Enhancement of endogenous plasminogen activator-induced thrombolysis by argatroban and APC and its control by TAFI, measured in an arterial thrombolysis model in vivo using rat mesenteric arterioles.
Recent in vitro studies have demonstrated that thrombin inhibits fibrinolysis through thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B). We have recently shown that endogenous fibrinolysis in vivo is enhanced by activated protein C (APC) and the selective thrombin inhibitor, argatroban. The aim of the present study was to examine the role of TAFI in these fibrinolytic mechanisms in vivo using purified porcine pancreatic carboxypeptidase B (PPCPB) and a specific TAFIa inhibitor, potato tuber carboxypeptidase B inhibitor (PTCI) in a newly established arterial thrombolysis model. Non-occlusive, mural, platelet-rich thrombi were formed by helium-neon laser irradiation in rat mesenteric arterioles and thrombus size was measured by computerised image analysis. We confirmed that endogenous thrombolysis was enhanced by argatroban (2.0 mg/4 ml/kg/h) or APC (1.62 mg/ 2.31 ml/kg). PTCI (5.0 mg/2 ml/kg) also accelerated endogenous thrombolysis. PPCPB (3.5 mg/2 ml/kg) inhibited thrombolysis in the absence and presence of argatroban or APC. PTCI tended to further promote APC-induced thrombolysis but the differences did not reach statistical significance. The present findings were in keeping with the results of earlier studies and demonstrated that arterial, platelet-rich thrombi in vivo are degraded by naturally generated plasminogen activators. TAFI may play a significant role in the control of these mechanisms.
Hashimoto
Masaru
M
Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University and Kobe Gakuin University High Technology Research Centre, Japan.
Yamashita
Tsutomu
T
Oiwa
Kazuhiro
K
Watanabe
Sadahiro
S
Giddings
John C
JC
Yamamoto
Junichiro
J
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001157:Arterial Occlusive Diseases / Q000097:blood* / Q000209:etiology; D001160:Arterioles; D001667:Binding, Competitive; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D007834:Lasers / Q000009:adverse effects; D008297:Male; D008638:Mesenteric Arteries; D023421:Models, Animal; D010875:Pipecolic Acids / Q000494:pharmacology*; D010940:Plant Proteins / Q000494:pharmacology; D010960:Plasminogen Activators / Q000502:physiology*; D011480:Protease Inhibitors; D011486:Protein C / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013449:Sulfonamides; D013552:Swine; D013927:Thrombosis / Q000097:blood* / Q000209:etiology
D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D010875:Pipecolic Acids; D010940:Plant Proteins; D011480:Protease Inhibitors; D011486:Protein C; D013449:Sulfonamides; D001120:Arginine; D025901:Carboxypeptidase B2; D010960:Plasminogen Activators; C031942:argatroban