The effect of the beta-D-xyloside naroparcil on circulating plasma glycosaminoglycans. An explanation for its known antithrombotic activity in the rabbit.
Beta-D-Xylosides are known to initiate or prime free glycosaminoglycan (GAG) chain synthesis in cell and tissue culture. As such, the effect of the venous antithrombotic beta-D-xyloside, naroparcil, was investigated on the plasma GAG profile in the rabbit after oral administration. Using dose-response experiments, we showed that antithrombin activity via antithrombin III and heparin cofactor II was increased in parallel with GAG plasma levels compared to control. A more detailed qualitative examination of plasma GAGs by cellulose acetate electrophoresis and ion-exchange chromatography, following oral administration of naroparcil at 400 mg/kg, revealed the presence of higher density charged molecules compared to control. The extracted GAGs were found to activate inhibition of thrombin by heparin cofactor II and contained approximately 25% of a dermatan sulfate-like compound (undetectable in control), which could be responsible for the antithrombotic effect. Using radiolabeled naroparcil, we found radiolabeled GAG fractions and the fact that naroparcil was a substrate for galactosyltransferase I, the second enzyme responsible for GAG chain polymerization, suggested that the compound could initiate in vivo the biosynthesis of antithrombotic free GAG chains. This is, to our knowledge, the first description of the in vivo effect of a beta-D-xyloside on GAG biosynthesis; furthermore, this is correlated with an antithrombotic action.
Masson
P J
PJ
Centre de Recherche et Développement, Laboratoires Fournier S.C.A., Daix, France.
Coup
D
D
Millet
J
J
Brown
N L
NL
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism / Q000494:pharmacology; D000991:Antithrombins / Q000378:metabolism / Q000494:pharmacology*; D002848:Chromatography, DEAE-Cellulose; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004588:Electrophoresis, Cellulose Acetate; D005700:Galactosyltransferases / Q000378:metabolism; D006025:Glycosaminoglycans / Q000096:biosynthesis / Q000097:blood*; D015844:Heparin Cofactor II / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D011817:Rabbits; D013865:Thioglycosides / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism
D000991:Antithrombins; D006025:Glycosaminoglycans; D007457:Iodine Radioisotopes; D013865:Thioglycosides; C092014:naroparcil; D015844:Heparin Cofactor II; D000990:Antithrombin III; D005700:Galactosyltransferases; C063053:xylosylprotein 4-beta-galactosyltransferase; D013917:Thrombin