This project is expected to provide significant information about a newly identified neutral lipid class that appears to be an important physiological factor in the regulation of blood pressure. Such biochemical knowledge could provide a framework for developing new clinical approaches for the control of hypertension. Recent work by our laboratory has demonstrated that a neutral class of ether-linked glycerolipids (alkylacetylglycerols) possesses potent and relatively long lasting hypotensive activity when administered intravenously to SHR hypertensive or normotensive rats (Blank et al. BBRC 118, 344, 1984). Our objective is to obtain a complete understanding about the levels, metabolism, and mechanism of action of the alkylacetylglycerols in rat kidneys because of this organ's role in the regulation of blood pressure. Methods to accomplish this work will utilize enzymological procedures, lipid chemistry, HPLC, TLC, GLC, and radiolabeled tracers. Studies will be done in vivo with rats and with intact renal cells maintained in suspension culture and monolayer cultures of MDCK kidney cells or capillary endothelial cells from rat adipose tissue. Subcellular fractions will be used for investigations of specific enzymatic steps involved. Specific objectives are to: (1) establish the levels of alkylacetylglycerols in the renal cortex and medulla (comparative results will be obtained for both normotensive controls and SHR genetic hypertensive rats), (2) characterize the enzymatic steps (at the subcellular level) for the complete pathway of alkylacetylglycerol metabolism (biosynthesis and catabolism), (3) determine whether the conversion of alkylacetylglycerols to PAF via a specific cholinephosphotransferase could explain the hypotensive action of the neutral antihypertensive lipid and if so whether the kidney medulla (known to produce an antihypertensive neutral renal lipid called ANRL) plays a key role in the production of PAF via the cholinephosphotransferase system, and (4) delineate how alkylacetylglycerols are metabolized in vivo and in selected cellular systems (rat endothelial cells and cultured MDCK kidney cells) and rat tissues [kidney (cortex vs medulla) and other key organs].
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