Biological properties of a specific Galpha q/11 inhibitor, YM-254890, on platelet functions and thrombus formation under high-shear stress

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,...

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Published in:British journal of pharmacology 2006-05, Vol.148 (1), p.61-69
Main Authors: Uemura, Toshio, Kawasaki, Tomihisa, Taniguchi, Masatoshi, Moritani, Yumiko, Hayashi, Kazumi, Saito, Tetsu, Takasaki, Jun, Uchida, Wataru, Miyata, Keiji
Format: Article
Language:English
Subjects:
Adenosine Diphosphate
Animals
Blood Platelets - cytology
Blood Platelets - drug effects
Blood Platelets - metabolism
Calcium - metabolism
Cell Shape
Disease Models, Animal
Dose-Response Relationship, Drug
Female
Femoral Artery - drug effects
Femoral Artery - physiopathology
Femoral Artery - surgery
Fibrinogen - metabolism
Fibrinolytic Agents - pharmacology
GTP-Binding Protein alpha Subunits, Gq-G11 - antagonists & inhibitors
GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism
Ligation
Macaca fascicularis
P-Selectin - metabolism
Peptides, Cyclic - pharmacology
Platelet Aggregation
Platelet Aggregation Inhibitors - pharmacology
Receptors, Thrombin
Regional Blood Flow
Stress, Mechanical
Thrombosis - metabolism
Thrombosis - physiopathology
Thrombosis - prevention & control
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Summary: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
ISSN:0007-1188