Pharmacological properties of YM-254890, a specific Gαq/11 inhibitor, on thrombosis and neointima formation in mice

Tomihisa Kawasaki; Masatoshi Taniguchi; Yumiko Moritani; Toshio Uemura; Takeshi Shigenaga; Hajime Takamatsu; Kazumi Hayashi; Jun Takasaki; Tetsu Saito; Koji Nagai

doi:10.1160/TH04-09-0635

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(01): 184-192
DOI: 10.1160/TH04-09-0635

Cell Signalling and Vessel Remodelling

Schattauer GmbH

Pharmacological properties of YM-254890, a specific Gα_q/11 inhibitor, on thrombosis and neointima formation in mice

Tomihisa Kawasaki

¹Pharmacology Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Masatoshi Taniguchi

²Fermentation Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Yumiko Moritani

¹Pharmacology Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Toshio Uemura

¹Pharmacology Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Takeshi Shigenaga

¹Pharmacology Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Hajime Takamatsu

¹Pharmacology Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Kazumi Hayashi

¹Pharmacology Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Jun Takasaki

³Molecular Medicine Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Tetsu Saito

³Molecular Medicine Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

,

Koji Nagai

²Fermentation Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

› Author Affiliations

Abstract

Summary

The pharmacological properties of YM-254890,a specific Gα_q/11 inhibitor, on acute thrombosis and chronic neointima formation after vascular injury have been investigated. FeCl₃ was used to induce vascular injury in the carotid artery of mice. For the thrombosis studies, the test drug was either intravenously or orally administered before vascular injury. For the neointima studies, the test drug was orally administered 1 h before and twice daily for 1 week after vascular injury. Histological analysis was then performed 3 weeks later. YM-254890 significantly inhibited ex vivo platelet aggregation 5 min after intravenous bolus injection at 0.03 mg/kg or more, and 1 h after oral administration at 1 mg/kg. YM-254890 significantly inhibited thrombus formation after intravenous bolus injection at 0.03 mg/kg as well as after oral administration at 1 mg/kg, but tail transection bleeding time was significantly prolonged at 0.1 mg/kg for intravenous injection and 3 mg/kg for oral administration. Furthermore, oral administration of YM-254890 dose-dependently inhibited neointima formation 3 weeks after vascular injury with significant effects at 1 mg/kg twice daily for 1 week. Clopidogrel also significantly inhibited neointima formation at its antithrombotic dose, but its inhibitory potency was less than that of YM-254890. However, YM-254890 significantly reduced systemic blood pressure at doses 3 times higher than those that produced significant inhibitory effects on thrombosis and neointima formation. Though the systemic use of YM-254890 may be limited, owing to its narrow therapeutic window, this unique compound is a useful research tool for investigating the physiological roles of Gα_q/11.

Keywords

Bleeding time - Gα_q/11 inhibitor - neointima formation - platelets - thrombosis

Full Text

References

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