The antiheparin effect of a heparinoid, pentosan polysulphate. Investigation of a mechanism.
A pentosan polysulphate [a fully sulphated (1-4)-beta-D-xylopyranose with a single laterally positioned 4-O-methyl-alpha-D-glucuronic acid] has been shown to inhibit the anticoagulant activity of high-affinity heparin as observed in plasma and when using purified enzyme and inhibitor. The activity was shown to be concentration-dependent with an apparent Ki of approx. 2 microM. The antiheparin property was not shown by a number of other anionic carbohydrates when tested. The rate of thrombin inhibition at 0.33 microM-heparin was reduced from 7.1 X 10(8) M-1 X min-1 in the absence of pentosan polysulphate to 2.3 X 10(8) M-1 X min-1 at 2 microM-pentosan polysulphate and to 0.3 X 10(8)M-1 X min-1 at 20 microM. Using the random bireactant model of heparin action [Griffiths (1982) J. Biol. Chem. 257, 13899-13902] it was observed that the pentosan polysulphate had no effect on the Km for antithrombin III (150 nM) but increased the Km for thrombin from 25 nM to 450 nM. A reduction in the inhibition rate by 17.3-fold predicted by substitution of these values into the general two-substrate reaction-rate equation was confirmed experimentally.
D000990:Antithrombin III / Q000378:metabolism; D001663:Bilirubin / Q000031:analogs & derivatives*; D001777:Blood Coagulation / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000494:pharmacology; D002850:Chromatography, Gel; D006493:Heparin / Q000494:pharmacology; D006494:Heparin Antagonists / Q000494:pharmacology*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D007700:Kinetics; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D011134:Polysaccharides / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism
D006494:Heparin Antagonists; D011134:Polysaccharides; C041079:cyclobilirubin; D010426:Pentosan Sulfuric Polyester; D000990:Antithrombin III; D006820:Hyaluronic Acid; D006493:Heparin; D002809:Chondroitin Sulfates; D013917:Thrombin; D001663:Bilirubin