Premium
Biological properties of a specific G α q/11 inhibitor, YM‐254890, on platelet functions and thrombus formation under high‐shear stress
Author(s) -
Uemura Toshio,
Kawasaki Tomihisa,
Taniguchi Masatoshi,
Moritani Yumiko,
Hayashi Kazumi,
Saito Tetsu,
Takasaki Jun,
Uchida Wataru,
Miyata Keiji
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706711
Subject(s) - platelet , chemistry , platelet activation , thromboxane a2 , thrombus , thapsigargin , medicine , arachidonic acid , ristocetin , endocrinology , thrombin , pharmacology , biochemistry , intracellular , von willebrand factor , enzyme
1 The effects of YM‐254890, a specific G α 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 μ M . 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 μ M , 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 μ M , 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 G α q/11 ‐coupled receptor signaling and the physiological roles of G α q/11 .British Journal of Pharmacology (2006) 148 , 61–69. doi: 10.1038/sj.bjp.0706711