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

Abstract

1. We tested the effects 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 PGE1 > 8-iso PGE2 > 8-iso PGF2α > 8-iso PGF3α > 8-iso-13,14-dihydro-15-keto PGF2α). 3. Blood incubated with LPS to induce a gross inflammatory 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 PGE1, 8-iso PGE2, 8-iso PGF2α, 8-iso PGF3α, and 8-iso-13,14-dihydro-15-keto PGF2α is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to inflammatory stimulation. British Journal of Pharmacology (2001) 132, 1699-1706.