ADP, adrenaline and serotonin stimulate inositol 1,4,5-trisphosphate production in human platelets.
Although adenosine diphosphate (ADP) is a well-known stimulus of platelet aggregation, it is not the generally accepted view that ADP stimulates phosphatidylinositolbisphosphate (PtdIns(4,5)P2) hydrolysis. Using a very sensitive competitive receptor binding assay for inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), we have detected Ins(1,4,5)P3 production at early ( < 10 s) time points after stimulation of human platelets by the weak agonists ADP, adrenaline and serotonin (5-hydroxytryptamine, 5-HT). When adrenaline or 5-HT was combined with ADP in the presence of aspirin, there was a significant potentiation of ADP-induced platelet aggregation, but there was no potentiation of Ins(1,4,5)P3 generation. Also, the increases in intracellular calcium (Ca2+) concentrations stimulated by ADP were not potentiated by adrenaline in the presence of aspirin. Therefore, the synergism between the purinergic and adrenergic pathways of platelet activation occurs downstream from PtdIns(4,5)P2 hydrolysis and intracellular Ca2+ mobilization, although prior to platelet aggregation.
Vanags
D M
DM
Department of Clinical and Experimental Pharmacology, University of Adelaide, South Australia, Australia.
Lloyd
J V
JV
Rodgers
S E
SE
Bochner
F
F
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology*
D010975:Platelet Aggregation Inhibitors; D012701:Serotonin; D000244:Adenosine Diphosphate; D015544:Inositol 1,4,5-Trisphosphate; D001241:Aspirin; D002118:Calcium; D004837:Epinephrine