Influence of Polyenoic Acids on Arachidonic Acid Metabolism and Platelet Function

Abstract

Epidemiologic discoveries suggesting beneficial effects of fish diets in lowering the risk for cardiovascular diseases (CVD) in Greenland Eskimos and Japanese fishermen have prompted many dietary studies aimed at prevention of CVD. Fish fats are rich in -3 polyenoic acids such as eicosa-pentaenoic acid (EPA, 20 : 5) and docosahexaenoic acid (DHA, 22 : 6). Several studies have attributed the salutary influence of a fish diet to the presence of large amounts of these fatty acids. A beneficial effect of polyenoic acids may be related to competitive inhibition of platelet arachidonic acid metabolism or to production of antiplatelet metabolites via the vascular cyclooxygenase or platelet lipoxygenase pathway. In this study we have examined polyenoic-acid-induced in vitro platelet dysfunction and followed the in vivo effects of these fatty acids in modulating ex vivo platelet function. The fatty acids evaluated in this study (EPA and DHA) were potent inhibitors of arachidonic acid conversion to thromboxane. Therefore, they blocked agonist-induced release of granule contents and irreversible aggregation of platelets. However, polyenoic-acid-induced inhibition of thromboxane synthesis was transient and could be reversed by washing platelets. Although radiolabeled polyenoic acids (EPA/DHA) were incorporated into membrane phospholipids, when stirred with agonists they did not generate significant quantities of cyclooxygenase metabolites. Platelets metabolized these fatty acids efficiently via the lipoxygenase pathway. Oral ingestion of two capsules of EPA™ (Shaklee Products, EPA 300 mg; DHA 130 mg) per day for 60 days or 15 capsules per day for 3 days had no significant effect on agonist-induced irreversible aggregation of platelets. Results of our investigation suggest that polyenoic-acid-induced inhibition of platelet function may be related to their ability to compete with substrate arachidonic acid for the active site on the enzyme rather than to the inhibitory metabolites formed via vascular cyclooxygenase or the platelet lipoxygenase pathway. In vivo studies suggest that ingestion of large amounts of the fatty acids may be essential to obtain any beneficial effect.