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Br J Pharmacol ; 138(3): 435-44, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12569068

ABSTRACT

1 The lysophospholipids, lysophosphatidic acid and sphingosine 1-phosphate, have been reported to activate platelets. Here we examined effects of the naturally occurring related sphingosylphosphorylcholine (SPC) on human platelet function. 2 Platelet activation was determined as aggregation, elevation of intracellular Ca(2+) concentrations, surface expression of P-selectin, GP 53, and GP IIb/IIIa neoepitope PAC-1, and of fibrinogen binding to the platelet surface. 3 Platelets were activated by ADP (5 and 20 micro M), the thrombin receptor-activating peptide TRAP-6 (5 and 20 micro M), the thromboxane A(2) mimetic U-46619 (1 micro M) and collagen (20 and 50 micro g ml(-1)) but not by SPC (up to 20 micro M). 4 SPC concentration-dependently (IC(50) approximately 1-10 micro M) inhibited activation of washed human platelets in response to all of the above agonists, with almost complete inhibition occurring at 20 micro M SPC. 5 The SPC stereoisomers, D-erythro SPC and L-threo SPC, exhibited similar concentration-response curves in inhibiting 20 micro M ADP-induced platelet aggregation, suggesting that SPC did not act via specific lysophospholipid receptors. 6 Although SPC slightly activated platelet protein kinase A (as assessed by VASP phosphorylation), this effect could not explain the marked platelet inhibition. Possible protein kinase C inhibition also did not explain the inhibition of platelet activation by SPC. On the other hand, SPC suppressed agonist-induced Ca(2+) mobilization and phospholipase C stimulation. 7 These results indicate that the lysophospholipid SPC is an effective inhibitor of human platelet activation, apparently primarily by uncoupling agonist-activated receptors from their effectors.


Subject(s)
Blood Platelets/drug effects , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Sphingosine/analogs & derivatives , Sphingosine/pharmacology , Blood Platelets/metabolism , Calcium/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Dose-Response Relationship, Drug , Flow Cytometry , Humans , In Vitro Techniques , Phosphorylcholine/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/metabolism , Sphingosine/administration & dosage , Time Factors , Type C Phospholipases/metabolism
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