PAF-acether-induced synthesis of prostacyclin by human endothelial cells.

Platelet activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF-acether) is a potent platelet-stimulating agent formed by most circulating cells. Added to cultured human endothelial cells, PAF-acether induced a dose-dependent synthesis of 6-keto-PGF1 alpha, the major stable metabolite of prostacyclin (PGI2), with a maximal effect at 100 nM, a concentration equivalent to that which aggregates human platelets. No release of von Willebrand factor (vWF) was noted under the same conditions. The poorly active PAF-acether analogue, methoxy-PAF failed to stimulate 6-keto-PFG1 alpha synthesis and the PAF-acether antagonists 48740 RP, BN 52021 and Ro 19-3704, prevented the stimulatory effect of PAF-acether. Methyl-carbamate-PAF, an equieffective analogue of PAF-acether on platelets, also stimulated 6-keto-PGF1 alpha production. After a first stimulation by PAF-acether or methyl-carbamate-PAF, no response was detected when endothelial cells were re-exposed to either agonist, indicating auto- and cross-desensitization as described for other cells. Since PAF-acether stimulated [3H]arachidonate release from pre-labelled endothelial cells, our results suggest that it stimulates phospholipase activity, which accounts for the increased PGI2 synthesis. The auto- and cross-desensitization between PAF-acether and methyl-carbamate-PAF, ineffectiveness of methoxy-PAF and inhibition by selective antagonists strongly suggest interaction with specific membrane receptors.

[Physiology of the interactions of blood and the blood vessel wall. Role of pharmacologically active lipids]. / Physiologie des interactions du sang et de la paroi des vaisseaux. Rôle des lipides pharmacologiquement actifs.

The interactions of blood cells (platelets and leukocytes) with the components of the vessel wall (endothelial cells, extracellular subendothelial matrix and smooth muscle cells) play an important role in the initiation of thrombosis and the development of atherosclerosis. These cellular interactions are partially regulated by the formation of pharmacologically active lipids (PAL): prostaglandins, leukotrienes, PAF-acether and related compounds. These biochemical mediators are produced from the phospholipids of the cell membrane in response to external stimulation. The metabolic precursors, such as arachidonic acid, are common. The subsequent enzymatic differentiation leads to the formation of different terminal products according to the cells, thromboxane A2 in the platelets and prostacyclin in the endothelial cells.