Characterization of the effects of isoprostanes on platelet aggregation in human whole blood.
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 PGE(1)>8-iso PGE(2)>8-iso PGF(2alpha)>8-iso PGF(3alpha)>8-iso-13,14-dihydro-15-keto PGF(2alpha)). 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 PGE(1), 8-iso PGE(2), 8-iso PGF(2alpha), 8-iso PGF(3alpha), and 8-iso-13,14-dihydro-15-keto PGF(2alpha) is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to inflammatory stimulation.
Cranshaw
J H
JH
Unit of Critical Care Medicine, Royal Brompton Hospital, NHLI Division of Imperial College School of Medicine, Sydney Street, London SW3 6NP.
Evans
T W
TW
Mitchell
J A
JA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000328:Adult; D003094:Collagen / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D010975:Platelet Aggregation Inhibitors; D011465:Prostaglandins, Synthetic; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester