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Alveolar macrophages (AM) may contribute to airway inflammation via release of superoxide anion (O^–₂). Elevation of intracellular cyclic adenosine monophosphate (cAMP) levels has been shown to suppress O^–₂ generation, although the exact mechanism is uncertain. To examine the inhibitory effect of cAMP against different stimuli for O^–₂ generation, we compared the effect of cAMP on O^–₂ generation caused by phorbol myristate acetate (PMA), a direct protein kinase C activator, and N-formyl-methionyl-leucyl-phenylalanine (FMLP), which couples its membrane receptor and stimulates guanosine triphosphate binding protein, in guinea pig AM. Cyclic nucleotide phosphodiesterase (PDE) isoenzyme inhibitors or CPT-cAMP, a cAMP analogue, were used in order to increase intracellular cAMP levels. The O^–₂ generation caused by either PMA or FMLP was reduced by cilostazol (PDE 3 inhibitor) and Ro20-1724 (PDE 4 inhibitor), but not by zaprinast (PDE 5 inhibitor). The degree of reduction in O^–₂ generation was not different between PMA and FMLP. Furthermore, CPT-cAMP also reduced PMA- or FMLP-induced O^–₂ generation to a similar degree, although only high concentrations (10^–5 or 10^–4 mol/l) of this agent were effective in producing significant inhibition. A remarkable elevation of the cAMP level is required to produce the inhibitory effect on O^–₂ generation in guinea pig AM. An elevation of cAMP may suppress O^–₂ generation by inhibiting plural sites of the intracellular signaling pathways.