PDE isoenzymes as targets for anti-asthma drugs.
Phophodiesterase (PDE) isoenzyme profiles of human cell preparations and tissues have been analysed by a semiquantitative method using selective PDE inhibitors and activators. Neutrophils, eosinophils and monocytes contain PDE IV exclusively. Lymphocytes, alveolar macrophages and endothelial cells contain PDE IV and PDE III, and in addition, PDE I is measured in macrophages and PDE II in endothelial cells. These basal cell-specific PDE isoenzyme profiles appear to be modified by: 1) substrate concentration; 2) kinase-dependent phosphorylation; and 3) regulated rate of synthesis. Therefore, PDE isoenzyme profiles represent dynamic patterns, which apparently adapt to pathological and environmental conditions. In parallel functional studies, the influence of mono-selective (rolipram, PDE IV; motapizone, PDE III), dual-selective (zardaverine) and non-selective (theophylline) PDE inhibitors were compared. Corresponding to isoenzyme analysis, it was demonstrated that both PDE III and PDE IV have to be inhibited for complete suppression of either tumour necrosis factor-alpha (TNF-alpha) release from macrophages, or lymphocyte proliferation (PDE III/IV cells). In eosinophils (PDE IV cells) platelet-activating factor (PAF)-induced chemotaxis or C5a-stimulated degranulation are only weakly inhibited by rolipram alone. After addition of a beta 2-agonist, however, the efficacy of rolipram is enhanced due to concomitant influence of synthesis and breakdown of cyclic adenosine monophosphate (cAMP). Theophylline inhibits PDE isoenzyme activities and functions of inflammatory cells with similar potency, and exhibits higher functional efficacy as compared to rolipram.
Schudt
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Dept of Biochemistry, Byk Gulden, Konstanz, Germany.
Tenor
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Hatzelmann
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A
D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases; D013806:Theophylline / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018927:Anti-Asthmatic Agents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013806:Theophylline; D010727:Phosphoric Diester Hydrolases