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 N(G)-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. Chemicals/CAS: 2 (3,4 dihydro 3,4 dioxo 1 naphthylamino)benzoic acid methyl ester, 114832-13-2; 3 [3 tert butylthio 1 (4 chlorobenzyl) 5 isopropyl 2 indolyl] 2,2 dimethylpropionic acid, 118414-82-7; 3 amino 1 (3 trifluoromethylphenyl) 2 pyrazoline, 66000-40-6; acetylsalicylic acid, 493-53-8, 50-78-2, 53663-74-4, 53664-49-6, 63781-77-1; cycloheximide, 642-81-9, 66-81-9; dexamethasone, 50-02-2; diltiazem, 33286-22-5, 42399-41-7; forskolin, 66575-29-9; ginkgolide B, 15291-77-7, 99796-69-7; heparin, 37187-54-5, 8057-48-5, 8065-01-8, 9005-48-5; hirudin, 8001-27-2; indometacin, 53-86-1, 74252-25-8, 7681-54-1; isobutylmethylxanthine, 28822-58-4; mepyramine maleate, 59-33-6; n [3 (3 phenoxyphenyl)allyl]acetohydroxamic acid, 106328-57-8; n(g) nitroarginine methyl ester, 50903-99-6; naloxone, 357-08-4, 465-65-6; phentolamine mesylate, 65-28-1; phentolamine, 50-60-2, 73-05-2; plasminogen activator inhibitor, 105844-41-5; propranolol, 13013-17-7, 318-98-9, 3506-09-0, 4199-09-1, 525-66-6; verapamil, 152-11-4, 52-53-9; 1-Methyl-3-isobutylxanthine, 28822-58-4; Aspirin, 50-78-2; BW-755C, 66000-40-6; Indomethacin, 53-86-1; Lipopolysaccharides; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator, EC 3.4.21.6