Effects of 9, 12, 15-octadecatrien-6-ynoic acid on the metabolism of arachidonic acid in platelets and on platelet aggregation.
An acetylenic fatty acid: 9,12,15-octadecatrien-6-ynoic acid (dicranin) was extracted from Dicranum Scoparium and preincubated with platelets which were then stimulated by exogenous arachidonic acid (20:4 n-6). This molecule at 10(-4) M weakly inhibited the cyclooxygenase activity as assessed by measurement of 12-hydroxy-heptadecatrienoic acid (HHT) In contrast, the 12-hydroxy-eicosatetraenoic acid (12-HETE) synthesized by the 12-lipoxygenase was strongly increased by about 650%. The same effects were observed with 10(-5) M and with 10(-6) M of dicranin but to a lesser extent. Platelet hydroxylated dicranin metabolites were also found and the structure of the main compound determined by GC-MS was a 13-hydroxy derivative. Its origin has not yet been elucidated. Platelet aggregation induced by 1 microgram/ml of U46619, a structural PGH2 analogue was completely abolished in the presence of dicranin. Platelet aggregation induced either by thrombin or by arachidonic acid was inhibited by 10(-4) M of dicranin only after preincubation. This observation indicates that the formation of metabolites of dicranin are necessary to effect this inhibition. Dicranin is thus a new inhibitor of platelet aggregation and may prove to be useful for elucidating the effects of 12-HETE in biological systems.
Guichardant
M
M
Nestec Ltd, Nestle Research Centre, Vers-chez-les-Blanc, Lausanne, Switzerland.
Michel
M
M
Borel
C
C
Fay
L
L
Magnolato
D
D
Finot
P A
PA
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D016718:Arachidonic Acid / Q000097:blood*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D066298:In Vitro Techniques; D008042:Linolenic Acids / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D008042:Linolenic Acids; D016859:Lipoxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C075673:dicranin