Zardaverine: a cyclic AMP specific PDE III/IV inhibitor.
Zardaverine is shown to inhibit selectively two out of five isoenzyme classes of phosphodiesterases, namely PDE III from human platelets and PDE IV from human polymorphonuclear leucocytes (PMN) with IC50 values of 0.58 and 0.17 microM, respectively. Motapizone or rolipram, for comparison, are more selective recognizing either PDE III or PDE IV. On the cellular level, agonist induced aggregation of platelets or activated secretions of PMN and several proinflammatory cells are synergistically inhibited by zardaverine and adenylate cyclase activators such as prostaglandins or forskolin. Application of zardaverine and selective drugs show that the effects of PDE inhibitors in platelets are mediated by a PDE III isoenzyme, whereas by a PDE IV isoenzyme in neutrophils, eosinophils, basophils and mast cells. An antiinflammatory potential in vivo of zardaverine is demonstrated by the inhibition of bronchial cell infiltration following inhalative allergen challenge in sensitized guinea pigs. Zardaverine and dexamethasone prevent bronchial eosinophilia and neutrophilia with similar dosage of 30 microM/kg orally, suggesting that this PDE III/IV inhibitor may be useful for both, bronchorelaxation and reduction of inflammation in asthma therapy.
Schudt
C
C
Department of Biochemistry, Byk Gulden Pharmaceuticals, Konstanz, Federal Republic of Germany.
Winder
S
S
Eltze
M
M
Kilian
U
U
Beume
R
R
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000485:Allergens / Q000276:immunology; D000818:Animals; D001982:Bronchial Diseases / Q000517:prevention & control; D004802:Eosinophilia / Q000517:prevention & control; D006801:Humans; D007114:Immunization; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology*
D000485:Allergens; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C066436:zardaverine