, an inhibitor of 5'-nucleotidase). Each muscle was stimulated to contract for 1, 3, 5, and 10 s during saline and drug infusions. For each contraction, the tension-time integral (TT), excess flow (EQ), and excess oxygen consumption (EVo2) were computed. Linear regression analyses were then performed on EQ vs. TT, EVo2 vs. TT, and EQ vs. EVo2. An alteration of the PCH response by the drug was determined as any significant change from the saline control in the slope of the linear regression of EQ vs. EVo2. Dipyridamole and EHNA caused increases of 73 and 48%, respectively, in the slope of EQ vs. EVo2, whereas AOPCP decreased the slope by 41%. The changes in the PCH produced by these drugs are consistent with the hypothesis that an increase in interstitial adenosine during muscular contraction contributes to PCH.
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PMID:Adenosine as a mediator of postcontraction hyperemia in dog gracilis muscle. 669 37

1 The effects of adenyl compounds were examined on the rat atrium and ventricle. 2 Adenosine, adenosine 5'-monophosphate, adenosine 5'-diphosphate, adenosine 5'-triphosphate (ATP) and beta, gamma-methylene ATP (APPCP) produced negative inotropic effects on the rat atrium. These inhibitory effects were antagonized by 8-phenyltheophylline (8-PT), a P1-purinoceptor antagonist, and potentiated by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), an adenosine deaminase inhibitor, but were not affected by dipyridamole, which blocks adenosine uptake. 3 alpha, beta-Methylene ATP (APCPP), which is resistant to degradation, did not produce a similar inhibitory response in the rat atrium. 4 Adenosine did not affect the basal developed force of the rat ventricle nor did it affect the beta-adrenoceptor-mediated positive inotropic effect. 5 Very high concentrations of ATP (0.1-3 mM) produced negative inotropic effects in the rat ventricle. APPCP (0.3 mM) also produced an inhibitory response, which was significantly smaller than that produced by ATP (0.3 mM). APCPP elicited excitation rather than the expected inhibitory response. 6 The inhibitory effect of ATP in the rat ventricle was not blocked by indomethacin, 8-PT or atropine. 7 It is possible that the action of ATP in the rat ventricle is mediated via P2-purinoceptors and that the lack of inhibitory action of APCPP on the rat ventricle is due to the difference in structural conformation between ATP and APCPP. 8 It seems likely that inhibitory P1-purinoceptors are present in the rat atrium and that the inhibitory responses produced by ATP in the rat ventricle may be mediated via P2-purinoceptors.
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PMID:The effect of adenyl compounds on the rat heart. 687 43

Adenine dinucleotides such as beta-NAD, alpha-NAD, NADP, 3-aminopyridine adenine dinucleotide, flavin adenine dinucleotide, 3',5'-and 2',5'-adenylyladenosine mimicked the inhibitory effects of adenosine and adenine nucleotides on electrically evoked contractions of the rat and mouse isolated superfused vas deferens. The inhibitory effects were blocked by theophylline or adenosine deaminase, unaffected by the nucleotidase inhibitor alpha, beta-methylene ADP and enhanced by inhibition of adenosine deaminase. The inhibitory effects were associated with a release of purines from the vasa after preloading with [3H]adenosine. It is suggested that these compounds activate a receptor, causing the release of adenosine which is largely responsible for the inhibitions. Diadenosine pyrophosphate and triphosphate caused only depression of the vas twitch, whereas the pentaphosphate and hexaphosphate derivatives caused contraction, followed by inhibition at higher concentrations. These inhibitions were only partly reduced by theophylline or deaminase, but both contractile and inhibitory effects were enhanced by alpha, beta-methylene ADP. Noradrenaline contractions were also reduced by the higher polyphosphates. It is suggested that there may be a receptor for these dinucleotides, located at least in part postjunctionally. The pentaphosphate and hexaphosphate compounds mimicked the effects of nerve stimulation on the guinea-pig bladder, being substantially more potent than beta, gamma-methylene-ATP, and on the taenia caeci, where contraction or relaxation could be produced depending on resting tone.
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PMID:Actions of adenine dinucleotides on the vas deferens, guinea-pig taenia caeci and bladder. 731 4

It has been claimed recently that, in several cell types, ATP can induce a stimulation of cAMP production which is sensitive to methylxanthine inhibition and is not mediated by the ATP degradation product, adenosine. One explanation for these results would be direct activation of adenosine A2 receptors by ATP itself. We have therefore investigated whether adenine nucleotides are ligands of adenosine A2A receptors from bovine striatum. We show here that ATP, ADP, AMP and their phosphorothioates analogues (ATP gamma S, ADP beta S and AMP alpha S), at a 100 microM concentration, produced a 83-91% inhibition of the binding of [3H]CGS21680, an adenosine A2A receptor agonist, to striatum membranes. However, this action was inhibited by adenosine deaminase or by adenosine 5'-O-(alpha, beta-methylene)diphosphate (APCP), an inhibitor of 5'-nucleotidase-mediated AMP degradation. The effects of adenosine deaminase and APCP were dependent on their concentration. These results indicate that ATP, ADP and even AMP can exert an effect on the adenosine A2A receptors only through their breakdown into adenosine by ectonucleotidases.
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PMID:Evidence that ATP, ADP and AMP are not ligands of the striatal adenosine A2A receptors. 822 25


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