Anti-thrombotic effect of a PAI-1 inhibitor in rats given endotoxin.
The aim of this study was to investigate the anti-thrombotic effects of an inhibitor of the plasminogen activator inhibitor-1 (PAI-1) in rats given endotoxin. In studies in vitro, PRAP-1, a Fab-fragment of a polyclonal antibody against human PAI-1, was shown to inhibit PAI-1 activity in rat plasma as well as to stimulate clot-lysis of the euglobulin fraction derived from rat plasma. Endotoxin administered to anaesthetised rats produced a marked increase in plasma PAI-1 activity. To study fibrin formation and lysis in vivo after intravenous (i.v.) injection of the coagulant enzyme batroxobin, 125I-fibrinogen was administered to the animals. The thrombi formed by batroxobin were rapidly lysed in control animals, while the rate of lysis was markedly attenuated in rats given endotoxin. PRAP-1 was administered i.v. (bolus+infusion) to rats given endotoxin and batroxobin and the PAI-1 inhibitor caused a dose-dependent decrease in the 125I-fibrin deposition in the lungs. An immunohistochemical technique was used to confirm this decrease in density of fibrin clots in the tissue. Furthermore, PRAP-1 decreased plasma PAI-1 activity in the rats and this reduction was correlated to the decrease in lung 125I-fibrin deposition at the corresponding time point. It is concluded that in this experimental model the PAI-1 antibody PRAP-1 may indeed inhibit thrombosis in animals exposed to endotoxin.
Abrahamsson
T
T
Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden.
Nerme
V
V
Strömqvist
M
M
Akerblom
B
B
Legnehed
A
A
Pettersson
K
K
Westin Eriksson
A
A
D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D012103:Batroxobin; D004731:Endotoxins / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008297:Male; D017395:Plasminogen Activator Inhibitor 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D014148:Tranexamic Acid / Q000494:pharmacology
D000933:Antifibrinolytic Agents; D004731:Endotoxins; D005343:Fibrinolytic Agents; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D014148:Tranexamic Acid; D012103:Batroxobin