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  • Title: Acrylyl-PAF, a synthetic platelet-activating factor analogue.
    Author: Duffy-Krywicki RH, Steinhelper ME, Olson MS.
    Journal: J Lipid Mediat; 1991; 3(3):345-59. PubMed ID: 1773032.
    Abstract:
    Acrylyl-PAF, a novel platelet-activating factor analogue with substantial agonist properties, was synthesized from lyso-PAF and acrylyl chloride. Incubation of acrylyl-PAF with partially purified human serum acetylhydrolase inhibited the action of acetylhydrolase on PAF. Kinetic studies using several concentrations of PAF as well as acrylyl-PAF suggested that acrylyl-PAF was a competitive inhibitor of the acetylhydrolase. Reciprocal Lineweaver-Burk plots and Dixon plots showed that acrylyl-PAF has an apparent Ki of 2.6 microM. Radiolabeled 18: 0-acrylyl-PAF was also synthesized. Studies comparing the effectiveness of acrylyl-PAF as a substrate for the acetylhydrolase versus PAF show that approximately 60% more PAF is metabolized by acetylhydrolase than acrylyl-PAF under identical conditions. Acrylyl-PAF was shown to aggregate washed rabbit platelets and to stimulate the release of glucose in the perfused rat liver. Dose-response curves illustrate that acrylyl-PAF was about half an order of magnitude less potent than PAF as an agonist. Tissue extracts of freeze-clamped livers that were perfused with radiolabeled acrylyl-APF indicated that approximately 26% of the label associated with acrylyl-PAF washed through the liver into the perfusate, while 48% of the acrylyl-PAF remained intact in the liver. Only 9% of the acrylyl-PAF was converted to k lyso-PAF with the ramainder metabolized to other lipids. This observations stands in contrast with livers perfused with radiolabeled PAF where less than 1% of the activity associated with PAF washed through the liver while about 70% remained as intact PAF and 30% was converted to lyso-PAF. Repeated bolus infusions of acrylyl-PAF exhibited desensitization of the glycogenolytic response of the perfused rat liver. The present study describes teh synthesis and characterization of acrylyl-PAF, which was shown to be: (a) poorly hydrolyzed by the human serum acetylhydrolase; (b) a competitive inhibitor of the acetylhydrolase; and (c) an agonist with potent activity in both platelet aggregation and hepatic glycogenolytic responses.
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