Stereospecific inhibition of PGH2-induced platelet aggregation by lipoxygenase products of icosaenoic acids.
Mono-hydroxylated fatty acids were prepared from the three prostaglandin precursors (20:3, 20:4 and 20:5) through the platelet 12-lipoxygenase or the soybean 15-lipoxygenase and were purified by HPLC. The inhibition of PGH2-induced human platelet aggregation by these hydroxy derivatives was compared. Other hydroxy derivatives of arachidonic acid of physiological importance were also tested in that respect. We have found that 12- or 15- hydroxy-icosaenoic acids are the most potent inhibitors. As compared to 12- or 15-hydroxy -20:4 (12- or 15-HETE), 5-HETE was about three fold less potent. We have also found that leukotriene B4 (5S, 12R-diHETE) is completely devoid of inhibitory activity while its isomer 5S, 12S-diHETE shares the activity of every mono-hydroxy-icosaenoic acids which are also S derivatives. We conclude that hydroxy derivatives of icosaenoic acids can inhibit PGH2-induced platelet aggregation by structural analogy and that they need a S configuration. These findings point out a possible negative feed back modulation of platelet aggregation by the lipoxygenase products of arachidonic acid and other icosaenoic acids which can arise in platelets subsequently to dietary manipulations.
D001095:Arachidonic Acids / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008084:Lipoxygenase / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011449:Prostaglandin Endoperoxides / Q000037:antagonists & inhibitors*; D011463:Prostaglandins H / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D001095:Arachidonic Acids; D005231:Fatty Acids, Unsaturated; D011449:Prostaglandin Endoperoxides; D011463:Prostaglandins H; D008084:Lipoxygenase