Function of Tissue-type Plasminogen Activator Releaser on Vascular Endothelial Cells and Thrombolysis In Vivo

Shigeru Ueshima; Hiroyuki Matsuno; Mikio Hayashi; Koji Horibuchi; Kiyotaka Okada; Hideharu Fukao; Toshihiko Uematsu; Osamu Matsuo

doi:10.1055/s-0037-1613134

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 87(06): 1069-1074
DOI: 10.1055/s-0037-1613134

Review Article

Schattauer GmbH

Function of Tissue-type Plasminogen Activator Releaser on Vascular Endothelial Cells and Thrombolysis In Vivo

Shigeru Ueshima

¹Department of Physiology, Kinki University School of Medicine, Osakasayama, Japan

,

Hiroyuki Matsuno

¹Department of Physiology, Kinki University School of Medicine, Osakasayama, Japan

²Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan

,

Mikio Hayashi

³Central Pharmaceutical Research Institute, Japan Tobacco Inc. Takatsuki, Japan

,

Koji Horibuchi

³Central Pharmaceutical Research Institute, Japan Tobacco Inc. Takatsuki, Japan

,

Kiyotaka Okada

¹Department of Physiology, Kinki University School of Medicine, Osakasayama, Japan

,

Hideharu Fukao

¹Department of Physiology, Kinki University School of Medicine, Osakasayama, Japan

,

Toshihiko Uematsu

²Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan

,

Osamu Matsuo

¹Department of Physiology, Kinki University School of Medicine, Osakasayama, Japan

› Author Affiliations

Abstract

Summary

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.

Keywords

Endothelial cells - t-PA - thrombolysis - t-PA deficient mice - animal model

Full Text

References

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