Pharmacological modulation of the endotoxin-induced increase in plasminogen activator inhibitor activity in rats.
Pharmacological modulation of the in vivo induction of plasminogen activator inhibitor type-1 (PAI-1) synthesis was studied in rats using the induction of PAI-1 by endotoxin as a model system. Both the cyclooxygenase inhibitors acetylsalicylic acid and indomethacin enhanced PAI-1 induction. The combined cyclooxygenase-lipoxygenase inhibitor, BW755C, dose-dependently inhibited induction. Since five other lipoxygenase inhibitors, a phospholipase inhibitor, an inhibitor of leukotriene formation and dexamethasone had no effect on the endotoxin-induced increase in PAI-1 synthesis, the effect of BW755C could not be ascribed to its known pharmacological properties. In addition, induction of PAI was enhanced by isobutyl-methylxanthine, a phosphodiesterase inhibitor, but not, however, by other phosphodiesterase inhibitors, or by forskolin or NG-nitro-L-arginine, suggesting an effect of isobutyl-methylxanthine other than through cyclic nucleotides. Heparin and hirudin had no effect either. Overall, the data showed that the induction of PAI-1 synthesis by endotoxin in vivo can be up- and down-regulated pharmacologically, but the mechanisms involved remain elusive.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology*; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D010959:Tissue Plasminogen Activator / Q000032:analysis
D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D010959:Tissue Plasminogen Activator; D001241:Aspirin; D015056:1-Methyl-3-isobutylxanthine; D007213:Indomethacin