Zardaverine as a selective inhibitor of phosphodiesterase isozymes.
The pyridazinone derivative zardaverine has recently been introduced as a potent bronchodilator in vivo and in vitro. In addition, zardaverine exerts a positive inotropic action on heart muscle in vitro. The actions of zardaverine are thought to be mediated via inhibition of phosphodiesterase (PDE) activity. Recent data suggest that there are multiple forms of phosphodiesterases and at least five different isozyme families are now recognized. In the present study, the effects of zardaverine on the different PDE isozymes were investigated in several tissues. PDE isozymes were separated by chromatography on Q-sepharose. Zardaverine inhibited the cyclic GMP-inhibitable PDE III from human platelets and the rolipram-inhibitable PDE IV from canine trachea and human polymorphonuclear (PMN) cells with IC50-values of 0.58, 0.79 and 0.17 microM, respectively. The pyridazinone derivative affected the calmodulin-stimulated PDE I, the cyclic GMP-stimulated PDE II and the cyclic GMP-specific PDE V only marginally at concentrations up to 100 microM. Zardaverine inhibits the ADP-induced aggregation of human platelets with an IC50 of 1.6 microM. This inhibition was synergistically increased by activators of adenylate cyclase such as PGE1 and forskolin. In human PMN cells, zardaverine inhibited the zymosan-induced superoxide anion generation with an IC50 of 0.40 microM. Again, this effect was increased by activators of adenylate cyclase. These data clearly demonstrate that zardaverine is a selective inhibitor of PDE III and PDE IV isozymes.
Schudt
C
C
Byk Gulden Pharmaceuticals, Dept, Biochemistry, Konstanz, Germany.
Winder
S
S
Müller
B
B
Ukena
D
D
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D004285:Dogs; D006801:Humans; D007527:Isoenzymes / Q000302:isolation & purification; D007700:Kinetics; D009206:Myocardium / Q000201:enzymology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000302:isolation & purification; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D014132:Trachea / Q000187:drug effects / Q000201:enzymology
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D010727:Phosphoric Diester Hydrolases; C066436:zardaverine