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)

Cilostazol, a selective type III phosphodiesterase inhibitor, is widely used for treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The activation of inflammatory cells and pro-inflammatory cytokine production play critical roles in the pathogenesis of aspirin-induced gastric irritation. The aim of the present study was to determine whether cilostazol can ameliorate aspirin-induced gastric mucosal lesions in rats, reduce neutrophil accumulation, and reduce the production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 ml/kg). Cilostazol (1-10 mg/kg, IP) was injected 30 min before aspirin administration. Also, we measured the gastric mucosal concentrations of myeloperoxidase and interleukin-1 beta, tumor necrosis factor-alpha, and cytokine-induced neutrophil chemoattractants-1, as an index of neutrophil accumulation, and the pro-inflammatory cytokines. Cilostazol ameliorated the gastric mucosal lesions induced by aspirin administration (P<0.01). The gastric contents of myeloperoxidase and pro-inflammatory cytokines were all increased after aspirin administration and significantly reduced by cilostazol treatment. In this study, we demonstrated that a selective type III phosphodiesterase inhibitor, cilostazol, reduced aspirin-induced gastric inflammation and damage via suppression of the production of proinflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions induced by aspirin.
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PMID:Attenuation of gastric mucosal inflammation induced by aspirin through inhibition of selective type III phospshodiesterase in rats. 1737 21

Dipyridamole, a well-known inhibitor of cGMP-dependent phosphodiesterase and the adenosine transporter, reportedly possesses antioxidant properties and attenuates reactive oxygen species (ROS) formation in platelet and endothelial cells. The relevance of the redox status of this compound or the mechanism for its redox-dependent effects is unknown. Oxidation of dipyridamole by horseradish peroxidase and hydrogen peroxide diminished its fluorescence and attenuated dipyridamole-mediated DPPH and ferric ferrozine reduction. Oxidation also led to elimination of dipyridamole's redox-sensitive properties, including inhibiting Cu (II)-induced LDL oxidation and ROS generation. Attenuation of activation- induced platelet release of soluble CD40 ligand (sCD40L) was diminished after dipyridamole oxidation. Dipyridamole but not oxidized dipyridamole effectively inhibited platelet adhesion to collagen-coated slides under flow conditions. By Western blot analysis, dipyridamole enhanced stimulation-induced platelet VASP phosphorylation, whereas oxidized dipyridamole caused attenuation. Using luciferase assays and nuclear translocation studies with confocal microscopy and Western blot analysis, native dipyridamole diminished TNF alpha or thrombin-induced NF kappa B activation and I kappa B alpha phosphorylation. Oxidized dipyridamole had no effect on TNFalpha-mediated NF kappa B activation. These results indicate: (1) the redox state of dipyridamole regulates its antioxidant properties; (2) dipyridamole's platelet inhibitory effects are manifested by enhanced VASP phosphorylation and platelet adhesion on collagen; and (3) dipyridamole's antioxidant effects in vascular cells are at least partially mediated via suppression of inflammatory NF kappa B signaling.
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PMID:Redox state of dipyridamole is a critical determinant for its beneficial antioxidant and antiinflammatory effects. 1804 14

A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA). Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4) inhibitors in a new animal model for the evaluation of pannus formation and cytokine production in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA) were challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution in the back of the mice. Drugs were orally administered for 10 days. The granuloma formed around the filter was collected on day 11. It was chopped into pieces and cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type of cytokines produced in the granuloma was quite similar to those produced in pannus in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production of IL-1beta, TNF-alpha, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors more strongly suppressed IL-12 production and the increase in myeloperoxidase activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-alpha and IL-12 production from thioglycolate-induced murine peritoneal macrophages and the proliferation of rat synovial fibroblasts. These results indicate this model makes it easy to evaluate the effect of drugs on various cytokine productions in a granuloma without any purification step and may be a relevant model for evaluating novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have therapeutic effects on pannus formation in RA by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.
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PMID:Administration of PDE4 inhibitors suppressed the pannus-like inflammation by inhibition of cytokine production by macrophages and synovial fibroblast proliferation. 1827 40

The effect of irsogladine maleate, a widely used antiulcer drug in Japan, on indomethacin-induced small intestinal lesions was examined in rats. Animals without fasting were given indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Irsogladine (1-10 mg/kg) or 16,16-dimethyl prostaglandin E2 (dmPGE2 0.03 mg/kg) was given p.o. twice, 0.5 before and 6 h after indomethacin, while ampicillin (800 mg/kg) was given twice, 18 and 0.5 h before. Indomethacin caused severe lesions in the small intestine, mainly the jejunum and ileum, accompanied by intestinal hypermotility, the up-regulation of inducible nitric oxide synthase (iNOS) expression, and an increase of myeloperoxidase (MPO) activity as well as enterobacterial invasion in the mucosa. These events were all prevented by both dmPGE2 and ampicillin, except the intestinal hypermotility which was only prevented by dmPGE2. Likewise, irsogladine also significantly and dose-dependently prevented these lesions at > 1 mg/kg. This agent alone increased mucus secretion and significantly suppressed the decreased mucus response to indomethacin, resulting in a suppression of the bacterial invasion as well as the increase in MPO activity and iNOS expression. The protective effect of irsogladine was mimicked by isobutylmethylxanthine, a nonselective inhibitor of phosphodiesterase (PDE), as well as rolipram, a selective PDE4 inhibitor. These results suggest that irsogladine protects the small intestine against indomethacin-induced lesions, and this effect may be associated with the increased mucus secretion, probably due to the inhibitory actions of PDE, resulting in suppression of enterobacterial invasion and iNOS expression.
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PMID:Prophylactic effect of irsogladine maleate against indomethacin-induced small intestinal lesions in rats. 1830 37

Eosinophils play a major role in the development and severity of asthma. Robust and rapid preclinical animal models are desirable to profile novel therapeutics inhibiting the influx of eosinophils into the airways. To develop a rapid, airway eosinophil recruitment model in the rat, Brown-Norway (BN) rats were immunised with ovalbumin (OVA)/alum on day 0, 1 and 2 and challenged with OVA aerosol on day 5 and 6. On day 7 bronchoalveolar lavage fluid (BALF) was analysed for eosinophil numbers, eosinophil peroxidase (EPO) activity and cytokines. Lung sections were also examined. The immunised animals showed a strong selective influx of eosinophils into the airways correlating with enhanced EPO activity, Interleukin (IL-4), IL-5 and monocytes chemo attractant protein levels in the BALF in comparison to sham-sensitised rats. In addition the immunised rats developed goblet cell metaplasia in the lung and showed OVA specific IgG1 and IgE levels in the serum but no airway hyperreactivity after metacholine challenge. Airway inflammation was suppressed by applying the steroids Budesonide (intra tracheally) and Prednisolone (per orally), Roflumilast a phosphodiesterase-4 inhibitor, and the H1 receptor antagonists Epinastine and Ketotifen. Montelukast, a Leukotriene receptor antagonist and Chromoglycate, a mast cell stabiliser, had no effect in this model. In summary, in this novel preclinical rat model therapeutics expected to inhibit the development of airway eosinophilia can rapidly be tested.
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PMID:Development and characterisation of a novel and rapid lung eosinophil influx model in the rat. 1849 Jan 84

The aim of this study was to look into a molecule in penile blood sample that shows correlation with the tumescence grade and/or penile Doppler ultrasound findings. Patients admitted to urology outpatient clinic with the complaint of erectile dysfunction between November 2006 and April 2007 were evaluated. Patients with the history of phosphodiesterase inhibitor usage or genital trauma, genital abnormalities, Peyronie's disease, endocrinopathies, cardiovascular diseases and major psychiatric or neurological disorders were excluded. Those patients were later evaluated with a penile Doppler ultrasound, 10-20 min after intracavernosal injection of 60 mg of papaverine hydrochloride. Tumescence grade, peak-systolic velocity (PSV), end-diastolic velocity (EDV) and resistive index (RI) were recorded. Blood samples were drawn from penis and the levels of calcium, myeloperoxidase, malondialdehyde, nitrite, nitrate, vasoactive intestinal peptide and cyclic guanosin monophosphate (cGMP) and the activity of superoxide dismutase were measured. A total of 46 patients with erectile dysfunction were included. The median age of the patients was 49.3+/-10.2 (range 24-67). We could not find any significant correlation between penile Doppler ultrasound parameters and any of penile blood measurements except cGMP that demonstrated a significant negative correlation with PSV (rho=-0.533, P=0.001) and RI (rho=-0.468, P=0.005). However, a positive correlation between cGMP and EDV was detected (rho=0.322, P=0.059). Mean cGMP levels were 3.347+/-0.694 pmol ml(-1) (2.295-4.685), 3.193+/-0.669 pmol ml(-1) (2.165-4.094) and 2.742+/-0.690 pmol ml(-1) (1.290-4.011) in grades 2, 3 and 4 tumescence groups, respectively, and the difference among mean cGMP levels of these groups were statistically significant (P=0.027). As a conclusion, penile blood cGMP level showed a significant negative correlation with mean PSV, RI values and tumescence grade, whereas there was a positive but insignificant correlation between cGMP and mean EDV value.
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PMID:Penile blood cyclic guanosin monophosphate level is associated with penile Doppler ultrasound findings. 1898 42

We examined the effect of sildenafil, an inhibitor of phosphodiesterase subtype 5, that catalyzes hydrolysis of 3',5'-cyclic guanosine monophosphate (cGMP), on indomethacin-induced small-intestinal ulceration in rats and investigated the mechanism of this action, especially in relation to endogenous nitric oxide (NO). Animals without fasting were given indomethacin (10 mg/kg) s.c. and then killed 24 h later. Indomethacin produced hemorrhagic lesions in the small intestine, accompanied by a promotion of enterobacterial invasion and the expression of inducible NO synthase (iNOS) as well as myeloperoxidase (MPO) activity in the mucosa. Sildenafil (3-20 mg/kg), given p.o. 30 min before indomethacin, dose-dependently reduced the severity of these lesions, with concomitant suppression of the increase in MPO activity, iNOS expression and bacterial invasion. These effects were attenuated by the prior administration of the nonselective NOS inhibitor, N (G)-nitro-L-arginine methyl ester, in an L-arginine-reversible manner. Indomethacin also decreased the secretion of mucus and fluid (enteropooling) and enhanced intestinal motility, but these responses were all prevented by the prior administration of sildenafil. Likewise, pretreatment of the animals with NOR-3, a NO donor, also reversed the functional changes caused by indomethacin, followed by suppression of bacterial invasion and iNOS expression, and prevented the development of intestinal lesions. These results suggest that sildenafil prevents indomethacin-induced small-intestinal ulceration in rats, via a NO/cGMP-dependent mechanism, and this effect is functionally associated with an increase in the secretion of mucus/fluid and a decrease of hypermotility, resulting in the suppression of bacterial invasion and iNOS expression following indomethacin treatment.
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PMID:Sildenafil, an inhibitor of phosphodiesterase subtype 5, prevents indomethacin-induced small-intestinal ulceration in rats via a NO/cGMP-dependent mechanism. 1910

Neutrophils are activated following hemorrhagic shock and the accumulation of neutrophils in the lung is associated with lung injury. This research investigated the effects of a semisynthetic 2-benzoylaminobenzoic acid derivative, methyl 2-(2-fluorobenzamido)benzoate (DSM-RX78), on superoxide anion (O(2)(-)) production in formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP)-activated human neutrophils, and on lung injury in Sprague-Dawley rats subjected to trauma-hemorrhage. DSM-RX78 concentration-dependently inhibited O(2)(-) production, but not elastase release, in FMLP-activated human neutrophils. DSM-RX78 displayed no superoxide-scavenging ability, and it failed to alter the subcellular NADPH oxidase activity. Significantly, DSM-RX78 increased cAMP formation and protein kinase (PK)A activity in FMLP-activated neutrophils, which occurred through the selective inhibition of cAMP-specific phosphodiesterase (PDE) activity but not an increase in adenylate cyclase function or cGMP-specific PDE activity. These results show that DSM-RX78 is a new inhibitor of cAMP-specific PDE. Moreover, DSM-RX78 reduced FMLP-induced phosphorylation of protein kinase B (Akt), but not calcium mobilization. The inhibitory effects of DSM-RX78 on O(2)(-) production and Akt phosphorylation were reversed by PKA inhibitors, suggesting that DSM-RX78 regulates O(2)(-) production of human neutrophils by promoting cAMP/PKA-dependent inhibition of Akt activation. On the other hand, administration of DSM-RX78 significantly attenuated the increase in myeloperoxidase activity and edema in the lung, as well as protein concentrations in bronchoalveolar lavage fluid in rats after trauma-hemorrhagic shock. In summary, these results strongly suggest that DSM-RX78 exerts anti-inflammatory effects, which result from the elevation of cAMP levels and PKA activity through its inhibition of cAMP-specific PDE. Also, our findings show that DSM-RX78 attenuates hemorrhagic shock-induced lung injury in rats.
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PMID:DSM-RX78, a new phosphodiesterase inhibitor, suppresses superoxide anion production in activated human neutrophils and attenuates hemorrhagic shock-induced lung injury in rats. 1954 Feb 9

Multiple mucosal immune factors, such as TNF-alpha and IL-1beta, are thought to be key mediators involved in inflammatory bowel disease. We evaluated the role of the pro-inflammatory cytokine TNF-alpha on nitric oxide synthase (NOS) expression in indomethacin-induced jejunoileitis in rats. Jejunoileitis was induced in rats with subcutaneous injections of indomethacin (7.5 mg/kg) 24 h apart for two consecutive days, and animals were randomized into four groups. Group 1 received only indomethacin. Group 2 was treated with a daily dose of phosphodiesterase (PDE) inhibitor (theophylline or pentoxifylline) by oral gavage for 2 days before and 4 days after indomethacin. Group 3 received a single dose of anti-TNF-alpha monoclonal antibody (TNF-Ab, IP) 30 min before indomethacin. Group 4 was treated with 1 h hyperbaric oxygenation (HBO(2)) for 5 days after indomethacin. Rats were sacrificed at 12 h or 4 days after final indomethacin injection. PDE inhibitor, TNF-Ab, or HBO(2) treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-alpha and nitrate/nitrite (NOx) concentrations above control values at 12 h, inducible NOS (iNOS) expression was detected only at day 4. Serum IL-1beta levels did not change at 12 h but increased 4-fold after 4 days. Indomethacin had no effect on constitutive NOS. Treatment with PDE inhibitor, TNF-Ab, or HBO(2) significantly reduced serum/tissue TNF-alpha, IL-1beta, NOx, and iNOS expression. Our data show TNF-alpha plays an early pro-inflammatory role in indomethacin-induced jejunoileitis. Additionally, down-regulation of NOx by PDE inhibitors, TNF-Ab, or HBO(2) suggests that TNF-alpha modulates iNOS expression.
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PMID:TNF-alpha modulates iNOS expression in an experimental rat model of indomethacin-induced jejunoileitis. 1980 25

Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis. Lung fibrosis was induced by intratracheal administration of 0.1 ml of bleomycin hydrochloride (5 mg/kg in 0.9% NaCl) under anesthesia to Sprague-Dawley rats (200-250 g; n = 7-8 per group). Control rats received an equal volume of saline intratracheally. In the treatment groups, the rats were treated with either sildenafil citrate (10 mg/kg per day; subcutaneously) or saline for 14 days. Another group of rats were administered subcutaneously with N(G)-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg in 0.9% NaCl) 5 min after sildenafil injections. After decapitation, the lungs were excised and taken for microscopic evaluation or stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity, and for the assessment of apoptosis. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. In the group with lung fibrosis, the lung tissue was characterized by microscopic lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and apoptosis. Serum TNF-alpha and IL-1beta levels were higher in the lung fibrosis group compared to control values. Sildenafil reversed tissue MDA levels, MPO activity and serum pro-inflammatory cytokine levels, and preserved GSH content although its effect on the extent of tissue lesion and apoptosis was not statistically significant. Treatment with l-NAME reversed the effect of sildenafil on GSH content. In conclusion, sildenafil citrate administration to rats with bleomycin-induced lung fibrosis seems to be beneficial via prevention of lipid peroxidation, cytokine production and/or release and neutrophil accumulation.
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PMID:Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis. 1994 40


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