Fatty acids as sources of potential “magic bullets” for the modification of platelet and vascular function

Platelet cyclooxygenase exhibits a pronounced structural specificity whereas the lipoxygenase does not. Agonist recognition by platelets appears to be highly discriminatory. Endoperoxides apparently act on different receptors than do the thromboxanes and furthermore, thromboxane receptor recognition and/or activation must differ in blood vessels and platelets. The α-chain of the fatty acid metabolites profoundly influences receptor recognition without apparent influence of substrate affinity by the synthetic enzymes. The availability of inactive products or of partial agonists for the vascular and platelet receptors could lead to the development of selective receptor agonists and antagonists. Obviously there would be a considerable advantage in developing platelet-specific receptor analogs which do not influence smooth muscle receptors. Fatty acids which possess a Δ 5 unsaturation are readily converted by a calcium-dependent, cell-free enzyme system into mono- and dihydroxy fatty acids. However, in the presence of glutathione, this enzyme system completely assembles the biologically active slow-reacting substance of anaphylaxis (now termed leukotrienes C and D). Thus, arachidonic acid (5, 8, 11, 14), eicosapentaenoic acid (5, 8, 11, 14, 17), and 20:3 (5, 8, 11; which accumulates during essential fatty acid deficiency) all are excellent substrates for the synthesis of potent biologically active leukotrienes. Eicosapentaenoic acid (EPA, 5, 8, 11, 14, 17-) can serve as a prototype for the utilization of a fatty acid as a dietary strategy for the manipulation of certain disease processes. EPA as well as other members of the ω3 fatty acid family are effective antagonists of arachidonic acid metabolism (both exogenous or endogenous) by platelet cyclooxygenase. A substitution of EPA or possibly its precursor (9, 12, 15-octadecatrienoic acid, α-linolenic acid) in the diet would be expected to lead to both an inhibition of arachidonic acid metabolism and the lowering of endogenous arachidonate in tissue (e.g., platelets) lipids. The net anticipated result would be a marked reduction in the generation of PGH 2 and thromboxane A 2 which cause platelet aggregation. A preliminary clinical trial supporting this hypothesis has recently appeared. However, the discovery of the ease of conversion of EPA into the bronchoconstrictor leukotrienes demands appropriate caution and additional experimentation prior to widespread dietary supplementation.