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: Toshio Uemura, Tomihisa Kawasaki, Masatoshi Taniguchi, Yumiko Moritani, Kazumi Hayashi, Tetsu Saito, Jun Takasaki, Wataru Uchida, Keiji Miyata
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 148 Issue 1 Pg. 61-9 (May 2006) ISSN: 0007-1188 [Print] England
• PMID: 16520742 (Publication Type: Journal Article)

Chemical References

• Fibrinolytic Agents
• P-Selectin
• Peptides, Cyclic
• Platelet Aggregation Inhibitors
• Receptors, Thrombin
• YM-254890
• Adenosine Diphosphate
• Fibrinogen
• GTP-Binding Protein alpha Subunits, Gq-G11
• Calcium

Topics

• Adenosine Diphosphate
• Animals
• Blood Platelets (cytology, drug effects, metabolism)
• Calcium (metabolism)
• Cell Shape
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Femoral Artery (drug effects, physiopathology, surgery)
• Fibrinogen (metabolism)
• Fibrinolytic Agents (pharmacology)
• GTP-Binding Protein alpha Subunits, Gq-G11 (antagonists & inhibitors, 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, physiopathology, prevention & control)