Specific Inhibition by BN 52021 and Structurally Related Compounds of the PAF-Acether-lnduced Increase in Cytosolic Free Calcium
When washed rabbit platelets loaded with the fluorescent probe Quin 2 were stimulated with 2 × 10-9 M PAF-acether, the intracytoplasmic free calcium [Ca2-]i increases to a concentration of about 10–12 times the basal level as shown by the fluorescence change of the preparation. This [Ca2+]i increase seems to initiate, at least partially, platelet aggregation and secretion. Indeed, pretreatment of loaded platelets with the platelet-activating factor receptor antagonist BN 52021 inhibited the PAF-acether-induced [Ca2+]i signal; the inhibition was dose related, and the signal was totally abolished with 3 × 10-6 M of BN 52021. The activity of BN 52021, as observed on platelet aggregation, is specific for PAF-acether stimulation, since it did not antagonize thrombin or A 23187 calcium-induced mobilization. The structurally related compounds BN 52020 and BN 52022 had the same profile of activity but were less potent than 52021; this is correlated with the results obtained on PAF-acether-induced aggregation—IC50(2.5 × 10-10M PAF-acether) 1.4 × 10-7M, 9.0 × l0-7 M, and l.6 × 10-6 M for BN 52021, BN 52020, and BN 52022, respectively. Our results show that BN 52021 is a useful tool to study the stimulus-activity coupling processes underlying PAF-acether action. As it has been postulated that focal release of PAF-acether may exacerbate the development of atherosclerosis, BN 52021 or related compounds could be of interest in this pathology.
KeywordsHuman Platelet Free Calcium Cytosolic Free Calcium Rabbit Platelet Cytoplasmic Free Calcium
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