title: Synergistic interaction of adrenaline and histamine in human platelet aggregation is mediated through activation of phospholipase, map kinase and cyclo-oxygenase pathways.
abstract: This study was conducted to examine the mechanism(s) of synergistic interaction of histamine- and adrenaline-mediated human platelet aggregation. We found that platelet aggregation mediated by subthreshold concentrations of histamine (1-4 microm) plus adrenaline (0.5-2 microm) is inhibited by both an alpha(2)-adrenoceptor blocker (yohimbine) and a histamine (H1) receptor antagonist (diphenhydramine). In examining the role of the downstream signalling pathway, we found that such an interaction is inhibited by the calcium channel blockers verapamil and diltiazem. However, platelet aggregation by adrenaline plus histamine was inhibited by very low concentrations of the phospholipase C (PLC) inhibitor, U73122 (IC(50)= 1.2 microm), the MEK inhibitor, PD98059 (IC(50)= 1.1 microm) and the cyclo-oxygenase (COX) inhibitor, indomethacin (IC(50)= 7 microm). However the inhibition of receptor tyrosine kinase, protein kinase C and phosphatidylinositol 3-kinase by genistien, chelerythrine and wortmannin, respectively, had no significant effect on aggregation. Similarly the nitric oxide donor (SNAP) had no effect on this synergism. These data suggest that the synergistic effect of histamine and adrenaline during human platelet aggregation is receptor mediated and involves activation of PLC, COX and MAP kinase signalling pathways.
authors.affiliation: Department of Physiology and Pharmacology, The Aga Khan University, Karachi-74800, P.O. Box 3500, Pakistan.
authors.forename: B H
authors.initials: BH
authors.lastname: Shah
authors.forename: I
authors.initials: I
authors.lastname: Lashari
authors.forename: S
authors.initials: S
authors.lastname: Rana
authors.forename: O
authors.initials: O
authors.lastname: Saeed
authors.forename: H
authors.initials: H
authors.lastname: Rasheed
authors.forename: S
authors.initials: S
authors.lastname: Arshad Saeed
mesh_terms: D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010740:Phospholipases / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D004963:Estrenes; D010975:Platelet Aggregation Inhibitors; D011760:Pyrrolidinones; D014665:Vasodilator Agents; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D006632:Histamine; D014700:Verapamil; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D010740:Phospholipases; D004837:Epinephrine