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)

In a guinea pig model of allergic asthma, we investigated the effects of the selective phosphodiesterase inhibitors rolipram (phosphodiesterase 4-selective), Org 9935 (phosphodiesterase 3-selective) and Org 20241 (dual phosphodiesterase 4/phosphodiesterase 3-selective), administered by aerosol inhalation in approximately equipotent bronchodilatory doses, on allergen-induced early and late asthmatic reactions, airway hyperreactivity and airway inflammation. Using ovalbumin-sensitized non-challenged animals, different nebulizer concentrations of each inhibitor were tested for their protective effects against histamine-induced bronchoconstriction. Inhalation of 2.5 mM rolipram, 100 mM 4,5-dihydro-6-(5,6-dimethoxybenzo[b]thien-2-yl-5-methyl-3(2H)pyridazinone (Org 9935) and 10 and 100 mM N-hydroxy-4-(3,4-dimethoxyphenyl)-thiazole-2-carboximidamide HCl (Org 20241) provided a similar, 1.8-fold (P<0.01), 2.0-fold (P<0.05), and 1.8- and 1.9-fold (P<0.05) protection, respectively. The duration of these bronchoprotective effects were different, the rate of decline being faster with rolipram and the lower Org 20241 concentration than with Org 9935 and the higher concentration of Org 20241. All compounds strongly protected against the immediate allergen-induced bronchoconstriction and significantly (P<0.05) diminished the overall early asthmatic reaction from 0 to 6 h following allergen-provocation. The severity of the late asthmatic reaction was also significantly inhibited by rolipram (P<0.05) and Org 9935 (P<0.05). Allergen-induced airway hyperreactivity to inhaled histamine after the early reaction, at 6 h after ovalbumin challenge, was strongly reduced by rolipram (P<0.05) and completely prevented by the two other phosphodiesterase inhibitors; in addition, airway hyperreactivity after the late asthmatic reaction, at 24 h, was abolished in all treatment groups. Bronchoalveolar lavage performed at 24 h after allergen challenge revealed no inhibition of eosinophil infiltration in the rolipram-treated animals, whereas inhalation of Org 9935 and the higher-but not the lower-concentration of Org 20241 strongly reduced the influx of these cells. Eosinophil peroxidase activity in the lavage fluid tended to be diminished in all treatment groups but significance was not reached with the exception of the lower concentration of Org 20241. Infiltration of lymphocytes and macrophages was significantly inhibited by Org 9935 only (P<0.05 and P<0.01, respectively), whereas neutrophil influx was not significantly affected. The results indicate that inhalation of phosphodiesterase 3-, phosphodiesterase 4- and dual phosphodiesterase 3/phosphodiesterase 4-selective inhibitors afford protection against acute histamine- and allergen-induced bronchoconstriction and prevent the development of airway hyperreactivity both after the early and late asthmatic reaction predominantly through inhibition of phosphodiesterase 4; in contrast, for significant reduction of eosinophil infiltration, both phosphodiesterase 3 and phosphodiesterase 4 inhibition seems to be required.
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PMID:Bronchodilatory and anti-inflammatory properties of inhaled selective phosphodiesterase inhibitors in a guinea pig model of allergic asthma. 1169 54

Inhibitors of phosphodiesterase 4 (PDE4) possess bronchospasmolytic and anti-inflammatory properties, which make them very attractive drugs for the treatment of asthma and COPD. Unfortunately, many PDE4 inhibitors also produce central nervous and gastrointestinal side effects, which have limited their clinical application. PDE4 has two binding sites for the archetypal PDE4 inhibitor rolipram, and it has been suggested that binding to the high-affinity rolipram binding site (HARBS) is responsible for the side effects of PDE4 inhibitors. Recently, we have synthesised the PDE4 inhibitor CC3 which shows low affinity to the HARBS. In the present study we investigated the bronchospasmolytic and anti-inflammatory properties of this novel compound in comparison to rolipram and the PDE3 inhibitor motapizone. The airway-relaxant properties of the PDE inhibitors were analysed in rat precision-cut lung slices (PCLS) in which airways were contracted by methacholine or in passively sensitised PCLS exposed to ovalbumin. The anti-inflammatory properties were investigated by measuring the release of TNF from endotoxin-treated human monocytes.Up to concentrations of 10 microM none of the PDE inhibitors significantly affected bronchoconstriction elicited by 10 microM methacholine. However, if rolipram or CC3 were given in combination with motapizone, methacholine-induced bronchoconstriction was concentration-dependently attenuated. Allergen-induced bronchoconstriction in passively sensitised PCLS was attenuated by CC3 (IC(50) 2.7 microM), rolipram (0.23 microM) and motapizone (8 microM). Combination of equimolar concentrations of motapizone and CC3 (0.34 microM) or rolipram (0.005 microM) showed an additive effect. Endotoxin-induced TNF release from human monocytes was attenuated by all three PDE inhibitors, i.e. CC3 (IC(50) 4.6 microM), rolipram (0.18 microM) and motapizone (5.8 microM). Our findings suggest that PDE4 inhibitors with only low affinity for the HABRS have bronchospasmolytic and anti-inflammatory properties.
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PMID:Airway relaxant and anti-inflammatory properties of a PDE4 inhibitor with low affinity for the high-affinity rolipram binding site. 1191 52

Precision-cut lung slices (PCLS) allow comparison of the airway responses of different species under identical experimental conditions. The aim of this study was to establish and characterise PCLS from guinea pigs (GPs) and to compare them with human PCLS. GP PCLS were prepared according to previously published procedures with the exception that the agarose solution and the initial incubation medium contained isoproterenol to avoid post mortem airway contraction. The median effective concentrations (EC50, expressed as nM) for agonist-induced bronchoconstriction in GP and human PCLS, respectively, were: leukotriene D4 (1.8, 5.0); thromboxane (16, 1.3); serotonin (69, unresponsive); histamine (217, 2,170); and methacholine (231, 234). Allergen-induced bronchoconstriction of passively sensitised PCLS was attenuated by histamine or thromboxane-prostanoid receptor antagonists and was almost completely prevented by their combination with leukotriene receptor antagonists. Airways pre-contracted with methacholine were relaxed by the beta-agonist salbutamol or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Simultaneous studies of airways and vessels are possible with, for example, EC50 values for endothelin-1 of 37 nM (pulmonary arteries), 10 nM (pulmonary veins) and 9.6 nM (airway). When compared with previous findings in rat and mouse, these data show that guinea pig lungs are a more appropriate model for human airway pharmacology than lungs from rats or mice.
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PMID:Characterisation of guinea pig precision-cut lung slices: comparison with human tissues. 1673 91