Comparative pharmacology of cyclooxygenase inhibitors on platelet function.
Previous studies from our laboratory have demonstrated a critical role for ferrous heme in prostaglandin synthesis. Based upon these studies, we proposed a model for heme-arachidonic acid interaction and demonstrated that compounds which interfere with this interaction inhibit arachidonic oxidation by ferrous heme. In this study, we have examined the effect of four different inhibitors for their effect on platelet arachidonic acid metabolism and function. The compounds studied were an iron chelator, 2,2'-dipyridyl, the cyclooxygenase inhibitors, Ibuprofen and aspirin, and a polyenoic acid, docosahexaenoic acid. All four compounds at approximately 100 microM concentration blocked the second wave of platelet aggregation in response to epinephrine or adenosine diphosphate. They were equally potent in inhibiting 14C-arachidonic conversion by platelets to thromboxane. However, inhibition of platelet thromboxane production and function by dipyridyl and DHA was reversible. Removal of these compounds from the medium restored platelets ability to respond to agonists and generate products through the cyclooxygenase pathway. The inhibitory effect of Ibuprofen and aspirin on cyclooxygenase activity could not be reversed by washing the platelets. However, Ibuprofen treated platelets aggregated when stirred with arachidonate in a normal way. No such response could be elicited from aspirin treated platelets. All compounds (except DHA) interfered with heme-arachidonic acid interaction in a cell-free system and prevented arachidonic acid oxidation. Results of our studies suggest a common mechanism of action for these different classes of compounds. In spite of the common mechanism, each class of drug seems to have a relatively different effect upon platelet cyclooxygenase and function.
Rao
G H
GH
White
J G
JG
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000328:Adult; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors; D004281:Docosahexaenoic Acids; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006418:Heme / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D006418:Heme; D015082:2,2'-Dipyridyl; D007501:Iron; D001241:Aspirin; D007052:Ibuprofen