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

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Abstract
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. None of the isoprostanes tested triggered aggregation alone, nor facilitated aggregation by a sub‐threshold 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). 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. 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. 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; doi:10.1038/sj.bjp.0704019