Function of tissue-type plasminogen activator releaser on vascular endothelial cells and thrombolysis in vivo.
The effect of monosodium[2-(6-hydroxynaphthalen-2-yl)-6-methylpyrimidin-4-yloxy]acetate dihydrate (JTV-926) on fibrinolysis was investigated in vitro and in vivo. JTV-926 released tissue-type plasminogen activator (t-PA) from human vascular endothelial cells in a dose-dependent manner. The thrombolytic effect of JTV-926 was studied using three animal thrombosis models; a photo-irradiation-induced mouse carotid artery thrombosis model, a photo-irradiation-induced rat femoral artery thrombosis model and a thrombin-induced rat venous thrombosis model. In the mouse thrombosis model, t-PA deficient mice (t-PA-/- mice) and their wild-type (t-PA+/+) were used. JTV-926 was injected as a bolus 30 min after the interruption of blood flow by an occlusion thrombi. Blood flow was continuously monitored for 180 min after intravenous administration of JTV-926 (1 mg/kg). Although the recanalization rate of the occluded artery was 37.5% in t-PA +/+ mice with the vehicle control, it increased to 75% in t-PA+/+ mice after JTV-926 administration. However, when JTV-926 was administrated in t-PA-/- mice, vascular recanalization was not observed in any arteries. In the photo-irradiation-induced rat femoral artery thrombosis model, intra-duodenal administration of JTV-926 induced thrombolysis. Moreover, in the thrombin-induced rat venous thrombosis model, the dose-dependent thrombolysis was also observed by oral administration of JTV-926. It was suggested that JTV-926 revealed a sufficient thrombolytic effect through the absorption from the intestine. Thus, a newly synthesized compound, JTV-926 induced t-PA release from vascular endothelial cells and effective thrombolysis in vivo.
Ueshima
Shigeru
S
Department of Physiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan. sueshima@med.kindai.ac.jp
Matsuno
Hiroyuki
H
Hayashi
Mikio
M
Horibuchi
Koji
K
Okada
Kiyotaka
K
Fukao
Hideharu
H
Uematsu
Toshihiko
T
Matsuo
Osamu
O
D000284:Administration, Oral; D000818:Animals; D002339:Carotid Arteries; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005263:Femoral Artery; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009284:Naphthols / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000628:therapy; D010959:Tissue Plasminogen Activator / Q000187:drug effects / Q000378:metabolism*; D014471:Umbilical Veins; D020246:Venous Thrombosis / Q000628:therapy
D005343:Fibrinolytic Agents; D009284:Naphthols; D011743:Pyrimidines; C476539:monosodium(2-(6-hydroxynaphthalen-2-yl)-6-methylpyrimidin-4-yloxy)acetate dihydrate; D010959:Tissue Plasminogen Activator