Biophysical and Biochemical Studies on the Regulatory Mechanism of Fatty Acids on Blood Platelet Functions

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cis-Polyunsaturated fatty acids such as linoleic acid and alpha-linolenic acid inhibit platelet aggregation induced by ADP and other agonists. They inhibited the aggregation due to the inhibition of agonist-induced increase in cytoplasmic Ca^<2+>. Therefore, we then observed the effects of the fatty acids on the levels of intracellular cyclic AMP which is known to be one of the substances to regulate intracellular Ca^<2+>. 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 times 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. cis-Polyunsaturated fatty acids did not affect the production of inositol- 1,4,5-trisphosphate (IP_3) which is suggested to trigger Ca^<2+> release from intracellular pools. The possibility was also denied that these unsaturated fatty acids inhibit platelet functions by inhibiting arachidonate metabolism. Adenylate cyclase, which is responsible for the synthesis of cyclic AMP, is believed to be modulated by the lipid environment of the membrane. Fluorescence analysis with diphenylhexatriene and its trimethylammonium derivative showed that polyunsaturated fatty acids commonly increased membrane fluidity in wide depths of the membrane in the concentration ranges in which these fatty acids increased cyclic AMP concentration and inhibited platelet aggregation. From these results it is concluded that polyunsaturated: fatty acids inhibit platelet aggregatio due to stimulation of adenylate cyclase which is mediated by membrane betturbation.