Inhibition of diacylglycerol metabolism in isolated cardiac myocytes by U-57 908 (RHC 80267), a diacylglycerol lipase inhibitor.
U-57 908 (RHC 80267) inhibited diacylglycerol (DG) lipase activity in soluble and microsomal subcellular fractions from cardiac myocytes isolated from adult rat hearts; half-maximal inhibition was observed at a concentration of 3.5 microM. Monoacylglycerol lipase activity was much less sensitive to inhibition, but U-57 908 reduced lipoprotein lipase activity in cardiac myocytes with the same sensitivity as observed for DG lipase. DG kinase activity was not inhibited by U-57 908. DG metabolism by intact cardiac myocytes was studied in incubations with a cell-permeable DG analog, [3H]-dioctanoylglycerol (diC8). DiC8 was mainly metabolized by conversion to mono-octanoylglycerol (monoC8) and glycerol (lipase pathway); much less radioactivity was incorporated into the triacylglycerol and total phospholipid fractions. U-57 908 reduced the loss of radioactivity from the exogenous diC8 substrate, with a corresponding decline in the formation of radiolabelled monoC8 and glycerol. The incorporation of radioactivity into phospholipids was slightly reduced, but triacylglycerol synthesis from diC8 was increased in the presence of U-57 908. Therefore, U-57 908 is an effective inhibitor of DG metabolism by the lipase pathway in intact cardiac myocytes.
Chuang
M
M
Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Calgary, Alberta, Canada.
Severson
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DL
D000818:Animals; D003512:Cyclohexanones / Q000494:pharmacology*; D019852:Diacylglycerol Kinase; D004075:Diglycerides / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014280:Triglycerides / Q000096:biosynthesis
D003512:Cyclohexanones; D004075:Diglycerides; D014280:Triglycerides; C044295:1,2-dioctanoylglycerol; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D010770:Phosphotransferases; D019852:Diacylglycerol Kinase; D008071:Lipoprotein Lipase