Antithrombotic and thrombolytic efficacy of YM-254890, a G q/11 inhibitor, in a rat model of arterial thrombosis.
We examined the antithrombotic and thrombolytic effects of the G(q/11) inhibitor YM-254890 in an electrically-induced carotid artery thrombosis model in rats. YM-254890 dose-dependently inhibited ex vivo ADP-induced platelet aggregation after i.v. bolus injection. In the thrombosis study, YM-254890 dosedependently prolonged time to occlusion at doses of 3 and 10 g/kg i.v. and decreased occlusion rate at 10 g/kg i.v. In the thrombolysis study, YM-254890 at 30 micro g/kg i.v. shortened the time to reperfusion and prevented reocclusion after thrombolysis with a modified tissue-type plasminogen activator. YM-254890, at 10 micro g/kg and more, significantly improved carotid patency status after thrombolysis. However, at 30 micro g/kg and more, YM-254890 decreased systemic blood pressure. These results suggest that YM-254890 may be effective for treating G(q)-mediated diseases, and that YM-254890 is a useful tool for investigating the biological roles of G(q/11).
Kawasaki
Tomihisa
T
Cardiovascular Diseases Research, Pharmacology Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kawasat@yamanouchi.co.jp
Taniguchi
Masatoshi
M
Moritani
Yumiko
Y
Hayashi
Kazumi
K
Saito
Tetsu
T
Takasaki
Jun
J
Nagai
Koji
K
Inagaki
Osamu
O
Shikama
Hisataka
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D016896:Treatment Outcome; D014654:Vascular Patency / Q000187:drug effects
D005343:Fibrinolytic Agents; D010456:Peptides, Cyclic; C475455:YM-254890; D010959:Tissue Plasminogen Activator; D043802:GTP-Binding Protein alpha Subunits, Gq-G11