The phospholipase C inhibitor U73122 inhibits phorbol ester-induced platelet activation.
Activation of phospholipase C (PLC) is a central component of the signal transduction process in numerous cells, including platelets. U73122 has been widely used as a selective PLC inhibitor. In the present study, the effects of U73122 on platelet function have been further examined. Platelets were stimulated with collagen (via PLC-gamma), the stable thromboxane mimetic U46619 (via PLC-beta), or phorbol myristate acetate (PMA) via protein kinase C (PKC). Consistent with inhibition of PLC, U73122 inhibited platelet aggregation and [3H]-serotonin release in response to collagen and U46619 in a concentration-dependent manner. Similarly, U73122 blocked collagen-induced release of thromboxane A2. U73122 also inhibited U46619-induced [32P]phosphatidic acid production and phosphorylation of the major PKC substrate, pleckstrin. U73122 had no effect on PMA-induced pleckstrin phosphorylation, [3H]-serotonin release, or intracellular vacuole formation. However, U73122 did inhibit PMA-induced platelet aggregation and fibrinogen binding. Overall, these results suggest that U73122, in addition to its inhibition of PLC, also affects PKC-independent events that interfere with platelet aggregation.
Lockhart
L K
LK
Departments of Pharmacology & Therapeutics and Oral Biology, University of Manitoba, Winnipeg, Manitoba, Canada.
McNicol
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001798:Blood Proteins / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology*; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D010712:Phosphatidic Acids / Q000097:blood; D010750:Phosphoproteins; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D012701:Serotonin / Q000097:blood; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*; D014617:Vacuoles / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D004963:Estrenes; D010712:Phosphatidic Acids; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D011760:Pyrrolidinones; D014662:Vasoconstrictor Agents; C039077:platelet protein P47; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D012701:Serotonin; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005340:Fibrinogen; D003094:Collagen; D010738:Type C Phospholipases; D013755:Tetradecanoylphorbol Acetate