Ebselen affects calcium homeostasis in human platelets.
Ebselen (PZ 51, 2-phenyl-1,2-benzoisoselenazol-3-(2H)-one) is a selenoorganic compound with anti-inflammatory properties. Its pharmacological action is thought to originate from its peroxidase activity which could lower the peroxide tonus required for cyclooxygenase and lipoxygenase activations. From experiments with aspirin-treated human platelets we now present evidence that ebselen also affects intracellular calcium homeostasis by inhibiting the agonist-triggered increase in intracellular calcium. Using Mn2+ entry to quench the fura-2 fluorescence after cell stimulation, we could exclude an interaction of ebselen with receptor-operated calcium channels and therefore an inhibition of extracellular calcium influx. It became evident from whole cell experiments and by using isolated platelet microsomal vesicles that ebselen inhibits the inositol 1,4,5-trisphosphate (IP3) induced calcium release. Besides this inhibitory effect of ebselen on the calcium release higher concentrations of the compound (greater than or equal to 5 microM) induced a calcium release from our microsomal vesicles which also could be reversed by dithiothreitol. An activation of inflammatory cells is usually associated with increased cytosolic calcium concentrations. An inhibition of such calcium movements by ebselen may account for an up to now unidentified anti-inflammatory mechanism of ebselen action which is linked to a direct effect of this compound rather than to its peroxidase-like activity.
Brüne
B
B
Faculty of Biology, University of Konstanz, Federal Republic of Germany.
Diewald
B
B
Ullrich
V
V
D000813:Anilides / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001345:Autoradiography; D001393:Azoles / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000097:blood* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005453:Fluorescence; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D054833:Isoindoles; D008861:Microsomes / Q000378:metabolism; D016566:Organoselenium Compounds; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D012643:Selenium / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology
D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; C068988:2-methylselenobenzanilide; D013917:Thrombin; D012643:Selenium; D001241:Aspirin; D002118:Calcium