Effect of ticlopidine ex vivo on platelet intracellular calcium mobilization.
The antiplatelet compound ticlopidine exerts its potent inhibitory activity through an as yet undetermined mechanism(s). The goal of this study was to determine the effect, if any, of ticlopidine ex vivo on platelet calcium mobilization. Ticlopidine inhibited ADP-induced platelet aggregation by 50-80%. In the presence of 1 mM EGTA, ticlopidine inhibited ADP- and thrombin-stimulated increases in [Ca2+]i in fura-2 loaded platelets. We evaluated further the effect of ticlopidine on calcium mobilization by examining both agonist-stimulated formation of inositol trisphosphate in intact platelets and the ability of inositol trisphosphate to release 45Ca from intracellular sites in permeabilized cells. We show here that while ticlopidine significantly affected agonist-induced intracellular calcium mobilization in intact platelets, the drug was without effect on agonist-stimulated formation of inositol trisphosphate in intact platelets and on inositol trisphosphate-induced 45Ca release in saponin-permeabilized platelets. Our study demonstrates that ticlopidine exerts at least part of its effect via inhibition of intracellular calcium mobilization but that its site of action remains to be determined.
Derian
C K
CK
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, PA.
Friedman
P A
PA
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D007294:Inositol / Q000494:pharmacology; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D013988:Ticlopidine / Q000494:pharmacology*
D002132:Calcium Radioisotopes; D010975:Platelet Aggregation Inhibitors; D007294:Inositol; D013988:Ticlopidine; D002118:Calcium