title: 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.
abstract: 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.
authors.affiliation: Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University and Kobe Gakuin University High Technology Research Centre, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oiwa
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Watanabe
authors.forename: John C
authors.initials: JC
authors.lastname: Giddings
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yamamoto
mesh_terms: 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
chemical_list: 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