INHIBITION OF RECEPTOR-MEDIATED PLATELET ACTIVATION BY NEDOCROMIL SODIUM

Background: Platelet activation by platelet activating factor (PAF) seems to be involved in the inflammatory process in asthma and may serve as a possible target for the antiinflammatory drug nedocromil sodium, which is known to inhibit cell activation by different stimuli. Methods: We investigated the effect and the mode of action of nedocromil sodium on platelet activation by PAF. In a set of healthy volunteers (n = 45) we investigated seven different parameters of platelet activation by PAF, thrombin, and Ca2+-ionophore. Results: Nedocromil sodium inhibited. (1) PAF-induced ''shape change'' reaction up to 78% (50% inhibitory concentration [IC50]: 3 x 10(-9) mol/L), thrombin-mediated ''shape change'' up to 80% (IC50: 2 x 10(-8) mol/L), but not the Ca2+-ionophore-dependent reaction, (2) platelet aggregation by PAF up to 85% (IC50: 2 x 10(-9) mol/L); (3) release of thromboxane B2 up to 82% (IC50: 5 x 10(-9) mol/L); (4) formation of inositol 1,4,5-triphosphate by PAF (IC50: 3 X 10(-7) mol/L), by thrombin (IC50: 1 X 10(-7) mol/L), but not by Ca2+ ionophore; (5) increase of intracellular free calcium (IC50: 4 x 10(-7) mol/L); (6) formation of diacylglycerol (IC50: 9 x 10(-9) mol/L), and (7) translocation of protein kinase C (IC50: 1 X 10(-7) mol/L). Conclusions: In the concentration range of the IC50 values found in these experiments, nedocromil sodium reduced PAF binding to platelets by only 10% to 20%, such that this interference cannot explain the observed effects of the compound. Inhibition of receptor-mediated platelet activation at an early stage in the signal transduction pathway, and without effect on Ca2+-ionophore-induced platelet activation, suggests an action of nedocromil sodium at the level of the cell membrane.