The influence of isoprostanes on ADP-induced platelet aggregation and cyclic AMP-generation in human platelets.

Abstract Isoprostanes are eicosanoids that are non-enzymatic products of free radical catalyzed peroxidation of arachidonyl containing phospholipids [1]. They are subsequently released from the site of generation as esters of phospholipid (bound) or through the action of phospholipase(s) A 2 in free form [2]. One F 2 -isoprostane whose formation is highly favored is 8-iso-PGF 2α which has been shown to be a potent pulmonary and renal vasoconstrictor [3, 4]. Actions of 8-iso-PGF 2α were demonstrated to be mediated through a receptor related to but probably distinct from the thromboxane (TXA 2 ) / endoperoxide (PGH 2 ) receptor [5]. Although 8-epi-PGF 2α is a potent agonist of TXA 2 /PGH 2 receptors in vascular smooth muscle, interestingly it acts primarily as an antagonist of TXA 2 /PGH 2 receptors on both human and rat platelets [6]. There is also evidence for the generation of D- and E-ring isoprostanes [7]and their receptor-mediated action on smooth muscle cells [8]and platelets [9]. Recent reports support the hypothesis that E 2 -isoprostane receptors are distinct from TXA 2 /PGH 2 receptors, suggesting at least different subtypes, one of these specifically recognizing E 2 -isoprostanes [9]. Isoprostanes have been suggested to be useful markers for oxidant injury. For example, F 2 -isoprostanes were significantly elevated in plasma of rats during reperfusion after hepatic ischemia [10]and in patients with hepatorenal syndrome [11]. It has been suggested that the release of F 2 -isoprostanes from oxidized LDL in macrophages could be a contributory factor in the development of atherosclerosis and at sites of inflammation, locally elevated levels of isoprostanes could contribute to blood cell activation. In this study we investigate possible pro- or antiaggregatory properties of various F- and E-type isoprostanes on human platelets.