The sulfhydryl reagent thimerosal elicits human platelet aggregation by mobilization of intracellular calcium and secondary prostaglandin endoperoxide formation.
The effect of the sulfhydryl (SH) group inhibitor ethylmercurithiosalicylate (thimerosal) on the function of human platelets was investigated. In contrast to known SH reagents such as p-chloromercuribenzoate or N-ethylmaleimide, thimerosal elicited both aggregation and [3H]serotonin release of washed human platelets at low micromolar concentrations (greater than or equal to 2 microM). Only a significant higher dose (greater than or equal to 15 microM) was effective when platelets were pretreated with the cyclooxygenase inhibitor aspirin, indicating an amplification of the proaggregatory effect of thimerosal by secondary prostaglandin (PG) endoperoxide and/or thromboxane (TX) formation. Consistent with this notion, thimerosal induced endogenous platelet arachidonic acid (20:4) metabolism which could be attributed to enhanced 20:4 liberation, presumably by activation of phospholipase A2. The latter effect was mediated by mobilization of intracellular calcium (Ca2+), and was not affected by removal of extracellular Ca2+. In the presence of aspirin, the thimerosal-induced Ca2+ elevation was completely reversed by dithiothreitol (DTT) which implicates SH groups in intracellular Ca2+ transport. In contrast to previous observations with other SH reagents, thimerosal had no effect on the inositoltrisphosphate (IP3)-mediated release or the sequestration (and/or extrusion) of intracellular Ca2+ following stimulation with thrombin, indicating an action on an as yet undefined CA2+ transport system.
Hecker
M
M
Faculty of Biology, University of Konstanz, Federal Republic of Germany.
Brüne
B
B
Decker
K
K
Ullrich
V
V
D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000097:blood*; D004533:Egtazic Acid / Q000494:pharmacology; D005035:Ethylmercury Compounds / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D010743:Phospholipids / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D011449:Prostaglandin Endoperoxides / Q000097:blood*; D013849:Thimerosal / Q000494:pharmacology*
D005035:Ethylmercury Compounds; D010743:Phospholipids; D011449:Prostaglandin Endoperoxides; D013849:Thimerosal; D004533:Egtazic Acid; D001241:Aspirin; D002118:Calcium