Alkylacetylglycerophosphocholines represent a novel group of bioactive phospholipids capable of producing hypotension, aggregation and degranulation of platelets and neutrophils, inflammatory and allergic responses, anaphylaxis, modulation of Ca2+ uptake, and stimulation of metabolism (phosphatidylinositol turnover, glycogenolysis, and the formation of 20:4 metabolites). A neutral glycerolipid, alkylacetylglycerols, has also been shown to elicit a striking hypotensive response in rats. The work in this renewal is directed toward developing an understanding of the metabolism, regulation, and mechanism of action of these important and unique group of glycerolipid cellular mediators. Experimental systems include platelets (rabbits), alveolar and peritoneal macrophages, neutrophils (human), endothelial cells (rat and human), and rat kidneys and spleens. WKY (normotensive) and SHR (hypertensive) rats are used for in vivo experiments and as organ sources. The proposed projects concern the following issues: (a) Source of arachidonate used by the CoA-independent arachidonoyl transacylase involved in the acylation of lyso-PAF formed during the inactivation of PAF and the purification and characterization of the transacylase responsible; (b) Identification of the acetate acceptor molecule in PAF inactivation; (c) Characterization of acetylhydrolase inhibitors (e.g., acetamide analog of PAF) for cellular investigations; (d) Purification of acetylhydrolase for more complete characterization of properties and the perparation of antibodies for use in regulatory studies; (e) Quantitative aspects of PAF biosynthesis (acetyltransferase vs. choline phosphotransferase, plus the possibilities of methylation and Ca2+-dependent polar head group exchange reactions in the formation of PAF); (f) Purification and characterization of the cholinephosphotransferase responsible for PAF synthesis; (g) The metabolism of alkylacetylglycerols and related """"""""diglyceride type"""""""" lipids; (h) Documentation of the composite ether lipid pathway in a model system (alveolar macrophages) involved in PAF metabolism; (i) Factors that regulate the metabolism and cellular processing of PAF; (j) Subcellular sites and membrane topography of PAF enzymes and products; (k) PAF transport systems (intracellular versus extracellular ); and (1) the metabolism of PAF and regulatory controls in animal models of hypertension (SHR genetic hypertensive rats) and inflammation (cotton pellet induced granulomas).
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