Inhibitory mechanism of cis-polyunsaturated fatty acids on platelet aggregation: the relation with their effects on Ca2+ mobilization, cyclic AMP levels and membrane fluidity.
The in vitro inhibitory effects of cis-polyunsaturated fatty acids, linolenic (18:2 delta 9,12), alpha-linoleic (18:3 delta 9,12,15) and eicosatrienoic (20:3 delta 11,14,17) acid, on bovine platelet aggregation and their inhibitory mechanism were investigated. These fatty acids inhibited platelet aggregation induced by ADP and thrombin to similar extent. Fluorescence analyses with fura-2-loaded platelets showed that, in the concentration ranges that inhibited aggregation, they also inhibited agonist-induced increase in cytoplasmic Ca2+. According to radioimmunoassay study, addition of these fatty acids increased cyclic AMP contents in the presence of theophylline corresponded with their inhibitory effects on aggregation. These fatty acids induced a 1.6-1.8-fold increase over basal concentration of cyclic AMP in the concentration ranges that fully inhibited aggregation. On the other hand, saturated fatty acid, stearic acid, affected neither aggregation nor cyclic AMP levels. As reported previously [1985) Biochim. Biophys. Acta 818, 391), these unsaturated fatty acids induced increase in membrane fluidity in the same concentration range. These results suggest that inhibition of platelet aggregation by cis-polyunsaturated fatty acids is due to the increase in cyclic AMP levels. This increase seems to be due to stimulation of adenylate cyclase which is mediated by membrane perturbation.
Kitagawa
S
S
Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
Kotani
K
K
Kametani
F
F
D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005454:Fluorescence Polarization; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000494:pharmacology; D008042:Linolenic Acids / Q000494:pharmacology; D008560:Membrane Fluidity / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D013229:Stearic Acids / Q000494:pharmacology; D013237:Stereoisomerism
D005231:Fatty Acids, Unsaturated; D008041:Linoleic Acids; D008042:Linolenic Acids; D010975:Platelet Aggregation Inhibitors; D013229:Stearic Acids; C031183:stearic acid; D019787:Linoleic Acid; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015126:8,11,14-Eicosatrienoic Acid; D002118:Calcium