Exp Mol Med.  2001 Dec;33(4):226-233.

Molecular mechanisms involved in human platelet aggregation by synergistic interaction of platelet-activating factor and 5-hydroxytryptamine.

• Shah BH
• Rasheed H
• Rahman IH
• Shariff AH
• Khan FL
• Rahman HB
• Hanif S
• Saeed SA

Abstract

Our recent studies have shown that co-activation of Gq and Gi proteins by 5-hydroxytryptamine (5-HT) and adrenaline show synergism in human platelet aggregation. This study was conducted to examine the mechanism(s) of synergistic interaction of 5-HT and platelet activating factor (PAF) in human platelets. We show that PAF, but not 5-HT, increased platelet aggregation in a concentration-dependent manner. However, low concentrations of 5-HT (2 microM) potentiated platelet aggregation induced by subthreshold concentration of PAF (40 nM) indicating a synergistic interaction between the two agonists and this synergism was blocked by receptor antagonists to either 5-HT or PAF. 5-HT also potentiated the effect of PAF on thromboxane A2 (TXA2) formation and phosphorylation of extracellularly regulated mitogen-activated protein kinases (ERK1/2). The synergism of 5-HT and PAF in platelet aggregation was inhibited by calcium (Ca2+) channel blockers, verapamil and diltiazem, phospholipase C (PLC) inhibitor, U73122, cyclooxygenase (COX) inhibitor, indomethacin, and MEK inhibitor, PD98059. These data suggest that synergistic effect of 5-HT and PAF on human platelet aggregation involves activation of PLC/Ca2+, COX and MAP kinase pathways.

Keyword

platelet aggregation; PAF; 5-HT; MAP kinase; synergism

MeSH Terms

Diltiazem/pharmacology
Dose-Response Relationship, Drug
Drug Synergism
Estrenes/pharmacology
Flavones/pharmacology
Human
In Vitro
Indomethacin/pharmacology
Kinetics
Mitogen-Activated Protein Kinases/metabolism
Phosphorylation/drug effects
Platelet Activating Factor/*pharmacology
Platelet Activation/drug effects
Platelet Aggregation/*drug effects/physiology
Pyrrolidinones/pharmacology
Serotonin/*pharmacology
Thromboxane A2/biosynthesis
Verapamil/pharmacology