Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst

Modulation of the human polymorphonuclear leukocyte (PMN) respiratory burst by selective cyclic 3′, 5′ adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitors was studied with respect to PDE isozyme characteristics. Zaprinast, an inhibitor of a cyclic guanosine monophosphate (cGMP)-specific PDE (PDE I), at concentrations up to 100 μmol/L, had no significant effect on the respiratory burst. Milrinone and imazodan, inhibitors of cAMP-metabolizing, cGMP-sensitive PDE (PDE III), reduced the respiratory burst to 60% of control magnitude but only had significant effects when they were introduced at high (100 μmol/L) concentrations. In contrast, rolipram and RO 20-1724, inhibitors of a cAMP-metabolizing, cGMP-insensitive PDE (PDE IV), had significant effects at low concentrations (0.1 μmol/L) and caused marked reduction of the respiratory burst at higher concentrations (25% of control at 10 μmol/L). The selective PDE IV inhibitors significantly potentiated PMN inhibition by isoproterenol. Diethylaminoethyl (DEAE)-Sepharose chromatography demonstrated a predominant PDE isozyme with high affinity and selectivity for cAMP that was insensitive to cGMP and was completely inhibited by rolipram, a PDE IV inhibitor. These results are consistent with the conclusion that the PMN respiratory burst is inhibited by an elevation of cAMP induced by PDE IV inhibition.