Inhibition of platelet aggregation by unsaturated fatty acids through interference with a thromboxane-mediated process.
cis- and trans-unsaturated fatty acids with 18 carbon atoms (oleic, linoleic, elaidic and linolelaidic acid) inhibited aggregation of washed rabbit platelets stimulated with collagen, arachidonic acid and U46619 when in the same concentration ranges. Thrombin-induced aggregation was not affected by any of them. Saturated fatty acid (stearic acid) had no effect on this response. The inhibition is independent of the induced change in membrane fluidity, since trans-isomers could not induce the change in fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene. Unsaturated fatty acids, except linoleic acid, did not interfere with the formation of thromboxane B2 from exogenously added arachidonic acid. All the unsaturated fatty acids only slightly inhibited the arachidonic acid liberation by phospholipase A2 in platelet lysate. This indicates that the unsaturated fatty acids may block a process after formation of thromboxane A2 in response to collagen and arachidonic acid. The increase in phosphatidic acid formation stimulated with U46619 was inhibited dose dependently by each of the unsaturated fatty acids but that stimulated with thrombin was not affected by any of them. Phospholipase C activity measured by diacylglycerol formation in unstimulated platelet lysate was not inhibited by the fatty acids. The elevation of cytosolic free Ca2+ induced by arachidonic acid or U46619 and Ca2+ influx by collagen were inhibited almost completely at the same concentration as that which inhibited their aggregation. These data suggest that the unsaturated fatty acids were intercalated into the membrane and inhibited collagen- and arachidonic acid-induced platelet aggregation by causing a significant suppression of the thromboxane A2-mediated increase in cytosolic free Ca2+, probably due to interference with the receptor-operated Ca2+ channel.
Sato
T
T
Department of Biochemistry, Kyoto Pharmaceutical University, Japan.
Nakao
K
K
Hashizume
T
T
Fujii
T
T
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000097:blood; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008560:Membrane Fluidity; D010712:Phosphatidic Acids / Q000096:biosynthesis / Q000097:blood; D010741:Phospholipases A / Q000097:blood; D054467:Phospholipases A2; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D013917:Thrombin / Q000502:physiology; D013929:Thromboxane B2 / Q000097:blood*; D010738:Type C Phospholipases / Q000097:blood
D005231:Fatty Acids, Unsaturated; D010712:Phosphatidic Acids; D013929:Thromboxane B2; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D013917:Thrombin; D002118:Calcium