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Phosphodiesterase Inhibitor

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6561. Effects of selective phosphodiesterase 3 inhibition in the perfused liver of the rat after endotoxin treatment. Full Text available with Trip Pro

Effects of selective phosphodiesterase 3 inhibition in the perfused liver of the rat after endotoxin treatment. 1. This study was designed to investigate the role of rat phosphodiesterase 3 (RPDE3) in regulation of liver metabolism in sepsis. We studied the effects of the phosphodiesterase 3 inhibitor (PDI), enoximone, alone and in combination with regulating factors of hepatic carbohydrate metabolism and bile secretion in the perfused liver of rats treated 4 h earlier with endotoxin (...) , the inhibition of the RPDE3 results in glucose release, vasodilatation and choleresis in endotoxin pretreated livers.

1996 British journal of pharmacology

6562. Nitric oxide, an enteric nonadrenergic-noncholinergic relaxant transmitter: evidence using phosphodiesterase V and nitric oxide synthase inhibition. Full Text available with Trip Pro

Nitric oxide, an enteric nonadrenergic-noncholinergic relaxant transmitter: evidence using phosphodiesterase V and nitric oxide synthase inhibition. 1. The effects of NG-nitro-L-arginine (L-NOARG), a nitric oxide synthase inhibitor, and SK&F 96231, a phosphodiesterase type V inhibitor, on electrical field stimulated (EFS) nonadrenergic noncholinergic (NANC) relaxations of rat fundal strips, guinea-pig isolated ileum longitudinal muscle with intact myenteric plexus, and guinea-pig taenia caeci (...) , depending on the tissue, by L-arginine (5 x 10(-3) M). 4. SK&F 96231 (10(-6)-10(-4) M) caused a concentration- and frequency-dependent potentiation of both the size and duration of the EFS-induced NANC relaxant response of rat fundal strips and guinea-pig isolated ileum longitudinal muscle with intact myenteric plexus, but not of the guinea-pig taenia caeci. 5. Zaprinast, another phosphodiesterase type V inhibitor (10(-6)-10(-4) M) caused a concentration- and frequency-dependent potentiation of the NANC

1995 British journal of pharmacology

6563. Tomato annexins p34 and p35 bind to F-actin and display nucleotide phosphodiesterase activity inhibited by phospholipid binding. Full Text available with Trip Pro

Tomato annexins p34 and p35 bind to F-actin and display nucleotide phosphodiesterase activity inhibited by phospholipid binding. Annexins are a family of proteins found in a range of eukaryotic cell types. They share a characteristic amino acid sequence and a Ca(2+)-dependent affinity for specific phospholipids. In plants, proteins with common properties and significant homology with annexins have been identified in a number of species and implicated in diverse cellular functions known (...) to be modulated by Ca2+. This study describes several novel biochemical properties of the tomato annexins p34 and p35 that are relevant to our understanding of their functions in the plant. First, the annexins were found to bind to actin in a calcium- and pH-dependent interaction that was specific for F-actin and not G-actin. Second, an enzyme activity defined as a nucleotide phosphodiesterase activity was found associated with the purified annexin preparation. Selective immunoprecipitation of p34 and p35

1996 The Plant cell

6564. KS-505a, an isoform-selective inhibitor of calmodulin-dependent cyclic nucleotide phosphodiesterase. Full Text available with Trip Pro

KS-505a, an isoform-selective inhibitor of calmodulin-dependent cyclic nucleotide phosphodiesterase. The effects of KS-505a, a novel microbial metabolite, on the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaM-PDE) were investigated. (1) KS-505a potently inhibited the purified 61 kDa isoenzyme of CaM-PDE from bovine brain and required much higher doses to inhibit the purified 59 kDa isoenzyme of CaM-PDE from bovine heart. The inhibition of both isoenzymes was observed (...) only in the presence of calcium-activated calmodulin (Ca2+/CaM). The IC50 values for the 61 and 59 kDa isoenzymes were 0.17 and 13 microM respectively with 20 microM cAMP as a substrate. (2) Kinetic analysis indicated that the inhibitory mode of KS-505a for the 61 kDa isoenzyme was competitive with respect to Ca2+/CaM; the K1 for KS-505a was 0.089 microM. The inhibition was not competitive with respect to the substrates cAMP or cGMP. (3) KS-505a did not interfere with the interaction between Ca2

1996 Biochemical Journal

6565. The insulinotropic mechanism of the novel hypoglycaemic agent JTT-608: direct enhancement of Ca2+ efficacy and increase of Ca2+ influx by phosphodiesterase inhibition Full Text available with Trip Pro

The insulinotropic mechanism of the novel hypoglycaemic agent JTT-608: direct enhancement of Ca2+ efficacy and increase of Ca2+ influx by phosphodiesterase inhibition We examined the effects of the novel hypoglycaemic agent JTT-608 [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid] on insulin secretion using rat pancreatic islets, and analysed the mechanism of its effect. JTT-608 augmented 8.3 mM glucose-induced insulin secretion dose-dependently, and there was a stimulatory effect of 100 microM (...) -isobutyl-1-methylxanthine (IBMX). JTT-608 inhibited phosphodiesterase (PDE) activity dose-dependently. We conclude that JTT-608 augments insulin secretion by enhancing Ca(2+) efficacy and by increasing Ca(2+) influx. This appears to be a result of the increased intracellular cyclic AMP concentration due to PDE inhibition.

2000 British journal of pharmacology

6566. Effect of type-selective inhibitors on cyclic nucleotide phosphodiesterase activity and insulin secretion in the clonal insulin secreting cell line BRIN-BD11 Full Text available with Trip Pro

Effect of type-selective inhibitors on cyclic nucleotide phosphodiesterase activity and insulin secretion in the clonal insulin secreting cell line BRIN-BD11 1. The cyclic nucleotide phosphodiesterases (PDEs) present in an insulin secreting cell line, BRIN - BD11, were characterized using calcium/calmodulin, IGF-1, isoenzyme-selective PDE inhibitors and RT - PCR. 2. Calmodulin activated cyclic AMP or cyclic GMP PDE activity in pellet and was 3 fold (P=0.002) more potent in activating cyclic (...) nucleotide hydrolysis in pellet compared with supernatant fractions. 3. The PDE1/PDE5 inhibitor zaprinast inhibited both cyclic AMP and cyclic GMP PDE activity in both pellet and supernatant fractions of cell homogenates by a maximum of around 25% (IC(50) 1 - 5 microM), while rolipram (PDE4 selective) inhibited only cyclic AMP hydrolysis. 4. The PDE3-selective inhibitors Org 9935 (0.02 - 10 microM) and siguazodan (0.1 - 10 microM) inhibited cyclic AMP PDE activity in the pellet but not the supernatant

2000 British journal of pharmacology

6567. Effects of phosphodiesterase inhibitors on human lung mast cell and basophil function Full Text available with Trip Pro

Effects of phosphodiesterase inhibitors on human lung mast cell and basophil function 1. The non-hydrolysable cyclic AMP analogue, dibutyryl (Bu2)-cyclic AMP, inhibited the stimulated release of histamine from both basophils and human lung mast cells (HLMC) in a dose-dependent manner. The concentrations required to inhibit histamine release by 50% (IC50) were 0.8 and 0.7 mM in basophils and HLMC, respectively. The cyclic GMP analogue, Bu2-cyclic GMP, was ineffective as an inhibitor of histamine (...) release in basophils and HLMC. 2. The non-selective phosphodiesterase (PDE) inhibitors, theophylline and isobutyl-methylxanthine (IBMX) inhibited the IgE-mediated release of histamine from both human basophils and HLMC in a dose-dependent fashion. IBMX and theophylline were more potent inhibitors in basophils than HLMC. IC50 values for the inhibition of histamine release were, 0.05 and 0.2 mM for IBMX and theophylline, respectively, in basophils and 0.25 and 1.2 mM for IBMX and theophylline in HLMC. 3

1997 British journal of pharmacology

6568. Amelioration of collagen II-induced arthritis in rats by the type IV phosphodiesterase inhibitor Rolipram Full Text available with Trip Pro

Amelioration of collagen II-induced arthritis in rats by the type IV phosphodiesterase inhibitor Rolipram The effect of Rolipram, a selective inhibitor of the cyclic AMP specific phosphodiesterase (PDE IV) was evaluated in the rat collagen type II (RCII)-induced arthritis model in the DA rat. Rolipram was given either shortly before expected onset of disease (days 10-14) or shortly after the onset of clinically evident arthritis (days 15-19 after immunization). Administration at days 10-14 (...) delayed the onset of arthritis for approximately 5 days, but the severity of arthritis was thereafter comparable to that seen in a non-treated control group. Rolipram treatment of animals with manifest arthritis inhibited further arthritis development and also tended to diminish its severity at a phase of disease where non-treated control animals showed a rapidly progressing disease development. Serum levels of antibodies to RCII were in all experiments similar between Rolipram-treated and control

1997 Clinical and experimental immunology

6569. Effects of inhibitors of phosphodiesterase, on antigen-induced bronchial hyperreactivity in conscious sensitized guinea-pigs and airway leukocyte infiltration Full Text available with Trip Pro

Effects of inhibitors of phosphodiesterase, on antigen-induced bronchial hyperreactivity in conscious sensitized guinea-pigs and airway leukocyte infiltration 1. The aim of this study was to determine the effects of inhibitors of phosphodiesterase (PDE) on the early and late phase bronchoconstriction in sensitized, conscious guinea-pigs and the subsequent development of acute airway hyperreactivity to the inhaled thromboxane mimetic, U46619, and leukocyte infiltration following ovalbumin (OvA (...) antigen-induced airway leukocyte infiltration. Rolipram and Ro 20-1724 additionally attenuated the development of acute airway hyperreactivity, effects which are probably mediated through inhibition of PDE type 4. A dose of PDE inhibitor 6 h after the antigen challenge appears to be essential to achieve this protection. Inhibitors of PDE type 3 were generally without effect. However, there was no effect of rolipram or Ro 20-1724 on the development of either the early or late phase type responses.

1997 British journal of pharmacology

6570. Phosphodiesterase profile of human B lymphocytes from normal and atopic donors and the effects of PDE inhibition on B cell proliferation Full Text available with Trip Pro

Phosphodiesterase profile of human B lymphocytes from normal and atopic donors and the effects of PDE inhibition on B cell proliferation 1. CD19+ B lymphocytes were purified from the peripheral blood of normal and atopic subjects to analyse and compare the phosphodiesterase (PDE) activity profile, PDE mRNA expression and the importance of PDE activity for the regulation of B cell function. 2. The majority of cyclic AMP hydrolyzing activity of human B cells was cytosolic PDE4, followed (...) lipopolysaccharide (LPS) induced a proliferative response in a time- and concentration-dependent manner, which was increased in the presence of interleukin-4 (IL-4). PDE4 inhibitors (rolipram, piclamilast) led to an increase in the cellular cyclic AMP concentration and to an augmentation of proliferation, whereas a PDE3 inhibitor (motapizone) was ineffective, which is in accordance with the PDE profile found. The proliferation enhancing effect of the PDE4 inhibitors was partly mimicked by the cyclic AMP

1998 British journal of pharmacology

6571. Expression and mutagenesis of the catalytic domain of cGMP-inhibited phosphodiesterase (PDE3) cloned from human platelets. Full Text available with Trip Pro

Expression and mutagenesis of the catalytic domain of cGMP-inhibited phosphodiesterase (PDE3) cloned from human platelets. We have used reverse transcriptase PCR, platelet mRNA and degenerate primers based on platelet peptide sequences, to amplify a fragment of platelet cGMP-inhibited phosphodiesterase (cGI-PDE; PDE3). Sequence analysis of this clone established that both the platelet and the cardiac forms of PDE3 were derived from the same gene (PDE3A). A RT-PCR product representing the C (...) ability to be photolabelled by [32P]cGMP, no cyclic nucleotide hydrolytic activities of the mutant were detectable. Mutation of amino acid residues in putative beta-turns at the beginning and end of the 44-amino-acid insert to alanine residues markedly reduced the ability of the enzyme to hydrolyse cyclic nucleotides. The PDE3 inhibitor, lixazinone, retained the ability to inhibit cAMP hydrolysis and [32P]cGMP binding by the N-terminal deletion mutants and the site-directed mutants, suggesting

1997 Biochemical Journal

6572. Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension Full Text available with Trip Pro

Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension 1. Chronic hypoxic treatment of rats (to induce pulmonary hypertension, PHT) for 14 days increased cGMP-inhibited cAMP specific phosphodiesterase (PDE3) and cGMP binding cGMP specific phosphodiesterase (PDE5) activities in pulmonary arteries. The objective of this study was to establish the molecular basis for these changes in both animal (...) in the intra-pulmonary and resistance vessels. 3. The expression of PDE3A was increased in HPASMCs maintained under chronic hypoxic conditions for 14 days. This may be mediated via a protein kinase A-dependent mechanism, as treatment of cells with Br-cAMP (100 microM) mimicked chronic hypoxia in increasing PDE3A expression, while the PKA inhibitor, H8 peptide (50 microM) abolished the hypoxic-dependent increase in PDE3A transcript. 4. We also found that the treatment of HPASMCs with the inhibitor of kappaB

2002 British journal of pharmacology

6573. Effects of phosphodiesterase inhibitors on normal and chemically-skinned isolated airway smooth muscle. Full Text available with Trip Pro

Effects of phosphodiesterase inhibitors on normal and chemically-skinned isolated airway smooth muscle. 1. The effects of three phosphodiesterase inhibitors (papaverine, isobutyl methyl xanthine (IBMX) and SKF 94120) were examined on tension responses and cyclic nucleotide content (both cyclic AMP and cyclic GMP) of normal and Triton X-100 skinned isolated trachealis of the guinea-pig. 2. The three inhibitors were approximately equipotent in eliciting concentration-dependent relaxation (...) of the guinea-pig trachealis. The results suggest that a functional sarcoplasmic reticular and/or plasma membrane is essential for the expression of IBMXand SKF 94120-induced relaxation. This is not the case for papaverine. The results also highlight the fact that significant relaxant responses of airway smooth muscle can be produced by phosphodiesterase- inhibiting drugs without concomitant elevations in tissue cyclic nucleotide content.

1987 British journal of pharmacology

6574. A model for the regulation of the calmodulin-dependent enzymes erythrocyte Ca2+-transport ATPase and brain phosphodiesterase by activators and inhibitors. Full Text available with Trip Pro

A model for the regulation of the calmodulin-dependent enzymes erythrocyte Ca2+-transport ATPase and brain phosphodiesterase by activators and inhibitors. Acidic phospholipids, unsaturated fatty acids and limited proteolysis mimic the activating effect of calmodulin on erythrocyte Ca2+-transport ATPase and on brain cyclic nucleotide phosphodiesterase, as has been reported previously in several studies. Three different antagonists of calmodulin-induced activation of these enzymes were tested (...) for their inhibitory potency on the stimulation produced by the other activators. Trifluoperazine and penfluridol were found to antagonize all the above mentioned types of activation of Ca2+-transport ATPase in the same concentration range. Both inhibitors also can reverse the activation of phosphodiesterase by oleic acid, phosphatidylserine and calmodulin at similar concentrations. However, in contrast with erythrocyte Ca2+-transport ATPase, activation of phosphodiesterase by limited tryptic digestion cannot

1982 Biochemical Journal

6575. The effect of phosphodiesterase inhibitors on the electrical activity of toad rods. Full Text available with Trip Pro

The effect of phosphodiesterase inhibitors on the electrical activity of toad rods. The membrane potential of toad rods was recorded during addition of small amounts of phosphodiesterase inhibitors to the extracellular medium. Separate application of 3-isobutyl-1-methylxanthine (IBMX), caffeine, theophylline, papaverine and RO 20-1724 slowed down the time course of rod photo-response to dim flashes of light. These changes were associated with a two to six-fold increase in the amplitude (...) . In the presence of 50 microM-IBMX a dim steady background of light enhanced the response to dim flashes. When the intensity of the light background was increased rods were desensitized and the supralinear behaviour disappeared. The antagonism between the effects of IBMX and the effects of background illumination on the kinetics of photoresponse suggests that phosphodiesterase activity controls the time course of light response in vertebrate rods.

1983 The Journal of physiology

6576. Chronotropic and inotropic actions of amrinone, carbazeran and isobutylmethyl xanthine: role of phosphodiesterase inhibition. Full Text available with Trip Pro

Chronotropic and inotropic actions of amrinone, carbazeran and isobutylmethyl xanthine: role of phosphodiesterase inhibition. 1. The chronotropic and inotropic effects of amrinone, carbazeran and 3-isobutyl-1-methyl xanthine (IBMX) were examined in isolated preparations of papillary muscle and right atria from rabbit heart. The effects of the drugs on cardiac phosphodiesterase and cyclic nucleotide content were also examined. 2. Amrinone (2.4 x 10(-4)M-2 x 10(-3) M), carbazeran (9.1 x 10(-6) M (...) compounds inhibited right atrial and ventricular phosphodiesterase, with amrinone being the least potent. There was, however, a marked difference between the IC50 and EC50 values for phosphodiesterase inhibition and positive inotropy. In contrast the positive chronotropic effects of amrinone and IBMX were observed in the same concentration ranges that produced phosphodiestrease inhibition. 6. The results indicate that amrinone possesses a similar rate/force selectivity to isoprenaline and IBMX

1989 British journal of pharmacology

6577. The effect of K-252a, a potent microbial inhibitor of protein kinase, on activated cyclic nucleotide phosphodiesterase. Full Text available with Trip Pro

The effect of K-252a, a potent microbial inhibitor of protein kinase, on activated cyclic nucleotide phosphodiesterase. K-252a, an indole carbazol compound of microbial origin, inhibited activation of bovine brain phosphodiesterase induced by calmodulin (CaM), sodium oleate, or limited proteolysis with almost equal potency. Kinetic analysis revealed that the CaM-activated phosphodiesterase (CaM-PDE) was competitively inhibited by K-252a with respect to CaM. On the other hand, inhibition (...) and calmidazolium. In conclusion, K-252a is an inhibitor of CaM-dependent cyclic nucleotide phosphodiesterase and it appears that it inhibits the enzyme not only via CaM antagonism but possibly also by interfering with the enzyme.

1988 Biochemical Journal

6578. The ability of denbufylline to inhibit cyclic nucleotide phosphodiesterase and its affinity for adenosine receptors and the adenosine re-uptake site. Full Text available with Trip Pro

as phosphodiesterase inhibitors whilst N6-cyclohexyladenosine, R(-)-N6-(2-phenylisopropyl)-adenosine, 5'-N-ethylcarboxamido-adenosine, 2-nitrobenzylthioinosine, theophylline and IBMX were examined for their affinity for adenosine binding sites. 2. This investigation confirmed the presence of four phosphodiesterase activities in rat cardiac ventricle; in rat cerebrum only three were present. 3. Denbufylline selective inhibited one form of Ca2+-independent, low Km cyclic AMP phosphodiesterase. The form inhibited (...) was one of two present in cardiac ventricle and the sole one in cerebrum. This form was not inhibited by cyclic GMP. The inotropic agent SK&F 94120 selectively inhibited the form of cyclic AMP phosphodiesterase which was inhibited by cyclic GMP present in cardiac ventricle. Theophylline and IBMX were relatively non-selective phosphodiesterase inhibitors. 4. Denbufylline was a less potent inhibitor of ligand binding to adenosine receptors than of cyclic AMP phosphodiesterase. This contrasted

1989 British journal of pharmacology

6579. Role of selective cyclic GMP phosphodiesterase inhibition in the myorelaxant actions of M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine. Full Text available with Trip Pro

Role of selective cyclic GMP phosphodiesterase inhibition in the myorelaxant actions of M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine. 1. The mechanism by which M&B 22,948, MY-5445, vinpocetine and 1-methyl-3-isobutyl-8-(methylamino)xanthine (MIMAX), which have been described as selective cyclic GMP phosphodiesterase (PDE) inhibitors, relax rat aorta was investigated. 2. Three cyclic nucleotide PDEs were identified in the soluble fraction of rat aorta; a Ca2 (...) +-insensitive form exhibiting substrate selectivity for cyclic GMP (cGMP PDE), a Ca2+/calmodulin-stimulated form which also preferentially hydrolyzed cyclic GMP (Ca2+ PDE), and a form demonstrating substrate selectivity for cyclic AMP (cAMP PDE). 3. M&B 22,948 and MIMAX inhibited cGMP PDE (Ki = 0.16 microM and 0.43 microM, respectively) and Ca2+ PDE (Ki = 9.9 microM and 0.55 microM, respectively), but exhibited weak activity against cAMP PDE (Ki = 249 microM and 42 microM, respectively). MY-5445 selectivity

1989 British journal of pharmacology

6580. Haemodynamic profile of an inhibitor of phosphodiesterase III, adibendan (BM 14.478): comparison with nitroprusside and dobutamine in conscious dogs. Full Text available with Trip Pro

Haemodynamic profile of an inhibitor of phosphodiesterase III, adibendan (BM 14.478): comparison with nitroprusside and dobutamine in conscious dogs. 1. This study was performed to investigate whether cardiac positive inotropic as well as peripheral vasodilator properties of adibendan contribute to its overall haemodynamic profile in conscious dogs. 2. Haemodynamic measurements were carried out in conscious chronically instrumented dogs after administration of adibendan, sodium nitroprusside

1990 British journal of pharmacology

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