title: Pharmacological properties of YM-254890, a specific G(alpha)q/11 inhibitor, on thrombosis and neointima formation in mice.
abstract: The pharmacological properties of YM-254890, a specific G(alpha)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 G(alpha)q/11 .
authors.affiliation: Pharmacology Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. tomihisa.kawasaki@jp.astellas.com
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Moritani
authors.forename: Toshio
authors.initials: T
authors.lastname: Uemura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shigenaga
authors.forename: Hajime
authors.initials: H
authors.lastname: Takamatsu
authors.forename: Kazumi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Jun
authors.initials: J
authors.lastname: Takasaki
authors.forename: Tetsu
authors.initials: T
authors.lastname: Saito
authors.forename: Koji
authors.initials: K
authors.lastname: Nagai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure; D002339:Carotid Arteries / Q000473:pathology; D049109:Cell Proliferation; D002712:Chlorides; D002867:Chromones / Q000494:pharmacology; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors*; D006339:Heart Rate; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008956:Models, Chemical; D009025:Morpholines / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010974:Platelet Aggregation; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology
chemical_list: D002712:Chlorides; D002867:Chromones; D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D009025:Morpholines; D010456:Peptides, Cyclic; C475455:YM-254890; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077144:Clopidogrel; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D013988:Ticlopidine; C024555:ferric chloride