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)

Cultured granulosa cells from intact immature rats produced large amounts of progestins in response to phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (MIX). MIX alone stimulated up to 9 times higher amounts of 20 alpha-hydroxy-4-pregnen-3-one (20 alpha-OH-P) when compared with FSH (100 ng/ml)-stimulated steroidogenesis. Combined action of MIX and FSH did not yield more activity than MIX action alone. MIX activity was demonstrable exclusively in serum-free culture medium (Dulbecco modified Eagle's medium/F-12) supplemented with insulin, transferrin, hydrocortisone, and fibronectin. Serum severely inhibited MIX induction of 20 alpha-OH-P production. MIX also caused dramatic cell shape changes which occurred within 14 h of exposure to the drug. The cells assumed a spherical shape and remained so as long as MIX was maintained in the culture medium. Upon removal of the drug, the cells respread and acquired the morphology of luteinized cells. In contrast to FSH action, MIX failed to induce the appearance of functional LH receptors. However, similar to FSH effect on immature granulosa cells, MIX successfully induced aromatase enzyme throughout 12 days in culture. MIX alone caused only a minute increase in the accumulation of cAMP. cAMP content in cells induced with FSH (100 ng/ml) was 46 times higher than the cyclic nucleotide levels measured under maximal effective doses of MIX. The discrepancy between the intensive steroidogenic activity of MIX and its inability to substantially raise cAMP content suggests a possible cAMP-independent mechanism for steroid production in the ovarian cells.
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PMID:Cyclic nucleotide phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, induces cytodifferentiation of follicular granulosa cells cultured in serum-free medium. 620 21

LPS greatly increases cGMP in rat fetal liver cells without affecting cAMP. The present experiments were undertaken to determine whether this effect occurs in an adult tissue, which might be exposed to LPS in vivo. Therefore cyclic nucleotides were measured in adult male rat spleen cells incubated in vitro in the presence or absence of LPS. A clear cGMP elevation was found in cultures treated with LPS. This was first evident at 2 hr and persisted for 4 hr. In contrast, cAMP was unaffected by LPS even in the presence of the phosphodiesterase inhibitor, MIX. CGMP rose progressively with LPS doses ranging from 0.8 to 20 ng, and addition of MIX potentiated the cGMP stimulatory effect. Several LPS concentrates prepared by different techniques and LPS exposed to vigorous heat treatment exhibited cGMP activity, whereas absorption of LPS with Limulus lysate abolished the cGMP response. Thus LPS increases cGMP in rat spleen cells in a dose-and time-dependent manner without affecting cAMP. Although the significance of this cGMP increase is unknown, its occurrence in spleen cells (a tissue likely to come in contact with LPS in vivo), its production by very small quantities of LPS, and the delayed but persistent nature of the effect (analogous to the aciton of cholera toxin on cAMP) are all consistent with an important role for cGMP in the action of LPS on cells.
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PMID:Stimulation of cyclic 3':5'-guanosine monophosphate levels in rat spleen cells by lipopolysaccharide preparations. 624 57

The role of cAMP and cGMP in triggering proliferation of rat myoblasts was evaluated by: (1) measuring effects of mitogens on intracellular cyclic nucleotide levels, and (2) observing effects of agents which altered cyclic nucleotide levels on cell proliferation. Multiplication stimulating activity (MSA, 1 microgram/ml), a member of the somatomedin family, stimulated cell proliferation after 48 hr. It had little effect on cellular cyclic nucleotide levels, measured by radioimmunoassay. Horse serum (HS) and fetal bovine serum (FBS) stimulated cell proliferation approximately equally. Neither affected cAMP levels; FBS reduced cGMP to 33% of control values, but HS had no effect. Thus, there was no simple correlation between mitogenic action and cyclic nucleotide levels at any time from 5 min to 24 hr after addition of a purified mitogen or serum. Furthermore, agents which caused substantial changes in cyclic nucleotide levels had no effect on cell proliferation. Prostaglandin E1 (5 microM) elevated cAMP 440% without affecting cGMP levels or cell growth. A potent phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine (MIX, 0.1 mM), when added alone or in the presence of MSA, HS, or FBS, elevated cAMP 200% and cGMP 167%, but it had little effect on their mitogenic action. Lastly, a purified mitogen such as MSA, unlike serum, must be present for extended periods of time in order to stimulate cell proliferation. This makes it unlikely that a trigger mechanism functions in initiating cell division. We conclude that neither cAMP nor cGMP appear to be second messengers for the mitogenic action of MSA or serum on muscle cells.
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PMID:The effect of serum and multiplication stimulating activity on L6 myoblast growth: the lack of correlation with cyclic nucleotide changes. 625 7

An analysis of prostaglandin-stimulated adenosine 3',5'-cyclic monophosphate (cyclic AMP) accumulation in cultured human umbilical vein endothelial cells showed prostacyclin (PGI2) to be the most potent agonist followed by prostaglandin (PG)H2, which was more potent than PGE2, while PGD2 was essentially inactive. The endothelial cells studied apparently have a high rate of cyclic AMP phosphodiesterase activity because significant PGI2-mediated increases in cyclic AMP could not be shown in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (MIX). Endoperoxide PGH2-stimulation of cyclic AMP accumulation was inhibited 75--80% by the prostacyclin synthetase inhibitors 12-hydroperoxyeicosatetraenoic acid or 9,11-azoprosta-5,13-dienoic acid. These data indicate that the PGH2-stimulation is due primarily to conversion to PGI2. The beta-adrenergic agonist L-isoproterenol stimulated cyclic AMP accumulation in the endothelial cells. This accumulation was completely blocked by propranolol. However, stimulation of cyclic AMP accumulation by the beta-adrenergic agent did not equal that induced by PGI2. Furthermore, the PGI2 response could not be blocked by propranolol. Thrombin-stimulated PGI2 biosynthesis was attenuated by PGE1 or isoproterenol in the presence of MIX. MIX alone was less effective than a combination of PGE1 or isoproterenol plus MIX. These data suggest two potential effects of PGI2 biosynthesis by endothelial cells: first, the PGI2 can elevate cyclic AMP in platelets, and second, endothelial cell cyclic AMP can be elevated as well, so that subsequent PGI2 synthesis will be attenuated.
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PMID:Regulation of endothelial cell cyclic nucleotide metabolism by prostacyclin. 625 64

Zymosan coated with complement (Zc) was observed to induce a transient elevation of the intracellular cyclic AMP in human polymorphonuclear cells: a two- to three-fold increase was observed within 1 min after stimulation and approached prestimulation levels by 2 min incubation. These changes in cyclic AMP were not associated with significant changes in cyclic GMP levels. Zymosan caused the release of PAF and beta-glucuronidase and particle uptake, which was initiated about 5 min after stimulation. These results suggest that the transient increase in cyclic AMP content might regulate an early event during mediator release. In an attempt to study further the significance of this rise in cyclic AMP, cells were preincubated with various phosphodiesterase inhibitors. Preincubation of the cells with methylisobutylxanthine (MIX, 10(-6) M to 5 X 10(-5) M), theophylline (3 X 10(-5) to 3 X 10(-3) M) or dipyridamole (10(-6) M to 10(-4) M) enhanced the increase in cyclic AMP levels, but resulted in dose-dependent inhibition of Zc-induced mediator release. Particle uptake and beta-glucuronidase release were less sensitive than PAF release to phosphodiesterase inhibitors, which argues in favour of the independence of both phenomena. Synergistic experiments with MIX and cyclic AMP indicate that the effect of this drug is through its action on cyclic AMP levels. These results suggest that while Zc-induced cyclic AMP elevation might occur in an intracellular place critical to its effect; phosphodiesterase inhibitors may elevate cyclic AMP levels throughout the cell and therefore inhibit the biological response.
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PMID:Modulatory role of cyclic AMP in the release of platelet-activating factor from human polymorphonuclear leucocytes. 627 75

Forskolin was found to cause concentration dependent, reversible relaxations of isolated smooth muscle preparations including rat aorta, bovine coronary artery, canine coronary artery, guinea pig taenia caeci and rabbit small intestine. The relaxant effects of forskolin in guinea pig taenia caeci and rabbit small intestine were potentiated by cyclic nucleotide phosphodiesterase inhibitors Ro 20-1724 and MIX. In rabbit small intestine, Ro 20-1724 also potentiated the relaxant effects of isoproterenol but not those of verapamil or 2-chloroadenosine. However, in bovine coronary arteries the phosphodiesterase inhibitors had to be used at concentrations of 100 nM or below because of relaxant effects and did not alter forskolin-induced relaxations. Forskolin caused a concentration dependent activation of adenylate cyclase in broken cell preparations from guinea pig taenia caeci and rabbit small intestine, exceeding the stimulatory effect of 10 mM NaF. These results indicate that relaxations of smooth muscle by forskolin are mediated by cyclic AMP and, in turn, that cyclic AMP may well serve as an intracellular mediator of physiological relaxant stimuli.
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PMID:Relaxant effects of forskolin in smooth muscle. Role of cyclic AMP. 630 24

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

Both prostaglandin F2 alpha (PGF2 alpha) and LHRH inhibit LH-stimulated cAMP accumulation and progesterone secretion in the intact luteal cell, but have no effect on LH-sensitive adenylate cyclase activity in isolated membranes. The present studies were conducted to assess the possibility that calcium (Ca2+) may mediate the inhibitory activity of PGF2 alpha and LHRH in the rat luteal cell. Removal of extracellular Ca2+ significantly enhanced cAMP accumulation in response to LH by about 2-fold, but blunted LH-stimulated progesterone secretion. Incubation of luteal cells with A23187 caused a highly significant and dose-related decrease in LH-stimulated cAMP accumulation with a concentration for half-maximal inhibition (IC50) of about 1 microM. No effect of A23187 was seen on LH-sensitive adenylate cyclase activity, but the ionophore elicited significant inhibition of LH-stimulated intracellular cAMP accumulation in the presence of isobutyl-methylxanthine (MIX), a phosphodiesterase inhibitor. Inhibition by A23187 was Ca2+ dependent, since a decrease in extracellular Ca2+ to less than 100 microM completely blocked the effect of the ionophore. A23187 also significantly inhibited LH-stimulated progesterone secretion in response to LH or cholera toxin and inhibited cholera toxin-stimulated cAMP accumulation in the absence or presence of MIX. In incubations of isolated luteal membranes, Ca2+ produced a dose-dependent inhibition of LH-stimulated adenylate cyclase activity in the absence or presence of MIX at free Ca2+ levels between 5-20 microM (IC50, approximately 10 microM). Depletion of extracellular Ca2+ had no effect on inhibition of LH-stimulated cAMP accumulation by PGF2 alpha in the intact cell, and the inhibitory activity of LHRH was slightly reduced, but not abolished, by depletion of extracellular Ca2+. Verapamil, a Ca2+ channel blocker, had no effect on inhibition of LH-stimulated cAMP accumulation by PGF2 alpha or LHRH. It is concluded that an acute increase in intracellular Ca2+ inhibits activation of adenylate cyclase by LH in the rat luteal cell. This conclusion is based on studies that showed enhanced cAMP accumulation by LH in Ca2+-depleted media, Ca2+-dependent inhibition of LH-stimulated cAMP production by a Ca2+ ionophore, and direct inhibition of LH-sensitive adenylate cyclase activity by Ca2+ in luteal membranes. It is suggested that a similar effect occurs in response to PGF2 alpha or LHRH in the luteal cell, but inhibition by these luteolytic agents is not dependent on an influx of extracellular Ca2+, but, rather, is due to an increase in intracellular Ca2+ by other mechanisms.
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PMID:Calcium is an inhibitor of luteinizing hormone-sensitive adenylate cyclase in the luteal cell. 632 34

The effects of papaverine, cyclic AMP and MIX(3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor) on calcium uptake by a microsomal fraction from rat uterus were tested in the presence of 3 mM ATP. Papaverine potentiated calcium uptake in the presence of oxalate but inhibited it in the absence of oxalate. However, cyclic AMP and MIX did not influence calcium uptake, neither in the presence nor the absence of oxalate. These results suggest that calcium uptake by plasma membrane-derived vesicles in the absence of oxalate is inhibited by papaverine and that papaverine potentiated calcium uptake by the internal membranes in the presence of oxalate. They suggest also that the stimulatory action of papaverine involves a cyclic AMP-independent mechanism in addition to the mechanism via cyclic AMP.
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PMID:A dual action of papaverine on calcium uptake by microsomal fraction isolated from rat uterus. 721 34

Phorbol 12-myristate 13-acetate (TPA) augmented the effects of forskolin, and inhibited the effects of isoproterenol on cAMP accumulation in mouse parotid acini. Treatment of intact cells with the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (MIX), blocked TPA inhibition of isoproterenol but not forskolin-stimulated cAMP accumulation. TPA also caused the translocation of protein kinase C (PKC) from cytosol to membrane. Pre-treatment of parotid acini with TPA for 30 min enhanced the forskolin and isoproterenol-stimulated adenylate cyclase activity in isolated parotid membranes. Addition of purified PKC (pPKC) to parotid membranes mimicked the effects of TPA in increasing cAMP synthesis; the effects were blocked in the absence of calcium and phospholipid, and in the presence of the synthetic peptide (PKC 19-36). Purified PKC also mimicked the effects of TPA in augmenting forskolin and isoproterenol-stimulated adenylate cyclase activities in the cell-free system. Data suggest that the differential regulation of forskolin and isoproterenol-stimulated cAMP accumulation by TPA results from modification of enzymes that synthesize and degrade cAMP.
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PMID:Phorbol ester has different effects on forskolin and beta-adrenergic-stimulated cAMP accumulation in mouse parotid acini. 750 31


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