Characterization of the effects of isoprostanes on platelet aggregation in human whole blood

Abstract

1 We tested the e ects of 11 commercially-available isoprostanes on platelet aggregation directly or when triggered by the thromboxane receptor agonist U46619 or collagen in healthy human citrated blood using a whole blood aggregometer.2 None of the isoprostanes tested triggered aggregation alone, nor facilitated aggregation by a subthreshold dose of U46619 or collagen. Five isoprostanes inhibited aggregation (rank order of potency 8-iso PGE 1 48-iso PGE 2 48-iso PGF 2a 48-iso PGF 3a 48-iso-13,14-dihydro-15-keto PGF 2a ). 3 Blood incubated with LPS to induce a gross in¯ammatory response exhibited a time dependent (2 ± 12 h) reduction in aggregation to U46619 but maintained a consistent response to collagen. Under these conditions, as in control blood, none of the isoprostanes tested induced aggregation. In fact, the inhibitory actions of isoprostanes on U46619-induced aggregation were enhanced in blood treated with LPS. 4 L-NAME inhibited aggregation induced by U46619 in fresh blood and in blood treated with LPS. In the presence of L-NAME, (with or without LPS) none of the isoprostanes tested induced aggregation but retained their inhibitory action. 5 Thus, in human whole blood the action of 8-iso PGE 1 , 8-iso PGE 2 , 8-iso PGF 2a , 8-iso PGF 3a , and 8-iso-13,14-dihydro-15-keto PGF 2a is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to in¯ammatory stimulation.

The 5‐series F2‐isoprostanes possess no vasomotor effects in the rat thoracic aorta, the human internal mammary artery and the human saphenous vein

“…The present study shows a third difference between 15‐F 2t ‐IsoP and 5‐F 2t ‐IsoP that is of the utmost importance: 15‐F 2t ‐IsoP is a vasoconstrictor, which has been hypothesized to be involved in the pathogenesis of coronary vasospasm (Iuliano et al ., 2001), whereas 5‐F 2t ‐IsoP has no vasomotor effects, and as such is not likely to be involved in the pathogenesis of vascular diseases. Our study does not rule out the possibility that the 5‐series may share other biological activity of 15‐F 2t ‐IsoP such as platelet aggregation inhibition (Cranshaw et al ., 2001), neutrophil adhesion (Fontana et al ., 2001), cardiomyocyte hypertrophy (Kunapuli et al ., 1998). Further studies are required to test whether these mediators may have effects on systems not being measured in the current study.…”

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

“…Urinary and plasma levels of 8‐ iso ‐PGF 2α have been demonstrated to be, respectively, risk marker and to be associated with the presence and extent of coronary stenosis in patients with CAD, suggesting a correlation between their levels and plaque instability . Furthermore, F 2 ‐isoPs induce endothelin release and proliferation of vascular SMCs, while there is also additional evidence that this molecule can increase resistance to aspirin inhibition of platelet aggregation, despite it has also been reported inhibition of platelet aggregation in whole blood . It should be remembered here that 8‐ iso ‐PGF 2α is a partial agonist of the TP receptor compared to U46619 in the coronary vasculature .…”

“…661 Furthermore, F 2 -isoPs induce endothelin release and proliferation of vascular SMCs, 662 while there is also additional evidence that this molecule can increase resistance to aspirin inhibition of platelet aggregation, 663,664 despite it has also been reported inhibition of platelet aggregation in whole blood. 665 It should be remembered here that 8-iso-PGF 2α is a partial agonist of the TP receptor compared to U46619 in the coronary vasculature. 666 Typically, the attitude of partial agonists to behave as agonist or antagonist depends on the level of the full agonist (TxA 2 in this case) simultaneously present, and this might in part explain these contradictory results.…”

The Isoprostanes: Unique Products of Arachidonic Acid Oxidation-A Review

“…In addition, 15-F 2t -IsoP induces endothelin release and proliferation of vascular smooth muscle cells [73,74]. There is also evidence that 15-F 2t -IsoP and 15-E 2t -IsoP possess additional biological activities, including induction of osteoclastic differentiation leading to bone resorption [75], increased resistance to aspirin inhibition of aggregation in platelets [76], and inhibition of platelet aggregation in human whole blood [77]. In addition, IsoPs have been shown to exert potent vasoactive properties in the lung.…”