Title

Calcium-dependent synergistic interaction of platelet activating factor and epinephrine in human platelet aggregation

Document Type

Article

Department

Biological and Biomedical Sciences

Abstract

AIM: To investigate the mechanism (s) involved in the synergistic interaction of platelet activating factor (PAF) and epinephrine.Methods: Blood was obtained from healthy human subjects reported to be free of medications for at least two weeks before sampling. Aggregation was monitored at 37 oC using Dual-channel Lumi-aggregometer. The resulting aggregation was recorded for 5 min by the measurement of light transmission as a function of time.Results: Platelet aggregation mediated by subthreshold concentrations of PAF (5-8 nmol/L) plus epinephrine (0.5-2 micromol/L) was inhibited by ?2-receptor blocker, yohimbine, and PAF receptor antagonist WEB 2086. This synergism was inhibited by calcium channel blockers, verapamil and diltiazem. In addition, platelet aggregation by co-addition of PAF and epinephrine was also inhibited by very low concentrations of phospholipase C (PLC) inhibitor (U73122; IC50=0.2 micromol/L), the MAP kinase inhibitor, PD 98059 (IC50=3 micromol/L), and cyclooxygenase (COX-1) inhibitors including indomethacin (IC50=0.25 micromol/L), flurbiprofen (IC50=0.7 micromol/L), and piroxicam (IC50=7 micromol/L). However, COX-2 inhibitors, nimesulide (IC50=26 micromol/L), NS-398 (IC50=7 micromol/L), and etodolac (IC50=15 micromol/L) were also effective in inhibiting the aggregation. The inhibitors of protein kinase C (chelerythrine) and tyrosine kinase (genistien), and phosphatidylinositol 3-kinase inhibitor (wortmannin) had no significant effect on platelet aggregation induced by PAF and epinephrine.CONCLUSION: The synergistic effect of PAF and epinephrine on human platelet aggregation is receptor-mediated and involves the activation of PLC/Ca2+, COX and MAP kinase signalling pathways.

Publication

Acta Pharmacologica Sinica

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