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).