Pharmacology of thromboxane A2, prostacyclin and other eicosanoids in the cardiovascular system.

The eicosanoids, a group of endogenous metabolites of the cell membrane phospholipid-derived fatty acid arachidonic acid (AA), are formed from AA via three main enzymatic pathways (cyclooxygenase, lipoxygenase, cytochrome P450) and include the classical prostaglandins (PGF2 alpha, E2, D2), TxA2, PGI2, the leukotrienes and HETEs/HPETEs, the lipoxins and various epoxy metabolites. In the cardiovascular system the current interest is focussed on TxA2 and PGI2. TxA2 is released from activated platelets, shows potent platelet aggregating and vasoconstricting properties and is therefore considered to be important in thrombotic and ischaemic diseases. Therapeutic strategies directed at interfering with endogenous TxA2 include inhibition of synthesis (aspirin, selective TxA2 synthase inhibitors) and, more recently, specific blockade of TxA2 receptors. PGI2 is released mainly from the vascular intima, potently inhibits platelet aggregation and shows vasodilator and cytoprotective properties. PGI2 and chemically stable PGI2-derivatives have been shown to be effective in the treatment of severe peripheral ischaemic diseases and offer further interesting prospectives like prevention of vascular reocclusion in bypass surgery and balloon catheter angioplasty as well as organ preservation in transplant surgery. Other eicosanoids like PGD2 and the leukotrienes may also be important mediators in cardiovascular disease. Whether they represent targets for innovative drug therapy in cardiovascular disease remains to be investigated.