Irreversible platelet aggregation does not depend on lipoxygenase metabolites.
Previous investigations in our laboratory demonstrated the existence of an intrinsic mechanism, termed membrane modulation, capable of restoring sensitivity to aspirin treated platelets, resulting in irreversible aggregation in response to arachidonic acid (AA). The mechanism underlying correction of aspirin induced inhibition of platelet function, however, was not clear. In the present study we have evaluated the role of lipoxygenase (LO) metabolites of AA in securing irreversible aggregation of drug induced cyclooxygenase (CO) deficient platelets. Platelets treated with aspirin or Ibuprofen did not convert radiolabeled AA to thromboxane, but generated significant quantities of hydroxy acids via the LO pathway. However, drug exposed platelets, when stirred with epinephrine first and then challenged with AA, aggregated irreversibly. Eicosatetraynoic acid (ETYA 1, U53119) inhibited AA conversion by the LO pathway, whereas 5,8,11,14-eicosatetraynoic acid (ETYA 2) inhibited AA conversion by both CO and LO enzymes. Yet, at the inhibitory concentration these fatty acids failed to prevent AA induced irreversible aggregation of CO deficient, alpha adrenergic receptor stimulated platelets. Results of four studies show that the generation of LO metabolites of AA are not essential for securing irreversible aggregation of platelets.
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology / Q000031:analogs & derivatives; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D008084:Lipoxygenase / Q000097:blood*; D016859:Lipoxygenase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D013931:Thromboxanes / Q000097:blood
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D013931:Thromboxanes; D015117:5,8,11,14-Eicosatetraynoic Acid; D016718:Arachidonic Acid; C029510:4,7,10,13-eicosatetraynoic acid; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen; D004837:Epinephrine