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)

Prostaglandins F1 alpha and F2 alpha, at high concentrations (greater than or equal to 28 microM) enhanced cyclic AMP accumulation in dog thyroid slices. At lower concentrations, they inhibited the cyclic AMP accumulation induced by thyrotropin (TSH), prostaglandin E1, and cholera toxin. This effect was rapid in onset and of short duration, calcium-dependent and suppressed by methylxanthines. Prostaglandin F alpha also inhibited TSH-induced secretion and activated iodide binding to proteins. These characteristics are similar to those of carbamylcholine action, except that prostaglandins F did not enhance cyclic GMP accumulation. The effect of prostaglandin F alpha was not inhibited by atropine, phentolamine and adenosine deaminase and can therefore not be ascribed to an induced secretion of acetylcholine, norepinephrine or adenosine. It is suggested that prostaglandins F act by increasing influx of extracellular Ca2+. Arachidonic acid also inhibited the TSH-induced cyclic AMP accumulation. However this effect was specific for TSH, it was enhanced in the absence of calcium and was not inhibited by methylxanthines or by indomethacin at concentrations which completely block its conversion to prostaglandin F alpha. Arachidonic acid action is sustained. This suggests that arachidonic acid inhibits thyroid adenylate cyclase at the level of its TSH receptor and that this effect is not mediated by prostaglandin F alpha or any other cyclooxygenase product.
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PMID:Effects of prostaglandins F alpha on dog thyroid cyclic AMP level and function. 628 47

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

Recently, an inhibitor of adenosine deaminase, erythro-9-(2-hydroxyl-3-nonyl)adenine (EHNA), was shown to selectively block the activity of purified cGMP-stimulated phosphodiesterase (PDE) (cGS-PDE, or PDE2) in human and porcine heart [J. Mol. Cell. Cardiol. 24 (Suppl. V):102 (1992)]. Because cGS-PDE was found to mediate the cGMP-induced inhibition of L-type Ca2+ current (Ica) in frog ventricular cells, we tested the effects of EHNA in this preparation. Ica was measured using the whole-cell patch-clamp technique and a perfusing pipette. EHNA (0.3-30 microM) had no significant effect on either basal Ica or isoprenaline (1 nM)- or cAMP (10 microM)-elevated Ica. However, EHNA dose-dependently (IC50 approximately 3 microM) reversed the inhibitory effect of cGMP on cAMP-stimulated Ica. EHNA (30 microM) also blocked the inhibitory effect of NO donors, such as sodium nitroprusside (1 mM) and 3-morpholinosydnonimine (30 microM), on isoprenaline-stimulated Ica. In addition, EHNA dose-dependently (IC50 approximately 4-5 microM) inhibited the cGMP-induced stimulation of PDE activity in frog ventricle particulate fraction, as well as purified soluble cGS-PDE. However, EHNA (up to 30 microM) did not modify the activities of three other purified soluble PDE isoforms. Moreover, EHNA did not change the Ka (40 nM) for cGMP activation of cGS-PDE, which suggests that EHNA does not inhibit cGS-PDE by displacing cGMP from the allosteric regulator site. Because adenosine did not mimic the effects of EHNA on Ica or PDE activity, it is unlikely that the effects of EHNA are due to adenosine deaminase inhibition. We conclude that EHNA acts primarily to inhibit cGS-PDE in intact cardiac myocytes. This compound should be useful in evaluating the physiological role of cGS-PDE in various tissues.
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PMID:Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic GMP-stimulated phosphodiesterase in isolated cardiac myocytes. 762 66

A comparison of the effects of various phosphodiesterase (PDE) inhibitors upon cellular cAMP levels was undertaken in human neuroblastoma SH-SY5Y cells. When inhibitors such as rolipram and Ro 20 1724 (selective for the low Km cAMP-specific PDE) were used, cAMP levels were seen to rise dramatically under basal (< or = 60 fold) or forskolin-stimulated (< or = 200 fold) conditions. However, the non-selective PDE inhibitor isobutylmethylxanthine (IBMX) was 7-18% as effective as these other agents even at 1 mM. The poor efficacy of IBMX was not attributable to concomitant increases in cGMP, to alterations in cAMP egress or to a lack of sensitivity of the cellular PDEs to IBMX inhibition. In additivity experiments, IBMX potently and rapidly reduced cAMP that had accumulated after rolipram treatment. The fact that the agonist 2-chloroadenosine can enhance cAMP accumulation in these cells, and that cAMP elevated by rolipram or forskolin can be reduced by adenosine deaminase and theophylline suggest that cell-derived adenosine enhances cAMP in these cells in an autocrine fashion. Since IBMX is an adenosine receptor antagonist, it is suggested that its blockade of endogenous adenosine effects is at least partly responsible for its poor response when compared to other PDE inhibitors which are weaker adenosine receptor antagonists. These results forewarn against assuming that similar levels of cAMP accumulate after application of PDE inhibitors in these cells.
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PMID:Comparison of the effect of isobutylmethylxanthine and phosphodiesterase-selective inhibitors on cAMP levels in SH-SY5Y neuroblastoma cells. 768 30

Treating rats with pertussis toxin (PTX) both elevated the adipocyte cAMP levels and impaired sensitivity and responsiveness to the antilipolytic effect of insulin in the presence of different beta-adrenergic agonists. However, in the presence of a fixed medium concentration of the degradable cAMP analogue, 8-bromo-cAMP, the effect of insulin was similar in PTX- and control cells. Elevating the cAMP levels in control cells either through different concentrations of the cAMP analogue or addition of adenosine deaminase impaired both insulin sensitivity and responsiveness to a similar extent as that seen in PTX-treated cells. The antilipolytic effect of insulin was exerted through the activation of the cGMP-inhibitable phosphodiesterase (cGI-PDE) as it was dose-dependently impaired by the specific cGI-PDE inhibitor OPC 3911. The results show the importance of the cellular cAMP levels in modulating insulin sensitivity and action. Gi plays a minor role, if any, for the signal transduction of the antilipolytic effect of insulin.
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PMID:Cellular cyclic AMP levels modulate insulin sensitivity and responsiveness--evidence against a significant role of Gi in insulin signal transduction. 821 2

1. The effects of adenosine receptor agonists on cyclic nucleotides accumulation were investigated in adult guinea-pig cerebellar slices by use of radioactive precursors. 2. Adenosine elicited a rapid and maintained increase in cyclic AMP, that was fully reversed upon addition of adenosine deaminase. Adenosine analogues stimulated cyclic AMP generation up to 40 fold with the rank order of potency: 5'-N-ethylcarboxamidoadenosine (0.6 microM) > 2-chloroadenosine (6 microM) > adenosine (13 microM). CGS 21680 (10 microM) elicited only a small stimulation (1.2 fold). 3. The cyclic AMP response to NECA was reversed by the 1,3-dipropylxanthine-based adenosine receptor antagonists 8-[4-[[[[(2-aminoethyl)amino]amino]carbonyl]methyl]oxy]- phenyl]-1,3-dipropylxanthine (XAC), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and N-[2-(dimethylamino)ethyl]N-methyl-4-(1,3-dipropylxanthine)benzene sulphonamide (PD 115,199) with estimated apparent inhibition constants of 15, 81 and 117 nM, respectively. 4. Pretreatment with adenosine also potentiated the cyclic GMP response to sodium nitroprusside, abolishing the decline in [3H]-cyclic GMP observed with sodium nitroprusside alone, and allowing [3H]-cyclic GMP levels to be maintained for at least an additional 10 min. This potentiation was fully reversed by adenosine deaminase. 5. Adenosine analogues potentiated the sodium nitroprusside-elicited cyclic GMP generation with the rank order of potency: 5'-N-ethylcarboxamidoadenosine (0.7 microM) > 2-chloroadenosine (6 microM) > adenosine (42 microM). 6. NECA potentiation of cyclic GMP formation was reversed by the antagonists XAC, DPCPX and PD 115,199 with apparent inhibition constants of 17, 102 and 242 nM, respectively. 7. The similar potencies of adenosine analogues and xanthine antagonists for stimulation of cyclic AMP and potentiation of cyclic GMP lead to the suggestion that these phenomena are mediated through the same adenosine receptor, the A2b receptor. Furthermore, we suggest that potentiation of the sodium nitroprusside-induced cyclic GMP response may be mediated at the level of phosphodiesterase hydrolysis of the cyclic nucleotides.
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PMID:Adenosine receptor-induced second messenger production in adult guinea-pig cerebellum. 829 96

Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a potential inhibitor of adenosine deaminase (ADA), was tested as an inhibitor of the soluble cyclic nucleotide phosphodiesterase (PDE) isoenzymes from pig and human myocardium. Four soluble PDE activities were resolved from human papillary muscle extracts using anion exchange chromatography (DEAE Sepharose CL-6B). These activities were designated PDE I-IV according to the nomenclature of Beavo. PDE I was stimulated by Ca(2+)-calmodulin and PDE II by cGMP (1 microM). PDE III was inhibited by cGMP (1 microM) as well as SK&F 94120, and PDE IV by both rolipram and Ro 20-1724. Enzyme kinetics and inhibition constants were similar with the PDE isoenzymes from pig heart. However, porcine myocardium lacked Ca(2+)-calmodulin-stimulated soluble PDE I activity. The present data reveal that EHNA exerted a concentration-dependent inhibition of the cGMP-stimulated PDE II (cGs-PDE) (IC50: 0.8 microM (human), 2 microM (pig)) but did not inhibit the other PDE isoenzymes (IC50 > 100 microM). These findings indicate that EHNA is a potent and, as far as cytosolic PDEs are concerned, selective inhibitor of cGMP-stimulated PDEs. The compound may lend itself for the rational design of other isozyme selective PDE II inhibitors and for examining the specific biological functions of cGs-PDEs. EHNA may be used in systems in which inhibition of ADA is of no concern. Conversely, dual inhibition of both ADA and cGs-PDE by EHNA may cause accumulation of two inhibitory metabolites, adenosine and cGMP, which may act in synergy to mediate diverse pharmacological responses, including antiviral, antitumour and antiarrhythmic effects.
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PMID:Isozyme selective inhibition of cGMP-stimulated cyclic nucleotide phosphodiesterases by erythro-9-(2-hydroxy-3-nonyl) adenine. 851 2

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

Previously, it had been observed that nitric oxide (NO) contributes to hypoxia-induced pial artery dilation in the newborn pig. Additionally, it was also noted that activation of ATP-sensitive K+ channels (KATP) contribute to cGMP-mediated as well as to hypoxia-induced pial dilation. Although somewhat controversial, adenosine is also thought to contribute to hypoxic cerebrovasodilation. The present study was designed to investigate the role of NO, cyclic nucleotides, and activation of KATP channels in the elicitation of adenosine's vascular response and relate these mechanisms to the contribution of adenosine to hypoxia-induced pial artery dilation. The closed cranial window technique was used to measure pial diameter in newborn pigs. Hypoxia-induced artery dilation was attenuated during moderate (PaO2 approximately 35 mm Hg) and severe hypoxia (PaO2 approximately 25 mm Hg) by the adenosine receptor antagonist 8-phenyltheophylline (8-PT) (10(-5) M) (26 +/- 2 vs. 19 +/- 2 and 34 +/- 2 vs. 22 +/- 2% for moderate and severe hypoxia in the absence vs. presence of 8-PT, respectively). This concentration of 8-PT blocked pial dilation in response to adenosine (8 +/- 2, 16 +/- 2, and 23 +/- 2 vs. 2 +/- 2, 4 +/- 2, and 6 +/- 2% for 10(-8), 10(-6), and 10(-4) M adenosine before and after 8-PT, respectively). Similar data were also obtained using adenosine deaminase as a probe for the role of adenosine in hypoxic pial dilation. Adenosine-induced dilation was associated with increased CSF cGMP concentration (390 +/- 11 and 811 +/- 119 fmol/ml for control and 10(-4) M adenosine, respectively). The NO synthase inhibitor, L-NNA, and the cGMP antagonist, Rp 8-bromo cGMPs, blunted adenosine-induced pial dilation (8 +/- 1, 14 +/- 1, and 20 +/- 3 vs. 3 +/- 1, 5 +/- 1, and 8 +/- 3% for 10(-8), 10(-6), and 10(-4) M adenosine before and after L-NNA, respectively). Adenosine dilation was also blunted by glibenclamide, a KATP antagonist (9 +/- 2, 14 +/- 3, 21 +/- 4 vs. 4 +/- 1, 8 +/- 2, and 11 +/- 2% for 10(-8), 10(-6), and 10(-4) M adenosine before and after glibenclamide, respectively). Finally, it was also observed that adenosine-induced dilation was associated with increased CSF cAMP concentration and the cAMP antagonist, Rp 8-bromo cAMPs, blunted adenosine pial dilation. These data show that adenosine contributes to hypoxic pial dilation. These data also show that NO, cGMP, cAMP, and activation of KATP channels all contribute to adenosine induced pial dilation. Finally, these data suggest that adenosine contributes to hypoxia-induced pial artery dilation via cAMP and activation of KATP channels by NO and cGMP.
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PMID:Role of nitric oxide, cyclic nucleotides, and the activation of ATP-sensitive K+ channels in the contribution of adenosine to hypoxia-induced pial artery dilation. 897 92

Diarrhea induced by Escherichia coli heat-stable enterotoxin (STa) is mediated by a receptor guanylyl cyclase cascade. The present study establishes that an intracellular nucleotide-dependent pathway disrupts toxin-induced cyclic GMP (cGMP) production and the associated chloride (Cl-) flux that underlie intestinal secretion. Incubation of Caco 2 human intestinal epithelial cells with the nucleoside analog 2-chloroadenosine (2ClAdo) resulted in a concentration- and time-dependent inhibition of toxin-induced cGMP production. Inhibition of cGMP production correlated with the metabolic conversion of 2ClAdo to 2-chloroadenosine triphosphate. The effect of 2ClAdo did not reflect activation of adenosine receptors, inhibition of adenosine deaminase, or modification of the binding or distribution of STa receptors. Guanylyl cyclase activity in membranes prepared from 2ClAdo-treated cells was inhibited, in contrast to membranes from cells not exposed to 2ClAdo, demonstrating that inhibition of guanylyl cyclase C (GCC) was mediated by a noncompetitive mechanism. Treatment of Caco 2 cells with 2ClAdo also prevented STa-induced Cl- current. Application of 8-bromo-cGMP, the cell-permeant analog of cGMP, to 2ClAdo-treated cells reconstituted the Cl- current, demonstrating that inhibition of Cl- flux reflected selective disruption of ligand stimulation of GCC rather than the chloride channel itself. Thus, the components required for adenine nucleotide inhibition of GCC signaling are present in intact mammalian cells, establishing the utility of this pathway to elucidate the mechanisms regulating ST-dependent guanylyl cyclase signaling and intestinal fluid homeostasis. In addition, these data suggest that the adenine nucleotide inhibitory pathway may be a novel target to develop antisecretory therapy for enterotoxigenic diarrhea.
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PMID:Interruption of Escherichia coli heat-stable enterotoxin-induced guanylyl cyclase signaling and associated chloride current in human intestinal cells by 2-chloroadenosine. 899 60


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