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)

Pretreatment of rat thymic lymphocytes with Concanavalin A induced a very early (30 min) and substantial increase (+90%) of the soluble cAMP phosphodiesterase activity. The crude cytosolic phosphodiesterase activity of rat thymocytes could reproducively be resolved by Mono-Q ion exchange high performance liquid chromatography into four separate phosphodiesterase peaks: a cGMP-stimulated, two cAMP-specific Rolipram-sensitive and a cGMP-inhibited cardiotrope-sensitive peaks. Concanavalin A stimulated very specifically the activity of the two predominant cAMP-specific Rolipram sensitive peaks whereas it only slightly modified the cGMP-stimulated and the cGMP-inhibited forms. The present results strongly suggest that the Rolipram-sensitive cAMP PDE activity may play a key role in the control and regulation of mitogen-induced thymocyte proliferation.
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PMID:Concanavalin A stimulates the Rolipram-sensitive isoforms of cyclic nucleotide phosphodiesterase in rat thymic lymphocytes. 216 36

In the absence of detergent, approximately 80-85% of the total cGMP-stimulated phosphodiesterase (PDE) activity in bovine brain was associated with washed particulate fractions; approximately 85-90% of the calmodulin-sensitive PDE was soluble. Particulate cGMP-stimulated PDE was higher in cerebral cortical gray matter than in other regions. Homogenization of the brain particulate fraction in 1% Lubrol increased cGMP-stimulated activity approximately 100% and calmodulin-stimulated approximately 400-500%. Although 1% Lubrol readily solubilized these PDE activities, approximately 75% of the cAMP PDE activity (0.5 microM [3H]cAMP) that was not affected by cGMP was not solubilized. This cAMP PDE activity was very sensitive to inhibition by Rolipram but not cilostamide. Thus, three different PDE types, i.e., cGMP stimulated, calmodulin sensitive, and Rolipram inhibited, are associated in different ways with crude bovine brain particulate fractions. After solubilization and purification by chromatography on cGMP-agarose, heparin-agarose, and Superose 6, the brain particulate cGMP-stimulated PDE cross-reacted with antibody raised against a cGMP-stimulated PDE purified from calf liver supernatant. The brain enzyme exhibited a slightly greater subunit Mr than did soluble forms from calf liver or bovine brain, as evidenced by protein staining or immunoblotting after polyacrylamide gel electrophoresis under denaturing conditions. Incubation of brain particulate and liver soluble cGMP-stimulated PDEs with V8 protease produced several peptides of similar size, as well as at least two distinct fragments of approximately 27 kDa from the brain and approximately 23 kDa from the liver enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of particulate cyclic nucleotide phosphodiesterases from bovine brain: purification of a distinct cGMP-stimulated isoenzyme. 216 58

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50 = 5.10(-8) M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the alpha i family (G alpha i2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20-1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of beta-receptor number, AC activation and cAMP accumulation, while Ro 20-1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in beta-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.
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PMID:The pharmacodynamic action of the cyclic AMP phosphodiesterase inhibitor rolipram on prolactin producing rat pituitary adenoma (GH4C1) cells. 217 76

The inhibitors of the cGMP-inhibited, low-Km cAMP phosphodiesterase--milrinone and OPC 3911--and an inhibitor of a non-cGMP-inhibited low-Km cAMP phosphodiesterase--rolipram--were used to evaluate the functional importance of the two cAMP phosphodiesterase activities in vascular smooth muscle and in platelets. Vinpocetine, an inhibitor of a calcium-calmodulin-dependent phosphodiesterase was also studied. OPC 3911 and milrinone relaxed the contracted rat aorta, inhibited ADP-induced platelet aggregation and also enhanced isoprenaline-induced relaxation as well as the antiaggregatory effects of adenosine. In platelets, OPC 3911 and milrinone increased cAMP levels, but in the rat aorta the increase was significant only for milrinone (OPC 3911 P = 0.062). In both tissues OPC 3911 and milrinone enhanced the increase in cAMP caused by activators of adenylate cyclase (isoprenaline/adenosine). Rolipram had no effects on aggregation or cAMP levels in platelets and no overadditive effects in combination with adenosine. Rolipram had little effect on relaxation and cAMP levels, did not alter isoprenaline-induced relaxation of guanfacin-contracted rat aorta, but showed synergistic effects with isoprenaline in raising cAMP levels. In PGF2 alpha-contracted aorta rolipram enhanced relaxation caused by isoprenaline. Vinpocetine had a relaxant effect without affecting cAMP levels, but had no effect on platelets. These results support the concept that the cGMP-inhibited phosphodiesterase is an important modulator of vascular smooth muscle tone and platelet function. The role of the non-cGMP-inhibited phosphodiesterase in these tissues is less obvious.
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PMID:Effects of isozyme-selective phosphodiesterase inhibitors on rat aorta and human platelets: smooth muscle tone, platelet aggregation and cAMP levels. 217 33

Rolipram is a racemic drug that increases brain cAMP availability by inhibiting phosphodiesterase. Lithium, on the other hand, reduces cAMP levels in brain by inhibiting adenylate cyclase and by increasing phosphodiesterase activity. Inbred strains of mice were used in the present study to determine whether the opposite effects of lithium and rolipram on cAMP levels were evident from behavioural effects of the drugs. In the first experiment, locomotor activity was measured in strains of male and female mice given an injection of either vehicle, (+)- or (-)-rolipram in order to find appropriate test conditions for studying interactions with lithium. (-)-Rolipram was more potent than its antipode in inducing hypokinesia, and the effects of (+)- and (-)-rolipram depended on mouse strain. In the second experiment, mice received lithium in their food for 3-4 weeks prior to testing, and they were then given an injection of vehicle, (+)- or (-)-rolipram before behaviour tests. Lithium reduced locomotor activity in mice given the vehicle, whereas it counteracted activity-suppressant effects of rolipram. The behavioural findings are consistent with the opposite pharmacological effects of lithium and rolipram on cAMP, and support the notion that cAMP availability in brain may play a role in behavioural effects of lithium and rolipram.
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PMID:Effects of lithium and rolipram enantiomers on locomotor activity in inbred mice. 231 65

This study examined the relative contributions of phosphodiesterase inhibition and adenosine receptor blockade in the respiratory-stimulant effects of selected xanthines. The respiratory effects of caffeine, theophylline, 8-phenyltheophylline (8-PT), 8-cyclopentyltheophylline (8-CPT), 3-isobutyl-1-methylxanthine and enprofylline, as well as the nonxanthine phosphodiesterase inhibitor, rolipram, and the adenosine analogs, N6-cyclopentyladenosine (CPA) and 5'-N-ethylcarboxamide adenosine (NECA), were studied in unanesthetized rhesus monkeys. Ventilation was measured continuously by enclosing the monkey's head in a fitted Lexan helmet while a pressure transducer measured differences in pressure produced by inspirations and expirations against a constant flow of air. Drugs were administered (i.m.) using cumulative-dosing procedures while the subjects breathed air or 5% CO2 mixed in air. All xanthines except 8-PT produced dose-related increases in respiratory frequency and less pronounced changes in tidal volume, both in air and in 5% CO2 mixed in air. 8-PT, an adenosine antagonist with little activity as a phosphodiesterase inhibitor, did not have respiratory effects over the range of doses studied. Enprofylline, a phosphodiesterase inhibitor with little activity as an adenosine antagonist, had effects that were comparable to those of caffeine. Rolipram also had effects on respiration that were similar to those of caffeine, and it was approximately 100 times more potent than caffeine. The adenosine A1/A2 agonist, NECA, produced dose-related increases in respiratory frequency, and both CPA (an A1-selective agonist) and NECA produced dose-related decreases in tidal volume; NECA was 30 to 100 times more potent than CPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Respiratory effects of xanthines and adenosine analogs in rhesus monkeys. 239 11

We tested the effects of the cyclic AMP-dependent phosphodiesterase inhibitor 4- (3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (rolipram) on c-fos protein-like immunoreactivity (FOS-IR) in adult rat brain. Rolipram (25-100 mg/kg, i.p.) did not detectability alter basal FOS-IR in neurons but induced FOS-IR in glial-like cells scattered in white matter regions and in ependymal cells lining the lateral and third ventricles. This induction was observed at 1 and 4 h after injection but was not detectable 10 min or 24 h after rolipram injection.
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PMID:Rolipram induces c-fos protein-like immunoreactivity in ependymal and glial-like cells in adult rat brain. 251 Sep 5

The present study was carried out to determine the ability of various pharmacological agents to selectively inhibit each cytosolic form of phosphodiesterase isolated from the longitudinal layer of human myometria near term. Among the drugs tested, zaprinast specifically inhibits the first form of PDE which hydrolyses both substrates (cAMP and cGMP) and is stimulated by the Ca2+-calmodulin complex. A second form of PDE specific for cAMP hydrolysis and Ca2+-calmodulin insensitive is only present during pregnancy. Rolipram is the most potent and selective inhibitor of this second form. It is also the most efficient compound to inhibit in vitro the spontaneous contractions of near term myometria. The double effect of rolipram suggests an important role of the second form of PDE in the mechanisms of contractility during the pregnancy. In addition rolipram or other derivatives might be of a therapeutic interest in the prevention of prematurity in so far as they are devoid of undesirable maternal and fetal side effects.
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PMID:Correlation between selective inhibition of the cyclic nucleotide phosphodiesterases and the contractile activity in human pregnant myometrium near term. 253 36

A series of synthetic pentasubstituted analogs of quercetin were evaluated for their ability to inhibit the various phosphodiesterase isoforms resolved from rat brain cytosol by isoelectric focusing. All the tested compounds were more potent in inhibiting the calcium plus calmodulin-independent isoforms than the dependent ones. Out of the two calcium-independent cyclic AMP-specific isoforms present in brain preparations, the Rolipram-sensitive enzyme proved to be the most sensitive to flavonoid inhibition. In contrast with the antidepressant compound Rolipram which is totally devoid of anticalmodulin property, these flavonoid derivatives exhibited anticalmodulin activity as illustrated by their higher inhibitory potency toward the calmodulin-dependent isoform in the presence of calcium plus calmodulin than in the presence of EGTA and by the ability of [3H] penta-O-ethylquercetin to bind to calmodulin in a calcium-dependent way.
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PMID:Inhibition of the different cyclic nucleotide phosphodiesterase isoforms separated from rat brain by flavonoid compounds. 254 24

Rolipram [(R,S)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone] has been shown to inhibit selectively the cAMP phosphodiesterase (PDE) of vascular smooth muscle. In order to further explore the structural requirements for selective PDE inhibition, we synthesized a series of rolipram derivatives differently substituted either at the pyrrolidinone or at the aromatic ring. Among these compounds, rolipram was the most active compound. Semirigid analogues were prepared and used for an evaluation of the active conformation of rolipram. Structural comparison with two other potent and chemically different smooth muscle cAMP-PDE inhibitors, trequinsin and Ro 20-1724, allows us to propose a first topological model of the smooth muscle cAMP-PDE pharmacophore.
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PMID:Inhibition of cyclic adenosine-3',5'-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogues. 254 22


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