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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine is an important inhibitory neuromodulator in the CNS, yet the sources of extracellular adenosine have yet to be well characterized. In this study we show that beta-adrenergic stimulation of cortical cultures results in the extracellular accumulation of cAMP as well as adenosine, and that the extracellular adenosine derives from extracellular cAMP. The concentration dependence of isoproterenol in evoking cAMP secretion was determined by radioimmunoassay, and the EC50 for this effect was found to be approximately 100 nM. In order to investigate the effect of beta-adrenergic stimulation on the regulation of extracellular adenosine, the effect of isoproterenol in stimulating the extracellular accumulation of adenine-containing compounds was examined by HPLC. Isoproterenol stimulated cAMP secretion in both astrocyte cultures and astrocyte-rich mixed cultures of astrocytes and neurons. However, no extracellular cAMP was detectable in neuron-enriched astrocyte-poor cultures. Extracellular adenosine increased in response to isoproterenol in the astrocyte-rich mixed cultures, but not in the neuron-enriched astrocyte-poor cultures. After 30 min exposure to isoproterenol, the concentration of adenosine in the extracellular medium increased by 47% in 56 experiments in the mixed astrocyte-rich cultures. In order to establish whether the adenosine that accumulates in response to isoproterenol stimulation actually derives from extracellular cAMP, phosphodiesterase inhibitors were tested for their ability to block isoproterenol-stimulated adenosine accumulation. Isobutylmethylxanthine (IBMX; 100 microM), RO 20-1724 (180 microM), carbazeran (10 microM), dipyridamole (10 microM), and trifluoperazine (10 microM) had no inhibitory effect on the isoproterenol-stimulated accumulation of extracellular adenosine. However 100 microM IBMX plus 180 microM RO 20-1724 effectively blocked isoproterenol-stimulated adenosine accumulation and, as expected, increased extracellular cAMP. As a further test of the origin of isoproterenol-stimulated adenosine accumulation, we attempted to block this phenomenon by blocking cAMP secretion itself. For this purpose probenecid, a known inhibitor of cAMP secretion in many different cell types, was used. We found that probenecid at 1 mM blocked isoproterenol-stimulated adenosine accumulation. These studies suggest that one potentially important source of extracellular adenosine in the cerebral cortex is endogenous extracellular cAMP, secreted from astrocytes in response to beta-adrenergic receptor stimulation. Since the receptors of neuromodulators other than norepinephrine may also be coupled to adenylyl cyclase in the cerebral cortex, there may be several neuromodulatory systems that regulate extracellular adenosine levels by this mechanism.
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PMID:Beta-adrenergic receptor-mediated regulation of extracellular adenosine in cerebral cortex in culture. 818 51

An injection of cobalt chloride solution into the unilateral sensorimotor cortex of rats induced electrographic epileptic activity, which was followed by a peripheral motor disturbance. Brain slices were prepared from the cortical region including the injection site and from the other cortical regions of rats between 8 and 50 days after the injection. In the cortical slices, we examined cyclic AMP accumulations elicited by adenosine and its stable analogue 2-chloroadenosine. Adenosine and 2-chloroadenosine at their maximal dose increased cyclic AMP accumulation six- to 10-fold and 10-15-fold, respectively, and the elicitation was markedly inhibited by the adenosine antagonist 8-phenyltheophylline. The cyclic AMP accumulation was increased in the primary epileptic region of the cortex adjacent to the injection site of cobalt chloride solution, whereas it was unchanged in the other cortical regions. The increase in cyclic AMP accumulation was observed regardless of the presence or absence of the adenosine uptake inhibitor dipyridamole, the phosphodiesterase inhibitor DL-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, and adenosine deaminase. Such an increased accumulation of cyclic AMP in the primary epileptic cortex was detected as early as 8 days after the injection. The cyclic AMP accumulation continued to increase and reached a peak level 17-19 days after the injection, and it returned to the control levels after 40-50 days, in correspondence with the electrographic and behavioral findings. It is concluded that alterations in adenosine receptor-mediated generation of cyclic AMP in the primary epileptic cortex are closely associated with the central process of cobalt-induced epilepsy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of adenosine-sensitive cyclic AMP-generating systems in cobalt-induced epileptic activity in the rat. 824 69

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

Odorant-stimulated formation of cAMP in olfactory receptor neurons may mediate olfactory signal transduction. The response is short and desensitization occurs rapidly, possibly by induction of cyclic nucleotide phosphodiesterase (PDE) activity. Previously, we showed that two low Km PDEs regulate hydrolysis of cAMP in olfactory cilia. One PDE is Ca2+/calmodulin-dependent and non-selective for both cAMP-PDE and cGMP; the other is Ca2+/calmodulin-independent, sensitive to rolipram and selective for cAMP. We have localized cAMP-selective PDE in olfactory, gustatory and retinal sensory systems by autoradiography with the selective inhibitor [3H]rolipram. We observe dense binding over olfactory neurons, particularly over olfactory nerve bundles and olfactory cilia. In the tongue apical regions of taste buds of the circumvallate papillae are strongly labeled as well as portions of the glossopharyngeal nerve. Retinal binding is most dense over the inner plexiform layer, ganglion cells and the optic nerve but is also substantial over the inner nuclear layer. The pattern of [3H]rolipram-binding in retina is reminiscent of adenosine localization. Accordingly, adenosine was immunohistochemically localized in olfactory, gustatory and retinal tissues. Adenosine immunoreactivity is observed in olfactory neurons, in the basal regions of taste buds and in retinal ganglion cells.
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PMID:High-affinity cAMP phosphodiesterase and adenosine localized in sensory organs. 839 70

Adenosine causes airway obstruction in asthmatics and smokers. Theophylline and cromolyn, drugs used to treat these patients, bind to human lung adenosine receptors (ARs). This study investigated whether A1ARs and/or A2ARs are functionally present in human lung and airways, and whether theophylline and/or cromolyn antagonize their function. Peripheral lung or airway fragments from 21 people were incubated for 15 min with (1) an A1AR agonist, N6-cyclopentyladenosine (CPA, 5 to 1,000 nM), or (2) an A2AR agonist, either 5'-N-ethylcarboxamido adenosine (NECA, 0.5 to 20 microM) or 2-[p-(2-carboxyethyl)-phenethyl amino]-5'-N-ethylcarboxamido adenosine (CGS 21680, 0.5 to 28 microM), in the presence of the A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (50 nM) and/or (3) theophylline (1 mM) and/or (4) cromolyn (500 microM). Adenosine deaminase (2 U/ml) and the phosphodiesterase inhibitor Ro 20-1724 (2 mM) were present in all incubations. Cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. In peripheral lung, CPA did not change baseline or isoproterenol-stimulated cAMP content. However, both NECA (20 microM) and CGS 21680 (28 microM) significantly (P < 0.05) increased cAMP content 220 +/- 4% and 201 +/- 32%, respectively (mean +/- SEM). In airways, 20 microM NECA increased cAMP content 129 +/- 34%, and 28 microM CGS 21680 increased it 52 +/- 20% (both P < 0.05). In both peripheral lung and airway tissue, NECA-induced increase in cAMP was antagonized by theophylline (P < 0.05) but not cromolyn. The lungs of younger, nonsmokers had lower baseline cAMP content but did not respond differentially to A2AR stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of adenosine receptor ligands on cAMP content in human airways and peripheral lung. 839 27

Adenosine and ATP have been shown to activate separate cell surface purinergic receptors which have been designated P1 for adenosine and P2 for ATP. The pharmacological characterization of P1 and P2 purinergic receptor-mediated signal transduction has been performed in cultured cell lines of the ciliary epithelium. In ODM Clone-2, a cell line derived from human nonpigmented ciliary epithelium (NPE) and in a clone derived from bovine pigmented ciliary epithelium (PE), we observed that adenosine inhibits adenylate cyclase activity at high potency (nM) and stimulates adenylate cyclase activity at low potency (microM) suggesting the presence of P1 subtypes on these cell membranes. The selective agonist cyclopentyladenosine (CPA) was effective at inhibiting forskolin-stimulated adenylate cyclase in these cells. The IC50 for CPA in both NPE and PE was approximately 1 nM in the absence, and 11 nM in the presence of 3-isobutyl-1-methylxanthine (IBMX). In NPE, the selective agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido adenosine (CGS 21680) stimulated adenylyl cyclase with an EC50 of 11 +/- 4 nM in the presence of 4-(3-butoxy-4-methyoxybenzyl)-2-imidazolidinone (RO-20-1724), a phosphodiesterase inhibitor devoid of adenosine receptor antagonism, and 61 +/- 8 microM in the presence of IBMX. In PE cells, EC50 value of RO-20-1724 was 19 +/- 5 nM (n = 3). The characterization of P2 receptors based upon the ability of ATP and its related analogues to stimulate inositol phosphate production reveal the presence of a putative P2u receptor in both cell types.
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PMID:Purinergic receptors in ocular ciliary epithelial cells. 840 76

Relationships between the alkyl substitutions (C1-C6) and cardiac inotropic activities of xanthine derivatives were studied in isolated guinea pig heart muscles. Most of the alkylxanthines exhibited positive inotropic activity on the left atrium, which was increased with an elongation of alkyl chain at the N3-position but decreased by substitution of a long alkyl group at the N1- or N7-position of the xanthine skeleton. Although positive inotropic activity in the right ventricular papillary muscle was also increased by longer alkyl groups at the N3-position, the inotropic activity became negative with an increment in alkyl chain length at the N1- or N7-position. The positive inotropic activity of alkylxanthines was correlated with their inhibitory activity on the phosphodiesterase (PDE) III isoenzyme. Adenosine A1 antagonism and PDE IV inhibitory activity were also partly associated with the inotropic activity because H-89, an inhibitor of cyclic AMP-dependent protein kinase, diminished the positive inotropic action and potentiated the negative inotropic action. These results indicate that the positive inotropic activity of alkylxanthines becomes weak with elongation of alkyl chains at the N1- and N7-positions; In particular, xanthines having two long alkyl chains show a negative inotropic activity on the right ventricular papillary muscle, an effect that could not be elucidated from their cyclic AMP-dependent action.
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PMID:Structure-activity relationships of alkylxanthines: alkyl chain elongation at the N1- or N7-position decreases cardiotonic activity in the isolated guinea pig heart. 856 57

Several endogenous factors generated within the vessel wall have been implicated in contributing to the vascular remodeling process associated with hypertension and atherosclerosis. Furthermore, substances generated by smooth muscle cells (SMCs) are known to regulate SMC proliferation in an autocrine fashion. Adenosine is a vasodilator synthesized by SMCs, and exogenous adenosine inhibits SMC proliferation. However, whether adenosine produced endogenously has antimitogenic effects is not known. Hence, we evaluated the effects of SMC-derived adenosine on 2.5% fetal calf serum-induced proliferation of rat aortic SMCs. SMC proliferation was assayed by measurement of DNA synthesis ([3H]thymidine incorporation) and cell counting. To determine the effects of endogenous adenosine on SMC proliferation, we stimulated growth-arrested SMCs with 2.5% fetal calf serum in the presence and absence of modulators of adenosine levels, including (1) erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA; inhibits adenosine deaminase), (2) dipyridamole (blocks adenosine transport and inhibits phosphodiesterase), (3) dipyridamole plus EHNA, and (4) adenosine with or without EHNA. [3H]Thymidine incorporation and cell number were measured after 24 and 96 hours, respectively. EHNA and dipyridamole inhibited both FCS-induced DNA synthesis and cell proliferation in a concentration-dependent manner. Furthermore, extracellular (in medium) adenosine levels were significantly increased when cultured cells were treated with EHNA, and the inhibitory effects of dipyridamole as well as exogenous adenosine were enhanced in the presence of EHNA. Additionally, the inhibitory effects of dipyridamole and EHNA on DNA synthesis were significantly reduced in the presence of KF17837, an A2 adenosine receptor antagonist. These results indicate that SMC-derived adenosine can inhibit SMC proliferation. Hence, it is possible that a defect in localized adenosine synthesis within the vessel wall could contribute to vascular thickening and neointima formation.
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PMID:Smooth muscle cell-derived adenosine inhibits cell growth. 861 38

Monocytes and macrophages produce tumor necrosis factor-alpha (TNF alpha) in response to microbial products including endotoxin. TNF alpha is a potent primer of neutrophil (PMN) oxidative activity. Certain xanthine phosphodiesterase (PDE) inhibitors such as pentoxifylline have been shown to inhibit stimulated oxidative activity in PMN. In the present study, the non-xanthine PDE type IV inhibitor rolipram (4-[3'-cyclopentyloxy-4'-methoxyphenyl]-2-pyrrolidone) alone and in combination with adenosine is examined as a potential modulator of TNF alpha-primed PMN oxidative activity. Attainable in vivo concentrations of rolipram and physiological concentrations of adenosine alone and together synergistically decreased rhTNF alpha-primed suspended PMN oxidative activity stimulated by the chemoattractant f-met-leu-phe. The rolipram effect was reversible by washing, and rolipram had a comparable effect if added before or after priming, indicating that its effect was on the primed response rather than on priming per se. In addition, rolipram especially when combined with adenosine, decreased rhTNF alpha-stimulated PMN adherence to a fibrinogen-coated surface, and the oxidative burst of rhTNF alpha-stimulated adherent PMN. The specific adenosine A2a receptor agonists CGS 21680 and WRC-0474 had comparable activity to adenosine in these experiments. Adenosine (or CGS 21680) combined with rolipram synergistically increased f-met-leu-phe-stimulated PMN cAMP content. The effects of both adenosine and rolipram with adenosine could be only partly counteracted by treatment of the PMN with the protein kinase A inhibitor KT 5720, indicating that protein phosphorylation is only partially involved. Rolipram activity was about 1000 x (by molar concentration) greater than pentoxifylline in comparable assays. Thus, rolipram, especially when combined with adenosine, has potent modulating effects on PMN activation and may be useful in decreasing inflammatory tissue damage in patients with sepsis.
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PMID:The specific type IV phosphodiesterase inhibitor rolipram combined with adenosine reduces tumor necrosis factor-alpha-primed neutrophil oxidative activity. 870 44

In the present report we describe a cAMP-responsive K channel in activated human T cells. Single channel events were recorded using the patch-clamp technique in cell-attached-patch configuration. The channel was K selective, as determined by reversal potentials under different K gradients, and displayed voltage-independent gating. When the applied potential (Vp) was equal to zero, the conductance of the channel was 21.8 +/- 0.9 pS with 150 mM K in the electrode. Typical patches contained between two and seven channels that were relatively quiet, or silent, before agonist stimulation. Adenosine (20-30 microM) increased the average open time probability from 0.017 +/- 0.008 to 0.108 +/- 0.054 over a period of 108 s. Subsequent addition of the phosphodiesterase inhibitor Ro 20-1724 (0.5 mM) increased the probability of being in the open state to 1.155 +/- 0.407 over a period of 180 s. Channel kinetics were well described by assuming two open and two closed states. Exponential time constants for the open states were 0.51 +/- 0.06 and 4.34 +/- 0.31 ms, and closed state time constants were 0.58 +/- 0.05 and 10.1 3 +/- 2.32 ms. In addition, extracellular ATP (0.3-1.0 mM) decreased channel activity. Moreover, Rp-cAMP (0.5-1.0 mM), an antagonist that specifically blocks the ability of cAMP to bind and activate protein kinase A, failed to inhibit adenosine- and Ro 20-1724-induced increases in channel activity, implying a direct action of cAMP on channel gating.
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PMID:Cyclic adenosine 3',5'-monophosphate increases the open probability of potassium channels in activated human T cells. 875 12


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