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)

The phosphodiesterase (PDE) inhibitors AY-31,390, milrinone and pelrinone (AY-28,768) were analyzed in human platelet aggregatory systems and in a rabbit arteriovenous shunt model to delineate their activity. AY-31,390 showed a remarkably potent capacity to inhibit human antithrombotic platelet aggregation. AY-31,390 inhibited arachidonic acid, U46619, collagen, epinephrine (second phase) and adenosine diphosphate (second phase) induced platelet aggregation (PA) with IC50 values of 0.18, 0.21, 0.54, 0.43 and 0.20 microM, respectively. Milrinone, although less potent than AY-31,390, inhibited PA with IC50 values of 2.1, 2.0, 5.4, 3.7 and 4.1 microM and pelrinone's IC50 values were 2.8, 6.6, 13.3, 18.6 and 11.8 microM, respectively. Platelets which were incubated with AY-31,390, milrinone or pelrinone, washed with Hanks' balanced salt solution and then resuspended in platelet poor plasma, lost their inhibitory activity in collagen and arachidonic acid PA systems. These results suggested that AY-31,390, milrinone and pelrinone did not bind tightly to cAMP PDE. If human platelet-rich plasma was pretreated with adenosine deaminase, an enzyme that degrades adenosine, the inhibitory effect of milrinone and to a lesser extent pelrinone was reversed. AY-31,390 did not produce a loss of activity with adenosine deaminase in the arachidonic acid system and only a small loss in the collagen system. Adenosine did not appear to be a meaningful factor in AY-31,390's inhibitory activity. Pelrinone, milrinone to a greater extent, and AY-31,390 to the greatest extent were effective inhibitors of white thrombus formation in the in vivo rabbit arteriovenous shunt model. These PDE III inhibitors were potent deterrants of platelet aggregation and white thrombus formation; these agents would be expected to be efficacious therapeutic antithrombotics.
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PMID:Comparative antithrombotic activities of the phosphodiesterase inhibitors pelrinone (AY-26,768), AY-31,390 and milrinone. 189 59

A potential physiologic role of extracellular adenosine triphosphate (ATP) on platelet function is proposed in this report. It is widely accepted that ATP competitively inhibits adenosine diphosphate (ADP)-induced platelet aggregation. Our observations of platelet aggregation with the agonists, collagen, epinephrine, and ADP in the presence of 180 mumol/L ATP could support this competitive nature of ATP. However, the disaggregation of maximally aggregated platelets induced by ATP, theophylline, or ATP plus theophylline indicates that additional mechanisms of ATP action may be present. Extracellular gamma-32P-ATP (7 pmol) labels surface-membrane proteins in intact platelets as demonstrated by several criteria. The reaction is Ca++-dependent. Stimulation by calcium occurs in the physiologic range of 1 to 5 mmol/L. Significant levels of phosphorylation occur within one minute with near maximal levels reached by five minutes. Platelet cyclic AMP (cAMP) levels were elevated in a dose-dependent fashion in cells incubated for four minutes with increasing amounts of extracellular ATP (18 to 540 nmol). The addition of ATP plus theophylline resulted in a synergistic stimulation of cAMP levels. ATP was not being hydrolyzed to adenosine by plasma nucleotidases, as demonstrated by the lack of effect of ten U of adenosine deaminase. The phosphorylation of surface proteins by extracellular ATP released from activated platelets may modulate platelet responsiveness to agonists at distances removed from the site of vascular injury. Phosphorylation may also play a role in signal transduction to regulate the levels of intracellular cAMP, which further inhibits platelet activation.
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PMID:Modulation of platelet function by extracellular adenosine triphosphate. 254 37

Forskolin, a plant (Coleus forskohlii) diterpene, inhibits ADP-induced (human: IC50, 2.3 +/- 1.0 microM; rat: IC50, 1.2 +/- 0.5 microM) and collagen-induced (human: IC50, 2.4 +/- 1.2 microM; rat: 0.6 +/- 0.2 microM) platelet aggregation in human and rat platelet-rich plasma (PRP). Human blood levels of adenosine (Ado) are low (100-300 nM) as compared to levels in rat plasma (7.55 +/- 0.51 microM). Ado is a natural antiplatelet and vasodilatory agent produced by vascular endothelium, heart and other body tissues. If the plasma Ado is degraded by pretreatment of PRP with adenosine deaminase (ADA), forskolin inhibition on platelet aggregation is reduced by 2-4 fold both in human and rat blood. On the other hand, if the physiological steady state levels of Ado are maintained by collecting the blood in the presence of the inhibitors of ADA (2'-deoxycoformycin, dCF, 5 microM) and Ado uptake (dipyridamole, 10 microM or dilazep, 2 microM), forskolin inhibition (IC50, 3.2 microM) on platelet aggregation in human PRP is potentiated by 20-40 fold (IC50, 0.075-0.15 microM). Similar potentiated forskolin effect (IC50, 0.53 microM) is seen if the ADA-treated human PRP is replenished with a low level of Ado (50 nM) after ADA inactivation by dCF and Ado-uptake blockade by dilazep. If the plasma is replenished with a higher concentration of Ado (300 nM), greater potentiation is seen (IC50, 0.23 microM). Forskolin is 2-4 fold more inhibitory in rat PRP than in human PRP, partially due to the presence of higher levels of Ado in the rat plasma. These studies demonstrate an important role of plasma Ado in the antiplatelet activity of forskolin and this effect can be greatly potentiated by the clinically used drugs, dipyridamole and dilazep.
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PMID:Significance of plasma adenosine in the antiplatelet activity of forskolin: potentiation by dipyridamole and dilazep. 274 84

The potent inhibitor of platelet cAMP phosphodiesterase (PDE) HL 725 (9,10-Dimethoxy-2-mesitylimino-3-methyl-3, 4,6,7-tetrahydro-2H-pyrimido(6,1-A)-isoquinoline-4-one-hydrochloride), was examined for its effects on human and rat platelet aggregation. Strong inhibitory effects are seen on collagen-induced platelet aggregation both in rat platelet-rich plasma (PRP) (IC50, 54 +/- 12 nM) and whole blood (IC50, 57 +/- 25 nM). Compared to the effects on rat platelets, HL 725 is about two-fold less inhibitory in human PRP (IC50, 94 +/- 29 nM) and whole blood (IC50, 126 +/- 50 nM). The inhibitory action of HL 725 can be reversed by washing and resuspension of the platelets, suggesting that HL 725 does not bind tightly to cAMP PDE. If human or rat PRP is pretreated with adenosine deaminase, an enzyme that degrades adenosine or 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, the inhibitory effect of HL 725 is reversed. Similar blockade of the inhibitory actions of several other inhibitors of cAMP PDE such as RA 233, RX-RA 69 (analogs of dipyridamole) and oxagrelate is seen by adenosine deaminase pretreatment. The nucleoside transport inhibitors, dilazep and dipyridamole which are non-inhibitory alone to platelet aggregation, strongly potentiate (about 10-fold) the inhibitory action of HL 725 on collagen-induced platelet aggregation in human whole blood. However, if the whole blood is pretreated with adenosine deaminase, no inhibitory effect of dipyridamole plus HL 725 is seen on platelet aggregation. These studies demonstrate that plasma adenosine plays a crucial role in the antiaggregatory actions of HL 725 and several other inhibitors of cAMP PDE both in human and rat blood.
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PMID:Role of plasma adenosine in the antiplatelet action of HL 725, a potent inhibitor of cAMP phosphodiesterase: species differences. 282 50

Activity of adenosine deaminase (EC 3.5.4.4) was studied in thrombocytes of donors and patients with various hematological diseases. The enzymatic activity was decreased in acute leukemia, chronic myeloleukemia, chronic leukemia and blast transformation myeloma, microspherocytic and hypoplastic anemias. Variable level of the activity was observed in chronic lympholeukemia and non-Hodgkin disease. In all the diseases studied functions of thrombocytes were altered after treatment with various aggregating agents (ADP, thrombin, collagen, adrenaline, ristomycin).
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PMID:[Platelet adenosine desaminase in various hematological diseases]. 406 12

EG626 (oxagrelate), a specific inhibitor of cyclic AMP phosphodiesterase, produced in vitro a concentration-dependent inhibition of platelet aggregation induced by collagen and ADP in human platelets. When adenosine was added to the platelet rich plasma (PRP) in the presence of a threshold concentration of EG626, the potency of adenosine in inhibiting platelet aggregation was markedly potentiated. This potentiating effect of EG626 proved to be synergistic, but not additive and was accompanied by a marked accumulation of cyclic AMP in the platelets. The antiaggregating and cyclic AMP increasing activities of adenosine were little affected by S-(p-nitrobenzyl)-6-thioguanosine (6TG), an uptake inhibitor of adenosine, or 2'-deoxycoformycin, an inhibitor of adenosine deaminase. The incorporation of adenosine into platelets was abolished by 6TG. These observations indicate that incorporation of adenosine into platelets is not required for inhibition of aggregation or an increase in cyclic AMP and that the site of action of adenosine is probably extracellular. It also appears that the synergistic action by EG626 is not the result of an inhibition of adenosine uptake and/or adenosine deaminase. This speculation is supported in part by the finding that EG626 also potentiates the antiaggregating activity of 2-chloroadenosine. Antiaggregating activity of prostaglandin E1, an activator of adenylate cyclase, was markedly potentiated in combination with EG626. Dibutyryl cyclic AMP showed a time-dependent inhibition of the platelet aggregation, and the inhibitory action was markedly potentiated by EG626. Qualitatively similar results were obtained with another phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). All these data suggest that the synergistic potentiation of the antiaggregating activity of adenosine by EG626 might be due to the synergistic accumulation of cyclic AMP in the platelets. This action is mediated through activation of adenylate cyclase by adenosine in combination with the inhibition of cyclic AMP phosphodiesterase by EG626.
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PMID:Potentiation of antiaggregating activity of adenosine by a phosphodiesterase inhibitor, EG626 (oxagrelate), in human platelets in vitro. 620 94

ATP and ADP are simultaneously released from activated platelets in equimolar concentrations. Micromolar concentrations of ATP inhibit platelet aggregation by both competitive and non-competitive mechanisms. The current studies addressed the question of how platelets respond to agonists in the presence of nanomolar and micromolar concentrations of ATP and ADP alone or in combination. This is a significant issue since the concentration of ATP +/- ADP may vary widely within a microenvironment depending upon the source and cause for the release of the nucleotides. ATP (1-10 nM) was found to significantly enhance the thromboxane A2 analog, U44619-, collagen- and thrombin-induced platelet aggregations. Conversely, ATP at 1-100 microM inhibited these same reactions. ADP, in general, behaved exactly opposite to ATP. When equal amounts of ATP and ADP were added together the ADP response appeared to predominate. The observed ATP-induced response was not due to a hydrolytic product as evidenced by an unaltered response to ATP in the presence of adenosine deaminase or the ATP generating system, creatine phosphate plus creatine phosphokinase. Adenosine (1-10 nM), like ADP, inhibited agonist-induced platelet aggregation. The stimulation of agonist-induced platelet aggregation by 1-10 nM extracellular ATP appears to depend upon the phosphorylation of platelet membrane ecto proteins. The ATP analog, beta gamma-methylene ATP, that is incapable of serving as a phosphate donor for protein kinases, inhibited rather than stimulated agonist-induced platelet aggregation. The dual response of platelets to low and high concentrations of extracellular ATP +/- ADP may play a physiological role in hemostasis and thrombosis under normal and pathological conditions.
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PMID:A possible dual physiological role of extracellular ATP in the modulation of platelet aggregation. 904 33

Although infectious, inflammatory and neoplastic diseases frequently involve the pleural space and walls, little is known about the immunological and molecular mechanisms underlying pleural disorders. This article provides an overview of recent insights into immunobiological processes likely to play a role in the pathogenesis of pleural disorders. Pleural involvement in certain diseases is associated with the infiltration of a number of different types of immune cells, such as neutrophils, eosinophils or lymphocytes, in various proportions depending on both the course and the aetiology of the underlying disease. In addition to infiltrating cells, mesothelial cells have been demonstrated to actively participate in pleural inflammation via release of various mediators and proteins, including platelet-derived growth factor (PDGF), interleukin-8, monocyte chemotactic peptide (MCP-1), nitric oxide (NO), collagen, antioxidant enzymes and the plasminogen activation inhibitor (PAI). Furthermore, several inflammatory mediators have been detected at increased concentrations within pleural effusions, including lipid mediators, cytokines and proteins (adenosine deaminase, lysosyme, eosinophil-derived cationic proteins, and products of the coagulation cascade). The presence of these mediators underline the concept of pleural inflammation, and certain cytokines seem to characterize a specific aetiology of pleurisy. The understanding of these processes and the sequence of events leading to pleural loculation, pleural adhesion or repair are likely to provide the basis for early therapeutic intervention and reduce pleural-associated morbidity.
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PMID:Immunobiology of pleural inflammation: potential implications for pathogenesis, diagnosis and therapy. 938 73

The objective of this study was to characterize the effects of exogenous and endogenous (cardiac fibroblast-derived) adenosine on [3H]proline and [3H]leucine incorporation, which are reliable markers of collagen and total protein synthesis, respectively, in rat left ventricular cardiac fibroblasts. Growth-arrested confluent cardiac fibroblast monolayers were stimulated with 2.5% fetal calf serum (FCS) in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), or modulators of adenosine levels including (1) erythro-9-(2-hydroxy-3-nonyl) adenine (adenosine deaminase inhibitor), (2) dipyridamole (adenosine transport blocker), and (3) iodotubericidin (adenosine kinase inhibitor). All agents inhibited in a concentration-dependent fashion FCS-induced [3H]proline and [3H]leucine incorporation. These effects were blocked by KF17837 (selective A2 antagonist) and 1,3-dipropyl-8-(p-sulfophenyl)xanthine (A1/A2 receptor antagonist) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A1 antagonist), thus excluding the participation of A1 receptors. The lack of effect of CGS21680 (selective A2A agonist) excluded involvement of A2A receptors, thus suggesting a major role for A2B receptors. Comparisons of the inhibitory potencies of N6-cyclopentyladenosine (selective A1 agonist), 5'-N-ethylcarboxamidoadenosine (A1/A2 agonist), and 5'-N-methylcarboxamidoadenosine (A1/A2 agonist) were consistent with that of an A2B receptor subtype mediating the inhibitory effects. We conclude that adenosine inhibits FCS-induced collagen and total protein synthesis in cardiac fibroblasts via activation of A2B receptors. These studies suggest, but do not prove, that endogenous adenosine may protect against cardiac fibrosis.
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PMID:Adenosine inhibits collagen and protein synthesis in cardiac fibroblasts: role of A2B receptors. 953 19

Estradiol inhibits smooth muscle cell growth; however, the mechanisms involved remain unclear. Because estradiol stimulates cAMP synthesis and adenosine inhibits cell growth, we hypothesized that the conversion of cAMP to adenosine (ie, the cAMP-adenosine pathway) mediates in part the inhibitory effects of estradiol on vascular smooth muscle cell growth. To test this hypothesis, we examined the effects of estradiol (0.001 to 1 micromol/L) on serum-induced DNA, collagen, and total protein synthesis and cell number in the absence and presence of 1, 3-dipropyl-8-p-sulfophenylxanthine (10 nmol/L; A(1)/A(2) adenosine receptor antagonist), KF17837 (10 nmol/L; selective A(2) adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (10 nmol/L; selective A(1) adenosine receptor antagonist), and 2', 5'-dideoxyadenosine (10 micromol/L; adenylyl cyclase inhibitor). Estradiol inhibited all measures of cell growth, and the concentration-dependent inhibitory curves for estradiol were shifted to the right (P<0.05) by 1,3-dipropyl-8-p-sulfophenylxanthine, KF17837, and 2',5'-dideoxyadenosine but not by 8-cyclopentyl-1, 3-dipropylxanthine. Moreover, the inhibitory effects of estradiol were enhanced by stimulation of adenylyl cyclase with forskolin and by inhibition of adenosine metabolism with erythro-9-(2-hydroxy-3-nonyl)adenine plus iodotubericidin (adenosine deaminase and kinase inhibitors, respectively). Estradiol also increased levels of cAMP and adenosine, and these effects were blocked by 2',5'-dideoxyadenosine (P<0.05). Our results support the hypothesis that estradiol stimulates cAMP synthesis and cAMP-derived adenosine regulates smooth muscle cell growth via A(2) adenosine receptors. Thus, the cAMP-adenosine pathway may contribute importantly to the antivasooclusive effects of estradiol.
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PMID:Estradiol inhibits smooth muscle cell growth in part by activating the cAMP-adenosine pathway. 1064 8


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