Recently we discovered a new class of ether-linked phospholipids that possesses profound antihypertensive properties (Blank et al., Biochem. Biophys. Res. Commun. 90, 1194, 1979). Independent experiments by Demopoulos et al. (J. Biol. Chem. 254, 9355, 1979) have reported the same lipid to be platelet activating factor. This biologically active phospholipid has been rigorously identified as 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (alkylacetyl-GPC). Our recent data demonstrate that alkylacetyl-GPC can be synthesized in a variety of tissues by at least two separate pathways; spleen and bone marrow were especially active. Essentially nothing is known about ether lipids that contain a short-chain acyl group at this position. Therefore, we propose to determine how alkylacetyl-GPC and its derivatives are metabolized, determined the subcellular sites for the metabolism and action of alkylacetyl-GPC, and elucidate the molecular mechanism(s) responsible for its biological properties. The possibility that alkylacetyl-GPC is a highly selective acetyl donor that modifies crucial components of the vascular system by acetylation will also be investigated. Experiments are planned to determine whether membrane binding sites exist for alkylacetyl-GPC and how this lipid transported to its site of action after oral and after intravenous administration. The possibility that alkylacetyl-GPC acts as a modifier of membrane permeability will also be examined. Although preliminary data indicate that alkylacetyl-GPC dosen't influence PGE2 synthesis from arachidonate, we plan to explore if it might affect the levels of prostacyclin and thromboxane, since a disruption in their balance could explain most of the effects elicited by alkylacetyl-GPC. The proposed investigations will be done with intact and enzymatic systems of neutrophils and platelets obtained from rabbits and with endothelial cells isolated from aortas of rabbits and rats.
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