Differential inhibition of neutrophil superoxide generation by nonsteroidal antiinflammatory drugs.
In order to further characterize the effects of nonsteroidal antiinflammatory drugs on neutrophil superoxide (O2-) generation, human neutrophils were incubated in the presence of sulfinpyrazone, phenylbutazone, and indomethacin prior to exposure to a variety of oxidative stimuli. Stimuli used included the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP, 5.0 X 10(-7) M), NaF (20 mM), phorbol myristate acetate (PMA, 3.2 X 10(-7) M), and opsonized zymosan (250 micrograms/ml). Superoxide release induced by FMLP was inhibited by all three drugs with half-maximal inhibition (KI50) at 2.5, 30, and 120 microM for sulfinpyrazone, phenylbutazone, and indomethacin, respectively. This inhibition was not due to drug interference with the assay system since comparable inhibition was not observed in a cell-free O2- -generating system. The neutrophil's response to NaF was blunted by sulfinpyrazone (KI50 = 400 microM) and phenylbutazone (KI50 = 65 microM), but was unaffected by indomethacin. A similar inhibitory pattern was observed when zymosan was used as the oxidative stimulus. Sulfinpyrazone and phenylbutazone inhibited the response to zymosan (KI50s of 425 and 32 microM, respectively), whereas indomethacin augmented it. PMA stimulation evoked O2- production which was inhibited by phenylbutazone (KI50 = 350 microM) but not by sulfinpyrazone or indomethacin in concentrations up to 1 mM. The results support the hypothesis that the enzyme system responsible for neutrophil O2- generation can be activated by more than one mechanism. The results also emphasize the need to evaluate pharmacologic modulation of neutrophil responses in light of the stimulus used to evoke the response.
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010653:Phenylbutazone / Q000494:pharmacology; D013442:Sulfinpyrazone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D013481:Superoxides; D015054:Zymosan; D010653:Phenylbutazone; D013755:Tetradecanoylphorbol Acetate; D013442:Sulfinpyrazone; D007213:Indomethacin