Molecular events involved in the proaggregating effect of heparin on human platelets.
Molecular mechanisms underlying the ability of heparin to enhance the platelet-aggregating effect of various agonists were studied. Heparin potentiates the aggregating effect of adenosine diphosphate (ADP) and epinephrine, but it is uneffective on the aggregation induced by ristocetin and collagen. Heparin inhibits aggregation induced by thrombin in the presence of plasma, but it is uneffective, or sometimes stimulates aggregation, in the absence of plasma. The effects on the platelet-activating factor- (PAF-acether) induced aggregation are very variable. The late phase of the ADP-induced aggregation is sensitive to proteinase inhibitors, but heparin overcomes this inhibitory effect. Drugs which inhibit remodeling of membrane phospholipids abolish the potentiating effect of heparin, while cyclooxygenase inhibitors do not. The proaggregating effect of heparin subfractions correlates with the lipoprotein lipase activity and, slightly, with the molecular weight, but it does not correlate with the anticoagulant activity. Platelets prelabelled with phosphatidyl[U14C]inositol show a very rapid effect of heparin in triggering phosphatidylinositor breakdown and a cooperative effect with ADP, a known agonist of the 'phosphatidylinositol cycle'. Heparin is also effective in stimulating the labelling of polyphosphoinositides in platelets prelabelled with 32Pi. These results, together with the selective sensitivity to drugs, lead to the conclusion that a stimulatory effect on the very early events of remodeling of membrane phospholipids is involved in the platelet proaggregating effect of heparin.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D010716:Phosphatidylinositols / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*
D010716:Phosphatidylinositols; D000244:Adenosine Diphosphate; D006493:Heparin; D004837:Epinephrine