Effects of 2,2'-dipyridyl and related compounds on platelet prostaglandin synthesis and platelet function.
2,2'-dipyridyl, a chelator of ferrous iron and inhibitor of platelet aggregation, was studied together with several similar compounds to determine the mechanism of their effects on platelets. All of these compounds were more potent inhibitors of arachidonic-acid-mediated aggregation (IC50, 0.17-1.8 mM) than of ADP-mediated aggregation (IC50, 7.6-19.7 mM). At low concentrations required to inhibit arachidonic-acid-mediated aggregation, 2,2'-dipyridyl, 4,4'-dipyridyl and 2-chloropyridine specifically inhibited the platelet cyclo-oxygenase. The mechanism of inhibition of ADP-induced aggregation was investigated, but was not explained. At concentrations needed to inhibit ADP-induced aggregation, 2,2'-dipyridyl did not alter cell ultrastructure, serotonin or nucleotide content or interfere with release of [14C]arachidonic acid or calcium movements. Therefore, our results indicate that 2,2'-dipyridyl and related compounds have two effects on platelets, both due to the unprotonated form. The inhibition of cyclo-oxygenase by low concentrations of these compounds is not due to bidentate iron chelation, since 4,4'-dipyridyl was almost as effective as 2,2'-dipyridyl, but is compatible with binding of these inhibitors to the iron in the heme of the cyclo-oxygenase.
D015082:2,2'-Dipyridyl / Q000494:pharmacology*; D000227:Adenine Nucleotides / Q000378:metabolism; D000328:Adult; D001095:Arachidonic Acids / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis / Q000097:blood*; D011725:Pyridines / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism
D000227:Adenine Nucleotides; D001095:Arachidonic Acids; D011453:Prostaglandins; D011725:Pyridines; D012701:Serotonin; D015082:2,2'-Dipyridyl; D002118:Calcium