Inhibition of receptor-mediated platelet activation by nedocromil sodium

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.

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 Ca(2+)-ionophore.

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 Ca(2+)-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).

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 Ca(2+)-ionophore-induced platelet activation, suggests an action of nedocromil sodium at the level of the cell membrane.