Reversal of thromboxane A2/prostaglandin H2 and ADP-induced calcium release in intact platelets.
We previously demonstrated that thromboxane A2 and/or prostaglandin H2 (TXA2/PGH2), ADP, and A23187 cause calcium mobilization in intact human platelets. Other studies have also shown that platelet shape change and aggregation induced by a variety of platelet agonists can be reversed by specific antagonists. In the present study, we used the fluorescent calcium probe chlortetracycline to evaluate whether the reversal of platelet activation involves a resequestration of intraplatelet calcium. It was found that the TXA2/PGH2 receptor antagonist 13-azaprostanoic acid (13-APA) reversed calcium mobilization and shape change induced by AA but not that induced by ADP. A similar specificity of action was observed using the specific ADP receptor antagonist, ATP, in that ATP only reversed ADP-induced calcium release and shape change. In contrast, prostacyclin reversed both AA and ADP-induced calcium redistribution and shape change. In the latter experiments, a net calcium sequestration was actually observed on prostacyclin addition. These findings indicate that the resequestration of released calcium leads to platelet deactivation. Furthermore, there appear to be at least two mechanisms by which a reduction in cytosolic calcium can be produced: specific interruption of the agonist-receptor interaction, for example, 13-APA antagonism of TXA2/PGH2; and stimulation of platelet adenosine 3',5'-cyclic monophosphate production by prostacyclin and consequent calcium sequestration.
Brace
L D
LD
Venton
D L
DL
Le Breton
G C
GC
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000097:blood* / Q000378:metabolism; D002751:Chlortetracycline / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D011449:Prostaglandin Endoperoxides / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011466:Prostanoic Acids / Q000494:pharmacology; D013268:Stimulation, Chemical; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013931:Thromboxanes / Q000494:pharmacology*
D001095:Arachidonic Acids; D007473:Ion Channels; D011449:Prostaglandin Endoperoxides; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D011466:Prostanoic Acids; D013931:Thromboxanes; D016718:Arachidonic Acid; D044262:Prostaglandin H2; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; C022574:13-azaprostanoic acid; D000255:Adenosine Triphosphate; D011464:Epoprostenol; D000242:Cyclic AMP; D002118:Calcium; D002751:Chlortetracycline