The specific type III and IV phosphodiesterase inhibitor zardaverine suppresses formation of tumor necrosis factor by macrophages.
Murine resident peritoneal macrophages were stimulated with lipopolysaccharide and treated with phosphodiesterase (PDE) inhibitors zardaverine, rolipram and motapizone. The PDE inhibitors suppressed the formation of tumor necrosis factor (TNF) by macrophages. The mono-selective PDE IV inhibitor rolipram and the dual-selective PDE III/IV inhibitor zardaverine had equal inhibitory potency, whereas the PDE III inhibitor motapizone was of lower inhibitory potency. All PDE inhibitors acted in synergy with the adenylate cyclase activators prostaglandin E2 and CG 4203, a prostacyclin analog, and super-additive effects of combinations were observed. The PDE inhibitors also blocked the formation of leukotriene C4 (LTC4); however, substantially higher doses were needed than for blockade of TNF synthesis. Furthermore, no additive or synergistic effects were observed upon combined treatment with adenylate cyclase activators. It is suggested that the suppression of TNF formation by PDE inhibitors is mediated mainly by a PDE isoenzyme of type IV. The effect of PDE inhibitors on LTC4 synthesis appears to be mediated by a different mechanism.
Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, Germany.
F U
FU
Schade
C
C
Schudt
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D013189:SRS-A / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D002317:Cardiovascular Agents; D007527:Isoenzymes; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; D013189:SRS-A; D014409:Tumor Necrosis Factor-alpha; C039188:taprostene; C051270:motapizone; D011464:Epoprostenol; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C066436:zardaverine