Superoxide generation by guinea-pig peritoneal macrophages is inhibited by rolipram, staurosporine and mepacrine in an agonist-dependent manner.

Platelet-activated factor (PAF) (EC50 -7.9 +/- 0.6 M), formyl-methionyl-leucyl-phenylalanine (fMPL) (EC50 -7.7 +/- 0.1M), phorbol 12-myristate 13 acetate (PMA) (EC50 -8.4 +/- 0.3 M), opsonized zymosan (OPZ) (0.01-1 mg/ml) were potent stimuli to superoxide generated by guinea-pig peritoneal macrophages. Superoxide generation by low (< or = -8M) concentrations but not high (> or = -7M) concentrations of PAF or fMLP were attenuated by rolipram (100 microM) in the presence of 1 microM prostaglandin E2 (PGE2). That stimulated by PMA or OPZ, however, was unaffected. At 1 microM, staurosporine was a potent inhibitor of superoxide generation stimulated by both fMLP and PAF but was without effect on that stimulated by OPZ. Superoxide generation stimulated by fMLP, PAF and OPZ was inhibited by 100 microM mepacrine. We conclude that superoxide generation stimulated by the chemoattractants fMLP and PAF involves a cyclic AMP regulated and cyclic AMP independent process. The cyclic AMP independent process is mediated by protein kinase C. Although protein kinase C seems a central element in the respiratory burst stimulated by fMLP, PAF and PMA that stimulated by OPZ bypasses this mechanism. Phospholipase A2 however, represents a common stage in the signal transduction pathway.