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)

Previous work in our laboratory led us to postulate that N2a cells release adenosine into growth medium, where it acts at the extracellular adenosine receptors to modulate the sensitivity of the cells to the cyclic AMP-elevating effect of adenosine [Green, RD, J Pharmacol Exp Ther 201:610, 1977]. We have now devised a high-performance liquid chromatographic (HPLC) procedure capable of quantitating the concentrations of adenosine in cells and tissue culture media. Growth media of N2a cells and a variant of N2a cells deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRT-) contain 10-20 nM adenosine, while that of a variant deficient in adenosine kinase (AK-) is elevated severalfold. It appears that the concentration of adenosine in growth media is determined by both the rate at which it is released by cells into the medium and the rate at which it is metabolized by adenosine deaminase present in the serum in the growth medium. Both N2a and AK- cells release considerable amounts of adenosine into serum-free medium (SFM) over a short period. Adenosine release is greater from AK- cells and is accelerated by erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), a potent adenosine deaminase inhibitor. This accelerated release is retarded by dipyridamole and homocysteine. Surprisingly, dipyridamole and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20 1724), a potent phosphodiesterase inhibitor, stimulate basal adenosine release from N2a but not from AK- cells. It remains to be determined if this is due to an effect of these compounds on adenosine kinase. These results give further support for the hypothesis that adenosine in growth medium modulates the sensitivity of the cells to the cyclic AMP-elevating affect of adenosine, and furthermore they suggest that adenosine in growth media may tonically stimulate adenylate cyclase and affect processes controlled by the cyclic AMP:cyclic AMP-dependent protein kinase system.
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PMID:Release of adenosine by C1300 neuroblastoma cells in tissue culture. 626 30

The possible role of cyclic AMP in the presynaptic alpha-adrenoceptor-mediated modulation of [3H]noradrenaline (NA) release induced by 13 mM K+ from superfused rat cerebral cortex slices was investigated. Both dibutyryl-cyclic AMP (db-cAMP) and 8-bromo-cyclic AMP (8-Br-cAMP) dose-dependently (10(-4) - 10(-2) M) enhanced K+-induced (3H]NA release, maximally to about 160% of control. In contrast, db-cAMP had no effect on calcium-induced [3H]NA release in the presence of the calcium ionophore A 23187. Surprisingly, the phosphodiesterase (PDE) inhibitors 3-isobutyl-1-methylxanthine (IBMX). 7-benzyl-IBMX, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62771), and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724) appeared to inhibit K+-induced [3H]NA release in a dose-dependent (10(-5) - 10(-3) M) manner. At a concentration of 10(-4) M, AK 62771 caused an inhibition of [3H]NA release by 30%, and this inhibitory effect was not affected by 10(-6) M phentolamine nor by 10(-3) M db-cAMP or 10(-4) M theophylline. Theophylline by itself enhanced [3H]NA release to about 135% of control. The inhibitor effect of the alpha-adrenoceptor agonist oxymetazoline (1 micro M) and the enhancing effect of the antagonist phentolamine (1 micro M) on [3H]NA release were significantly decreased in the presence of 10(-3) M db-cAMP or 8-Br-cAMP, whereas 10(-4) M ZK 62771 had no effect. In the presence of 10(-2) M NaF, a potent activator of adenylate cyclase, the inhibitory effect of oxymetazoline (1 micro M) on [3H]NA release was significantly decreased. The data obtained with the cyclic AMP analogues support the hypothesis that activation of presynaptic alpha-receptors modulating NA release results in an inhibition of a presynaptic adenylate cyclase. Possible causes for the anomalous effects of th PDE inhibitors are discussed.
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PMID:Effects of cyclic AMP analogues and phosphodiesterase inhibitors on K+-induced [3H]noradrenaline release from rat brain slices and on its presynaptic alpha-adrenergic modulation. 628 25

Human monocytes in vitro respond to various agents (immune complexes, lectins, endotoxin, the divalent ionophore A 23187, 12-O-tetradecanoyl-phorbol 13-acetate [TPA], purified protein derivative [PPD] of Bacille Calmette-Guerin) with an increased synthesis of the protein component of thromboplastin. The effect of cyclic AMP and cyclic GMP on this response has been studied. Dibutyryl-cyclic AMP, prostaglandin E1 and the phosphodiesterase inhibitors 3-butyl-1-methyl-xanthine (MIX) and rac-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724), separately and in combination have a pronounced inhibitory effect on the response to immune complexes and PPD, and a moderate effect on the response to endotoxin and lectins. The effect on TPA response and on the response to A 23187 was slight. Dibutyryl-cyclic GMP (1 mM) gave a slight inhibition of the TPA and IC response, but had essentially no effect on the response to other inducers. The intracellular cAMP level increased when monocytes were incubated with IC, TPA or A 23187 followed by a decrease to basal levels within 1-2 hr, whereas lectin (PHA) and PPD did not induce such changes. The cAMP response to endotoxin varied. Stimulation with IC induced an increase in monocyte cGMP levels, whereas the other stimulants did not cause such changes.
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PMID:Effect of cyclic AMP and cyclic GMP on thromboplastin (factor III) synthesis in human monocytes in vitro. 632 Apr 87

In dog thyroid slices stimulated by thyrotropin (TSH), activation of muscarinic cholinergic receptors leads to a decrease in cyclic AMP levels. Previous studies have established that carbamylcholine enhances cyclic GMP levels and inhibits cyclic AMP accumulation. Several experimental data have suggested that these effects are mediated by an increase in intracellular Ca2+ levels. The inhibition of cyclic AMP accumulation results in accelerated catabolism. Dog thyroid phosphodiesterase activity is due to a mixture of three enzyme forms: a calmodulin-sensitive form, a cyclic GMP-stimulated form and a cyclic AMP-specific form. This report is concerned with the comparison of the effects of several phosphodiesterase inhibitors on cell-free phosphodiestease activity and on cyclic nucleotide accumulation in intact cells. Alkylated xanthines, 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724), and 2-O-propoxyphenyl-8-azapurin-6-one (M & B 22948) were studied as inhibitors of partially purified dog thyroid phosphodieterases and for their ability to alter cyclic AMP and cyclic GMP accumulation in dog thyroid slices that had been stimulated with TSH and/or carbamylcholine. 1-Methyl-3-isobutylxanthine (MIX) and 7-benzyl MIX were the most potent inhibitors of phosphodiesterase activities in the crude soluble and particulate fractions but exhibited no selectivity for inhibiting cyclic AMP or cyclic GMP hydrolysis. In dog thyroid slices stimulated by TSH and in the absence of carbamylcholine, Ro 20-1724 and 1-isoamyl-3-isobutylxanthine (IIX) were the most effective compounds to potentiate the accumulation of cyclic AMP. The rank order of abilities to potentiate cyclic AMP accumulation in dog thyroid slices stimulated by TSH paralleled the rank order of potencies to inhibit the cyclic AMP-specific phosphodiesterase. In the presence of carbamylcholine, the observed decrease in cyclic AMP levels was attenuated by MIX, 8-methoxymethyl MIX (8-MeOMe MIX), 7-benzyl MIX, and M & B 22948, the most potent inhibitors of the calmodulin-sensitive phosphodiesterase. MIX, 8-MeOMe MIX, and 7-benzyl MIX inhibited the cyclic GMP-stimulated phosphodiesterase in the same rank order of potencies as the calmodulin-sensitive enzyme, but M & B 22948 did not significantly inhibit the cyclic GMP-stimulated enzyme activity. IIX and Ro 20-1724 did not alter the carbamylcholine-induced inhibition of cyclic AMP accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effects of alkylated xanthines on cyclic AMP accumulation in dog thyroid slices exposed to carbamylcholine. 632 49

We characterized cyclic nucleotide phosphodiesterases isolated from rat mesangial cells and assessed their roles in regulating cellular cyclic nucleotide levels. Three peaks of phosphodiesterase activity were eluted by a linear sodium acetate gradient from a Q Sepharose column loaded with the mesangial cell extract. The first peak activity was stimulated by Ca(2+)-calmodulin and inhibited by calmodulin-stimulated phosphodiesterase inhibitors but not by a selective cGMP specific phosphodiesterase V inhibitor. The second, minor activity peak was stimulated by cyclic GMP and inhibited by EHNA [erythro-9-(2-hydroxy-3-nonyl)-adenine], a selective inhibitor of cyclic GMP-stimulated phosphodiesterase II. The last peak activity was not inhibited by cyclic GMP but selectively inhibited by rolipram [4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidene] or Ro 20-1724 [4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone], inhibitors of cyclic AMP specific, cyclic GMP insensitive phosphodiesterase IV. Based on their order of chromatographic elution, kinetic properties and sensitivity to allosteric agents and inhibitors, the peak 1, 2 and 3 correspond to phosphodiesterase I, II and IV. The basal cyclic GMP level was raised more effectively by selective inhibitor of phosphodiesterase I than phosphodiesterase II. In contrast, the atrial natriuretic factor-induced cyclic GMP elevation was potentiated more effectively by selective inhibitors of phosphodiesterase II than phosphodiesterase I. The forskolin-induced cyclic AMP increase was greatly potentiated by selective phosphodiesterase IV inhibitors but not by other phosphodiesterase inhibitors. These data suggest that phosphodiesterase I and II are responsible for cyclic GMP hydrolysis whereas phosphodiesterase IV is mainly responsible for cyclic AMP hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic nucleotide phosphodiesterase isozymes in rat mesangial cells. 778 11

We have examined the effects of short-term exposure to low (50 nM) levels of the beta-adrenoceptor agonist isoproterenol on the ability of intact rat ventricular myocytes to increase their intracellular levels of cyclic AMP (cAMP) in response to subsequent isoproterenol exposure. Exposing freshly isolated, nonstimulated myocytes (which contained 3.5 +/- 0.3 pmol cAMP/mg protein) to isoproterenol resulted in rapid, dose-dependent increases in cAMP formation; 5-min exposure raised intracellular cAMP content to 6.5 +/- 0.7 pmol/mg protein and 54.6 +/- 0.9 pmol/mg protein, respectively, in the absence and presence of the phosphodiesterase inhibitor 4-(3-butoxy-4-methoxybenzyl)imiazolidin-2-one (RO 20-1724). In myocytes incubated for 5-20 min with isoproterenol, washed twice to remove the agonist, and then rechallenged for 20 min with the agonist in the presence of Ro 20-1724, a 10-min preexposure to the agonist resulted in a significant reduction (approximately 20%; P < 0.05) in the receptors' responsiveness to the rechallenge, and increasing the preexposure time to 20 min resulted in the maximum attenuation in responsiveness (approximately 30%; P < 0.001). Myocytes preincubated with forskolin (1 microM), which directly activates adenylate cyclase contained 9.0 +/- 0.7 pmol cAMP/mg protein after 5 min exposure, and up to 20 min preexposure to forskolin did not alter the cells' responsiveness to subsequent challenge with isoproterenol. The results of this study indicate that exposing freshly isolated rat ventricular myocytes to nanomolar levels of isoproterenol for as little as 10 min desensitizes them to subsequent challenge with agonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Short-term exposure of intact ventricular myocytes to isoproterenol results in desensitization of adenylate cyclase. 795 34

Alkylation of the selective type IV phosphodiesterase inhibitor, 8-amino-1,3-bis(cyclopropylmethyl)-xanthine (1, BRL 61063), led exclusively to the N-7 substituted derivatives 2-9, which showed varying selectivities for the PDE type IV isoenzyme relative to PDE Va. The 4-methoxybenzyl derivative 6 in particular was a highly potent PDE Va inhibitor (IC50 0.14 microM) and showed a 24-fold selectivity for this isoenzyme relative to PDE IV. Sulfonation of 1 was more complex, with the product profile being highly dependent on the reaction conditions. As with alkylation, sulfonation at N-7 generally increased potency against PDE Va, especially in the aryl-containing moieties lacking strongly electron-withdrawing substituents (12, 15-17, 19). Bis-arylsulfonation at the exocyclic amino group generally reduced inhibitory potency against both PDE IV and Va. An 8-amidino compound 33, formed by the unusual reaction of 1 with N-methylpyrrolidinone in the presence of benzenesulfonyl chloride, had an IC50 value of 0.05 microM against PDE Va and is believed to be the most potent inhibitor of this isoenzyme reported. No correlation of PDE IV inhibition with displacement of [3H]rolipram from its high-affinity binding site was demonstrated. This suggests that either the catalytic site and the rolipram binding site are not the same or that PDE IV can exist in two conformations, only one of which binds to rolipram with high affinity, and that the compounds described vary in their selectivity for this isoform.
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PMID:Inhibition of cyclic nucleotide phosphodiesterase by derivatives of 1,3-bis(cyclopropylmethyl)xanthine. 812 Aug 66

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

Adenosine has both pro- and anti-inflammatory effects on neutrophils. Exposure of cultured neutrophils to 2-chloroadenosine or 5'-N-ethylcarboxamidoadenosine (NECA) decreased apoptosis after 16 h, with half-maximal responses for NECA and 2-chloroadenosine of 7.1 +/- 7.7 and 59.0 +/- 32.0 nM, respectively. Adenosine receptor agonists exhibited a rank order of potency for decreasing apoptosis of 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) > NECA > or = 2-chloro-N6-cyclopentyladenosine >> 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide, which is consistent with the affinity order profile established for human A2a receptors. The reduction in apoptosis in cultured neutrophils at 16 h by CGS 21680 was due to a delay in apoptosis. The addition of CGS 21680 (100 nM) increased the half-life for the appearance of apoptosis from 10.9 +/- 3.1 to 21.0 +/- 1.0 h. Addition of the non-xanthine phosphodiesterase inhibitor 4-(3-butoxy-4-methoxybenzyl)-2-imidazalidinone (Ro-20-1724; 1 microM) enhanced the effects of CGS 21680 at all agonist concentrations. PGE1 (10 microM), PGE2 (0.1-10 microM), and dibutyryl cAMP (5-500 microM) all decreased apoptosis in cultured neutrophils. The enhancement of the effect of adenosine by a phosphodiesterase inhibitor and the similar actions of PGE2, PGE1, and dibutyryl cAMP suggest that this decrease in apoptosis may be mediated by a cAMP-dependent pathway.
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PMID:Adenosine A2a receptor activation delays apoptosis in human neutrophils. 905 31

We synthesized various 4-benzylamino-1-chloro-6-substituted phthalazines (15) and 4-benzylamino-1-chloro-7-substituted phthalazines (16) and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) purified from porcine platelets. The PDE5-inhibitory activities of 15 were greater than those of the isomers (16). The preferred substituent at the 4-position of phthalazine was a (3-chloro-4-methoxybenzyl)amino group, and those at the 6-position were cyano, nitro, and trifluoromethyl groups. Compounds 15a (IC50 = 4.8 nM), 15f (3.5 nM), and 15i (5.3 nM) were more potent inhibitors than E4021 (8.6 nM). Compounds 15a and 15f also showed vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The EC50 values for vasorelaxant action of 15a, 15f, and E4021 were 150, 160, and 980 nM, respectively. These results show that novel PDE5 inhibitors possessing a potent vasorelaxant effect may exist among phthalazine derivatives.
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PMID:4-Benzylamino-1-chloro-6-substituted phthalazines: synthesis and inhibitory activity toward phosphodiesterase 5. 971 89


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