The influence of isoprostanes on ADP-induced platelet aggregation and cyclic AMP-generation in human platelets.
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) A2 in free form (2). One F2-isoprostane whose formation is highly favored is 8-iso-PGF2 alpha which has been shown to be a potent pulmonary and renal vasoconstrictor (3,4). Actions of 8-iso-PGF2 alpha were demonstrated to be mediated through a receptor related to but probably distinct from the thromboxane (TXA2)/endoperoxide (PGH2) receptor (5). Although 8-epi-PGF2 alpha is a potent agonist of TXA2/PGH2 receptors in vascular smooth muscle, interestingly it acts primarily as an antagonist of TXA2/PGH2 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 E2-isoprostane receptors are distinct from TXA2/PGH2 receptors, suggesting at least different subtypes, one of these specifically recognizing E2-isoprostanes (9). Isoprostanes have been suggested to be useful markers for oxidant injury. For example, F2-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 F2-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.
Leitinger
N
N
Department of Nuclear Medicine, University of Vienna, Austria. nleit@pathology.medsch.ucla.edu
Blazek
I
I
Sinzinger
H
H
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D015777:Eicosanoids / Q000378:metabolism / Q000494:pharmacology*; D028441:F2-Isoprostanes; D005260:Female; D006801:Humans; D028421:Isoprostanes; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*
D015777:Eicosanoids; D028441:F2-Isoprostanes; D028421:Isoprostanes; C075750:8-epi-prostaglandin F2alpha; D000244:Adenosine Diphosphate; D015237:Dinoprost; D000242:Cyclic AMP; D015232:Dinoprostone; C011987:8-isoprostaglandin E2