Manipulation of platelet aggregation by prostaglandins and their fatty acid precursors: pharmacological basis for a therapeutic approach.
Addition of the one-, two- or three- series endoperoxide to human platelet-rich plasma tend to suppress aggregation, through the action of their respective non-enzymatic breakdown products PGE1, PGD2, or PGD3 all of which elevate cyclic AMP levels. On the other hand, these stable primary products do not arise in appreciable amounts from intrinsic endoperoxides generated from either endogenous or exogenous free fatty acids. 5,8,11,14,17-Eicosapentaenoic acid (EPA) suppresses arachidonic acid (5,8,11,14-eicosatetraenoic acid) conversion by cyclooxygenase (as well as lipoxygenase) to aggregatory metabolites in platelets. Exogenously added EPA was capable of inhibiting PRP aggregation induced either by exogenous or endogenous (released by ADP or collagen) arachidonate. The hypothetical combination of an EPA-rich diet and a thromboxane synthetase inhibitor might abolish production of the pro-aggregatory species, thromboxane A2, and enhance formation of the anti-aggregatory metabolite, prostacyclin. Whereas EPA is not detectably metabolized by platelets, dihomo-gamma-linolenic acid (8,11,14-eicosatrienoic acid) is primarily converted by cyclooxygenase and thromboxane synthetase into the inactive metabolite, 12-hydroxyheptadecadienoic (HHD) acid. Pretreatment of human platelet suspensions with the thromboxane synthetase inhibitor imidazole unmasks the aggregatory property of PGH1 and DLL which was partially compromised by the PGE1 formed. The combination of the thromboxane synthetase inhibitor and an adenylate cyclase inhibitor unmasks a complete irreversible aggregation by DLL or PGH1. The basis of a dietary strategy that replaces AA with DLL must rely on the production by the platelet of an inactive metabolite (HHD) rather than thromboxane A2.
D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D004537:Eicosanoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D011449:Prostaglandin Endoperoxides / Q000494:pharmacology*; D011453:Prostaglandins / Q000494:pharmacology*; D011457:Prostaglandins D / Q000494:pharmacology; D011458:Prostaglandins E / Q000494:pharmacology; D011463:Prostaglandins H / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D004537:Eicosanoic Acids; D005231:Fatty Acids, Unsaturated; D011449:Prostaglandin Endoperoxides; D011453:Prostaglandins; D011457:Prostaglandins D; D011458:Prostaglandins E; D011463:Prostaglandins H; D011465:Prostaglandins, Synthetic; D000244:Adenosine Diphosphate; D015118:Eicosapentaenoic Acid; D013930:Thromboxane-A Synthase; D015126:8,11,14-Eicosatrienoic Acid