Antithrombotic and thrombolytic efficacy of YM-254890, a G q/11 inhibitor, in a rat model of arterial thrombosis

Thromb Haemost. 2003 Sep;90(3):406-13. doi: 10.1160/TH03-02-0115.

Abstract

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).

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Carotid Artery Diseases / drug therapy
  • Carotid Artery Diseases / prevention & control
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Drug Therapy, Combination
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / pharmacology*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / antagonists & inhibitors*
  • Peptides, Cyclic / administration & dosage
  • Peptides, Cyclic / therapeutic use*
  • Platelet Aggregation / drug effects
  • Rats
  • Thrombolytic Therapy / methods*
  • Thrombosis / drug therapy*
  • Thrombosis / prevention & control
  • Tissue Plasminogen Activator / pharmacology
  • Treatment Outcome
  • Vascular Patency / drug effects

Substances

  • Fibrinolytic Agents
  • Peptides, Cyclic
  • YM-254890
  • Tissue Plasminogen Activator
  • GTP-Binding Protein alpha Subunits, Gq-G11