Blocking platelet aggregation inhibits thromboxane A2 formation by low dose agonists but does not inhibit phosphorylation and activation of cytosolic phospholipase A2.
Inhibition of aggregation by Ro 44-9883, a potent and selective non-peptide GPIIb/IIIa antagonist, resulted in inhibition of serotonin secretion induced by weak agonists such as ADP or low doses of either thrombin receptor agonist peptide (TRAP) or collagen. In contrast, alpha granule secretion was inhibited to different extents dependent on donor, averaging 60% inhibition. Inhibition of serotonin secretion correlated with an inhibition of thromboxane A2 (TxA2) formation, both of which were overcome by higher doses of TRAP or collagen. Ro 44-9883 had no effect on the already reduced serotonin secretion and TxA2 formation in Glanzmann's thrombasthenic platelets. Restoration of serotonin secretion in the absence of aggregation requires both TxA2 and lysophosphatidic acid. In addition, Ro 44-9883 inhibition of TxA2 formation was not due to a lack of phospholipase A2 (PLA2) phosphorylation and activation as assayed in vitro. These results suggest that aggregation is required for weak or low dose agonist induced in vivo activity of PLA2, possibly by either regulating phospholipid substrate availability or interaction of PLA2 with platelet membranes.
Carroll
R C
RC
University of Tennessee Graduate School of Medicine, Department of Medical Biology, Knoxville 37920, USA. RCARROL1@UTCC.UTKUX.UTK.EDU
Wang
X F
XF
Lanza
F
F
Steiner
B
B
Kouns
W C
WC
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001792:Blood Platelets / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010762:Phosphorylase a / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010949:Plasma / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D013915:Thrombasthenia / Q000097:blood; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000085:Acetates; D008246:Lysophospholipids; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014662:Vasoconstrictor Agents; C072032:thrombin receptor peptide (42-55); D012701:Serotonin; D014443:Tyrosine; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C084062:lamifiban; D010762:Phosphorylase a