Inhibition by nonsteroidal antiinflammatory drugs of luminol-dependent human-granulocyte chemiluminescence and [3H]FMLP binding. Effect of sulindac sulfide, indomethacin metabolite, and optical enantiomers (+) and (-) MK830.
A system is described to evaluate for nonsteroidal antiinflammatory drugs by means of luminol-dependent human-granulocyte chemiluminescence (CL) is described. The CL is produced using either opsonized zymosan (yeast cells) or the soluble chemotactic peptide f-Met-Leu-Phe as the perturbant of the granulocyte membrane. Using either system, the following drug effects 2 x 10(-5) M were noted: only sulindac sulfide, and not sulindac sulfone or sulindac, displayed marked inhibition of chemiluminescence, following the in vivo data regarding inflammatory effects. The 5-OH indomethacin metabolite was likewise inactive as an inhibitor of CL mirroring in vivo effects. MK(+)410, MK(-)830 and MK835 all showed approximately 50% inhibition of CL, displaying deviation from in vivo data. MK(+)830 markedly stimulated CL, 4-6 times the control (without drug), which is clearly different from its enantiomer, MK(-)830. The reasons for this behavior are unclear. However, receptor binding studies with [3H]FMLP were accomplished in the presence and absence of the various drugs at 2 x 10(-5) M that were effective inhibitors of chemiluminescence (CL). Indomethacin, MK(-)830 and MK(+)410 had equivalent percent control binding and percent control CL. Sulindac sulfide and MK(+)835 both had higher percent control binding than percent control CL, with MK(+)835 displaying apparent increased numbers of available receptors relative to control. MK(+)830, which produces large increases in CL, produced a minor effect on percent control binding. A direct relationship between binding and CL does not exist with each drug. Chemiluminescence is dependent on ion movement and oxidative metabolism and is a secondary event to agonist-receptor occupation.
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007192:Indenes / Q000494:pharmacology*; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008163:Luminescent Measurements; D008165:Luminol / Q000502:physiology*; D008715:Methionine / Q000031:analogs & derivatives*; D009239:N-Formylmethionine / Q000031:analogs & derivatives* / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009842:Oligopeptides / Q000378:metabolism*; D011724:Pyridazines / Q000502:physiology*; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology*; D014316:Tritium
D000893:Anti-Inflammatory Agents; D007192:Indenes; D009842:Oligopeptides; D011724:Pyridazines; D014316:Tritium; D013467:Sulindac; C034674:5-hydroxyindomethacin; D009239:N-Formylmethionine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D008165:Luminol; C025462:sulindac sulfide; D008715:Methionine; C025463:sulindac sulfone; D007213:Indomethacin