title: Biological properties of a specific Galpha q/11 inhibitor, YM-254890, on platelet functions and thrombus formation under high-shear stress.
abstract: 1 The effects of YM-254890, a specific Galpha(q/11) inhibitor, on platelet functions, thrombus formation under high-shear rate condition and femoral artery thrombosis in cynomolgus monkeys were investigated. 2 YM-254890 concentration dependently inhibited ADP-induced intracellular Ca(2+) elevation, with an IC(50) value of 0.92+/-0.28 microM. 3 P-selectin expression induced by ADP or thrombin receptor agonist peptide (TRAP) was strongly inhibited by YM-254890, with IC(50) values of 0.51+/-0.02 and 0.16+/-0.08 microM, respectively. 4 YM-254890 had no effect on the binding of fibrinogen to purified GPIIb/IIIa, but strongly inhibited binding to TRAP-stimulated washed platelets. 5 YM-254890 completely inhibited platelet shape change induced by ADP, but not that induced by collagen, TRAP, arachidonic acid, U46619 or A23187. 6 YM-254890 attenuated ADP-, collagen-, TRAP-, arachidonic acid- and U46619-induced platelet aggregation with IC(50) values of <1 microM, whereas it had no effect on phorbol 12-myristate 13-acetate-, ristocetin-, thapsigargin- or A23187-induced platelet aggregation. 7 High-shear stress-induced platelet aggregation and platelet-rich thrombus formation on a collagen surface under high-shear flow conditions were concentration dependently inhibited by YM-254890. 8 The antithrombotic effect of YM-254890 was evaluated in a model of cyclic flow reductions in the femoral artery of cynomolgus monkeys. The intravenous bolus injection of YM-254890 dose dependently inhibited recurrent thrombosis without affecting systemic blood pressure or prolonging template bleeding time. 9 YM-254890 is a useful tool for investigating Galpha(q/11)-coupled receptor signaling and the physiological roles of Galpha(q/11).
authors.affiliation: Institute for Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. toshio.uemura@jp.astellas.com
authors.forename: Toshio
authors.initials: T
authors.lastname: Uemura
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: Kazumi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Tetsu
authors.initials: T
authors.lastname: Saito
authors.forename: Jun
authors.initials: J
authors.lastname: Takasaki
authors.forename: Wataru
authors.initials: W
authors.lastname: Uchida
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyata
mesh_terms: D000244:Adenosine Diphosphate; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D048430:Cell Shape; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005263:Femoral Artery / Q000187:drug effects* / Q000503:physiopathology / Q000601:surgery; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008026:Ligation; D008252:Macaca fascicularis; D019007:P-Selectin / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D018179:Receptors, Thrombin; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013927:Thrombosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D005343:Fibrinolytic Agents; D019007:P-Selectin; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D018179:Receptors, Thrombin; C475455:YM-254890; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium