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)

We studied the effect of several compounds that influence different cell activation steps on platelet-activating factor (PAF)-induced basophil histamine secretion. Isobutylmethylxanthine (1-100 microM), dimaprit (1-100 microM) and dibutyryl adenosine 3',5'-cyclic phosphate (cAMP; 0.01-1 mM), that increase intracellular cAMP levels, concentration-dependently inhibited PAF-elicited histamine release. Rolipram (phosphodiesterase, PDE, isotype IV inhibitor; 0.1 nM-10 microM) potently inhibited histamine secretion activated by PAF, whereas SKF95654 (PDE III inhibitor; 0.01-10 microM) was ineffective. The kinase inhibitor, staurosporine (0.1-100 nM), enhanced PAF-induced basophil histamine release, whereas the G-protein inhibitor, pertussis toxin (1 microgram/ml), had an inhibitory effect. The specific lipoxygenase inhibitor, AA-861 (0.1-10 microM), inhibited PAF-activated histamine release, while the leukotriene A4 hydrolase inhibitor, bestatin (100 microM), had only a marginal effect. Finally, the Ca2+ channel entry blockers, verapamil (3-30 microM) and zinc (1.5-50 microM), inhibited PAF-induced histamine release. These results suggest that PAF is a unique secretagogue for human basophils unlike antigen, anti-IgE or univalent stimuli.
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PMID:Pharmacologic control of histamine release from human basophils induced by platelet-activating factor. 769 3

1. We have examined the effect of elevation of cellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) on alpha 1- and alpha 2-adrenoceptor-mediated contraction of the isolated palmar lateral vein of the pig. Cellular cyclic AMP was increased by either inhibition of phosphodiesterase by rolipram, or direct activation of adenylyl cyclase by forskolin. 2. Noradrenaline (1 nM-10 microM) caused concentration-dependent contractions of the porcine isolated palmar lateral vein (pD2 7.32 +/- 0.07, n = 10). The selective alpha 1-adrenoceptor antagonist, prazosin (0.1 microM) and the selective alpha 2-adrenoceptor antagonist, rauwolscine (1 microM) caused a 10 fold rightward displacement of the concentration-response curve and a combination of the two antagonists caused a 200 fold rightward displacement of the concentration-response curve. The selective alpha 2-adrenoceptor agonist, UK-14304, also produced concentration-dependent contractions of the palmar lateral vein (pD2 7.70 +/- 0.15, n = 5), but the maximum response was 55.5 +/- 7.6% (n = 5) of that produced by noradrenaline. Prazosin (0.1 microM) failed to affect responses to UK-14304 but rauwolscine, 1 microM, caused a 200 fold rightward displacement. The estimated pKB value for rauwolscine (8.28 +/- 0.19, n = 10) is consistent with inhibition of alpha 2-adrenoceptors. Thus, the porcine isolated palmar lateral vein has a population of alpha 1- and alpha 2-adrenoceptors capable of producing a contraction. 3. Rolipram, 10 micro M, and forskolin, 1 micro M, caused a 2-3 fold rightward displacement of the noradrenaline concentration-response curve (CRC), but 1,9-dideoxyforskolin, 1 micro M, a forskolin analogue which does not activate adenylyl cyclase, failed to produce a significant inhibition of noradrenaline induced contractions. The combination of forskolin (1 micro M) and rolipram (10 micro M) were additive, producing a 20 fold rightward displacement of the noradrenaline CRC.4. Responses to noradrenaline were similarly affected by a combination of rolipram (10 micro M) and prazosin (0.1 micro M) (isolation of alpha 2-adrenoceptors) and the combination of rolipram (10 micro M) and rauwolscine(1 micro M) (isolation of alpha l-adrenoceptors), resulting in a 100 fold rightward displacement of the noradrenaline CRC. Although forskolin inhibited both alpha l- and alpha 2-adrenoceptor-mediated contractions,the effects produced were not similar. In particular, noradrenaline, 0.3-3 micro M, produced a significant contraction in the presence of forskolin (1 micro M) and prazosin (0.1 micro M) (an alpha 2-adrenoceptor-mediated response) but not in the presence of forskolin (1 micro M) and rauwolscine (1 micro M) (an alpha l-adrenoceptor mediated response).5. Five minute exposure to either rolipram (10 micro M) or forskolin (1 micro M) elevated [3H]-cyclic AMP of the porcine isolated palmar lateral vein by approximately 70% and 150-200%, respectively. Neither noradrenaline (1 nM- 100 micro M) nor UK-14304 (1 nM- 100 micro M) affected basal levels of [3H]-cyclic AMP,but both produced a concentration-dependent inhibition of forskolin-stimulated [3H]-cyclic AMP accumulation with a pKi of 7.43 +/- 0.1 (n = 3) and 7.97 +/- 0.18 (n = 3), respectively. The effect of noradrenaline against forskolin-stimulated [3H]-cyclic AMP accumulation was reversed by rauwolscine(1 micro M) but not by prazosin (0.1 micro M). In contrast, alpha 2-adrenoceptor activation did not affect rolipram induced elevation of [3H]-cyclic AMP.6. These findings indicate that M2-adrenoceptor contractions of the porcine isolated palmar lateral vein are not produced by reduction in cellular cyclic AMP per se. It is proposed that this response involves a novel signal transduction mechanism. However, when cellular cyclic AMP has been elevated by agents that stimulate adenylyl cyclase, rather than through inhibition of phosphodiesterase, the ability of alpha 2-adrenoceptors to inhibit cyclic AMP formation may be of functional importance in vascular smooth muscle.
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PMID:Examination of the role of inhibition of cyclic AMP in alpha 2-adrenoceptor mediated contractions of the porcine isolated palmar lateral vein. 771 12

We examined the effects of rolipram, a cyclic AMP-selective phosphodiesterase inhibitor, on cerebral ischemia-induced neuronal damage in Mongolian gerbils. Transient forebrain ischemia was induced by 3-min occlusion of bilateral common carotid arteries. Rolipram, at a dose of 0.3 or 3 mg/kg, was injected i.p. 30 min before ischemia. Histopathological observations showed that neuronal damage to the hippocampal CA1 subfield, which was seen 7 days after ischemia in vehicle-treated animals, was reduced in animals treated with the higher dose of rolipram.
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PMID:Rolipram, a cyclic AMP-selective phosphodiesterase inhibitor, reduces neuronal damage following cerebral ischemia in the gerbil. 771 41

In several cell types, the expression of the proenkephalin (PEnk) gene is enhanced after activation of protein kinase A. In the present study, astroglial cells cultured from rat cortex were used to investigate whether protein kinases A and C can act in a synergistic manner on the endogenous proenkephalin gene. The activator of protein kinase C tetradecanoylphorbolacetate (0.001-1 microM) increased the level of proenkephalin-mRNA in a concentration dependent manner. When used together with the phosphodiesterase inhibitor Rolipram (1 microM), the effect of tetradecanoylphorbolacetate (0.01 microM) was potentiated. 8-Bromoadenosine 3',5'-cyclic monophosphate (0.01-1 mM) also enhanced the expression of the proenkephalin gene. When used together with tetradecanoylphorbolacetate (0.01 and 0.1 microM), respectively, both agents had additive effects. Inhibition of protein synthesis with cycloheximide (35 microM) significantly changed the effects of both agents. While the effect of 8Br.cAMP (1 mM) on PEnk-mRNA was enhanced, that of tetradecanoylphorbolacetate (0.1 microM) was abolished. The results provide evidence for a synergistic effect of protein kinase A and C on the expression of the proenkephalin gene in astroglial cells. However, the protein kinases seem to act via different transcription factors on the expression of the proenkephalin gene.
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PMID:Interaction of protein kinases A and C in their effects on the proenkephalin gene in astroglial cells. 782 71

Three phosphodiesterase (PDE) isoenzymes were separated by Mono Q h.p.l.c. column chromatography from the soluble fraction of a homogenate of pig aortic smooth muscle cells. The first peak of PDE activity was stimulated by calmodulin in the presence of calcium. The second broad peak contained at least two activities, which were sensitive to inhibition by CI-930 or rolipram respectively. The distribution of total cellular enzyme activity in different subcellular fractions was also determined. The majority (78%) of the total activity was present in the cytosolic fraction, 18% of activity was in a membrane-bound form and 4% of activity was associated with the cytoskeleton. Rolipram-sensitive PDE was present predominantly in the cytosolic fraction, whereas cyclic GMP-inhibited, CI-930-sensitive PDE was evenly distributed between the cytosolic and particulate fractions. All of the calmodulin-dependent PDE activity was found in the soluble fraction. CI-930 and rolipram enhanced, by 2-fold and 3-4-fold respectively, the adenosine-stimulated rise in cellular cyclic AMP level. The increase in cyclic AMP levels due to CI-930 or rolipram was dose-dependent. Removal of adenosine once cyclic AMP had risen resulted in a rapid fall in cyclic AMP levels even in the presence of rolipram and CI-930. M&B 22,948, the calmodulin-dependent PDE inhibitor, caused less than a 25% increase of the adenosine-stimulated cyclic AMP levels by itself, but it contributed substantially to controlling the cyclic AMP levels after the removal of adenosine when used together with CI-930 and rolipram. These phenomena suggested that all three PDE isoenzymes participated in modulating cellular cyclic AMP levels after adenosine stimulation, and that differential importance of the individual isoenzymes depends on cellular cyclic AMP levels.
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PMID:Role of phosphodiesterase isoenzymes in regulating intracellular cyclic AMP in adenosine-stimulated smooth muscle cells. 783 82

Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selective for different classes of phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production by human monocytes. The selective cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effective in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF alpha production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNF alpha mRNA expression, and at the protein level was also active when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNF alpha production in vivo in a rat endotoxemia model. Collectively, these data suggest that the prototypic inhibitor of PDE IV isozyme, rolipram, can effectively and selectively inhibit LPS-induced TNF alpha production through elevation of intracellular cAMP.
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PMID:Characterization of cAMP-dependent inhibition of LPS-induced TNF alpha production by rolipram, a specific phosphodiesterase IV (PDE IV) inhibitor. 784 52

1. We have investigated the effects of RP 73401, a novel, potent and highly selective cyclic nucleotide phosphodiesterase (PDE) type IV inhibitor, in guinea-pig and rat models of bronchoconstriction and allergic inflammation. In some models, the effects of RP 73401 have been compared with those of the standard PDE type IV inhibitor, rolipram. 2. RP 73401 (0.4-400 micrograms kg-1, intratracheally (i.t.) on lactose) inhibited antigen-induced bronchospasm in previously sensitized conscious guinea-pigs (ID50: 7 +/- 1 micrograms kg-1) and in anaesthetized rats (ID50: 100 +/- 25 micrograms kg-1). Rolipram inhibited the antigen-induced bronchospasm in guinea-pigs with an ID50 of 5 +/- 1 micrograms kg-1. In guinea-pig bronchoalveolar lavage (BAL) fluid, total inflammatory cell and eosinophil numbers were reduced by RP 73401 (ID50s: 3.9 +/- 0.8 micrograms kg-1 and 3.2 +/- 0.7 micrograms kg-1, respectively). In the rat, inflammatory cell numbers are less affected. Only the highest dose of RP 73401 (400 micrograms kg-1) significantly inhibited eosinophil influx (41 +/- 16% inhibition). 3. RP 73401 (0.02-100 micrograms kg-1, i.v.) inhibited PAF-induced bronchial hyperreactivity to bombesin in the anaesthetized guinea-pig (ID50: 0.09 +/- 0.03 micrograms kg-1) and inhibited (0.4-40 micrograms kg-1, i.t.) histamine-induced airway microvascular leakage in the anaesthetized guinea-pig by approximately 60% at all doses. 4. RP 73401 relaxed guinea-pig isolated trachea under basal tone (EC50: 9 nM) and when precontracted with histamine (IC50: 2 nM), methacholine (IC50: 29 nM) or leukotriene D4 (LTD4, IC50: 4 nM). 5. RP 73401 (0.4-100 microg kg-1, i.t.) inhibited bronchospasm induced by histamine (ID.%: 34 +/- 6 microg kg-1), methacholine (ID50: 66 +/- 12 pg kg-1) and LTD4 (ID50: <4 microg kg-1) in the anaesthetized guinea pig.Against these same bronchoconstrictors, rolipram (i.t.) had ID5o values of 44 +/- 4, 72 +/- 18 and<4 pg kg- respectively. RP 73401 (4 and 40 pg kg-, i.t.) increased the magnitude and duration of bronchodilatation produced by salbutamol in the anaesthetized guinea-pig. At doses producing significant bronchodilatation, RP 73401 was without effect on heart rate or blood pressure in the anaesthetized guinea-pig. RP 73401 (0.01 -0.25 mg kg-1, i.v.) did not affect heart rate and produced only a small fall in blood pressure in the anaesthetized rat.6. These data demonstrate that RP 73401 and rolipram inhibit antigen- and mediator-induced bronchospasmin guinea-pigs with the same potency. Furthermore, RP 73401 administered directly into the airways, protects against allergic airway inflammation. These results indicate the importance of PDE IV in regulating smooth muscle and inflammatory cell activity. At doses suppressing the inflammatory response in the lung, RP 73401 had little effect in the cardiovascular system. RP 73401 may have a role as a bronchodilator and, more importantly, as a prophylactic anti-inflammatory agent in the treatment of asthma.
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PMID:Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor. 788

Several independent studies indicate that synthetic inhibitors of cyclic-3',5'-nucleotide phosphodiesterase (PDE) isozymes, especially inhibitors of PDE-IV, are potent agents which suppress generation of reactive oxygen metabolites (ROM) by NADPH oxidase in leukocytes. Recent studies also show that NADPH oxidase is present in all cell types populating glomeruli. In view of this, we investigated PDE isozymes and their relation to ROM in isolated rat glomeruli. Glomeruli have the capacity to hydrolyze cAMP by isozymes PDE-II, PDE-III and PDE-IV, whereas cGMP is hydrolyzed by PDE-I and PDE-V. Inhibitor of PDE-IV rolipram inhibited significantly (cca 40 to 50%) ROM generation in response to stimulation by phorbol myristate acetate (PMA). Inhibitor of PDE-III cilostamide had only minor suppressive effects and inhibitors of other PDE isozymes did not influence ROM generation. Rolipram (3 microM) suppressed ROM generation without detectable increase in cAMP content. Incubation of glomeruli with forskolin, which increased cAMP content in glomeruli tenfold, inhibited ROM generation to a similar degree as rolipram. The suppression of ROM generation by rolipram was prevented by Rp-cAMPS, a specific inhibitor of protein kinase A (PKA) activity. Further, incubation of glomeruli with rolipram elicited marked in situ activation of PKA (+ 100%), as documented by increase in the (-cAMP/+cAMP) PKA activity ratio. We suggest that selective inhibitor of PDE-IV rolipram acted via the cAMP-signaling pathway and suppressed ROM generation possibly via phosphorylating ras-type GTP-binding protein component of NADPH oxidase and thereby blocking assembly of functional NADPH oxidase complex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Formation of reactive oxygen metabolites in glomeruli is suppressed by inhibition of cAMP phosphodiesterase isozyme type IV. 793 46

Chronic ethanol (EtOH) use during pregnancy can be associated with fetal injury including the fetal alcohol syndrome (FAS). A contributing factor in this fetal injury may be the effect of EtOH on the placenta. In this study, we have examined the effect of in vitro EtOH treatment on adenosine 3':5'-cyclic monophosphate (cAMP) production by cultured trophoblasts, in response to various ligands. Epinephrine (10(-6) M) rapidly stimulated cAMP with a peak between 2.5 and 5 min, which gradually returned to basal levels over 3-4 hr. EtOH treatment for > 16 hr resulted in an up-regulation of epinephrine-stimulated cAMP production. Inhibition of phosphodiesterase with Rolipram enhanced the effect of EtOH on cAMP production, suggesting that the effect of EtOH treatment was not due to phosphodiesterase inhibition. In cultured trophoblasts, EtOH treatment increased both epinephrine and 16,16'-dimethylprostaglandin E2 (dm-PGE2)-dependent cAMP production at varying ligand concentrations, suggesting an increased capacity to respond. When trophoblasts were treated with forskolin, a stimulator of adenylyl cyclase, cAMP production was enhanced in EtOH-treated cells. This suggests that EtOH treatment enhances adenylyl cyclase activity in these intact, cultured cells. Unlike trophoblasts from term human placenta, JAR choriocarcinoma cells did not respond to epinephrine, adenosine, or dm-PGE2. The choriocarcinoma cells appeared to have lost the ability to respond to these ligands. Although the JAR cell adenylyl cyclase was stimulated by forskolin, EtOH treatment did not alter forskolin-stimulated cAMP production. In summary, EtOH-induced up-regulation of cAMP production appears to be cell specific, being present in normal human trophoblasts but not in undifferentiated choriocarcinoma cells.
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PMID:Ethanol enhancement of ligand-stimulated cAMP production by cultured human placental trophoblasts. 794 50

Human bronchial rings were contracted with histamine (3 microM), and inhibitory responses were obtained with electrical field stimulation (EFS) in the presence of propranolol (1 microM), atropine (1 microM), and indomethacin (3 microM). These nonadrenergic noncholinergic (NANC) relaxations were frequency-dependent (1 to 32 Hz) and inhibited by either tetrodotoxin or Nw-nitro-L-arginine (L-NNA, 100 microM). The selective cAMP-specific phosphodiesterase (PDE) type IV inhibitors rolipram (3 microM) and Ro 20-1724 (3 microM) significantly potentiated NANC relaxations at each frequency of stimulation. The selective cGMP-specific PDE type V inhibitor zaprinast (3 microM) failed to significantly alter the maximal NANC response, but it caused a slight potentiation of the response at lower frequencies. The adenylyl cyclase stimulant forskolin, the nitric oxide donor compound 3-morpholinosydnonimine (SIN-1), and the guanylyl cyclase stimulant sodium nitroprusside caused concentration-dependent relaxation of histamine-contracted airway smooth muscle. Rolipram significantly potentiated the relaxation elicited by forskolin. Rolipram also potentiated responses to SIN-1 and sodium nitroprusside. Considered together these data support the hypothesis that cAMP plays a facilitory role in NANC relaxation of the human bronchi.
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PMID:Potentiation of nonadrenergic noncholinergic relaxation of human isolated bronchus by selective inhibitors of phosphodiesterase isozymes. 773 37


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