Pharmacological modulation of the endotoxin-induced increase in plasminogen activator inhibitor activity in rats

• Published in: Blood coagulation & fibrinolysis Vol. 3; no. 5; p. 575
• Main Authors: Emeis, J J, Van den Hoogen, C M
• Format: Journal Article
• Language: English
• Published: England 01.10.1992
• Subjects: 1-Methyl-3-isobutylxanthine - pharmacology; 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine - pharmacology; Animals; Aspirin - pharmacology; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Indomethacin - pharmacology; Lipopolysaccharides - administration & dosage; Male; Plasminogen Activator Inhibitor 1 - metabolism; Rats; Rats, Wistar; Tissue Plasminogen Activator - analysis
• ISSN: 0957-5235; 1473-5733
• DOI: 10.1097/00001721-199210000-00008

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.