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

Summary

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 dose-dependently prolonged time to occlusion at doses of 3 and 10 μg/kg i.v. and decreased occlusion rate at 10 μg/kg i.v. In the thrombolysis study, YM-254890 at 30 μg/kg i.v. shortened the time to reperfusion and prevented reocclusion after thrombolysis with a modified tissue-type plasminogen activator. YM-254890, at 10 μg/kg and more, significantly improved carotid patency status after thrombolysis. However, at 30 μg/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.

Keywords

YM-254890 - a Gq/11 inhibitor - thrombosis - thrombolysis - rat

• References

• 1 Birnbaumer L. Receptor-to-effector signaling through G proteins: roles for beta gamma dimers as well as alpha subunits. Cell 1992; 71: 1069-72.
• 2 Clapham DE, Neer EJ. New roles for G-protein beta gamma-dimers in transmembrane signalling. Nature 1993; 365: 403-6.
• 3 Offermanns S. The role of heterotrimeric G proteins in platelet activation. Biol Chem 2000; 381: 389-96.
• 4 Gabbeta J, Yang X, Kowalska MA. et al. Platelet signal transduction defect with Galpha subunit dysfunction and diminished Galphaq in a patient with abnormal platelet responses. Proc Natl Acad Sci U S A 1997; 94: 8750-5.
• 5 Offermanns S, Toombs CF, Hu YH. et al. Defective platelet activation in G alpha(q)-deficient mice. Nature 1997; 389: 183-6.
• 6 Heximer SP, Watson N, Linder ME. et al. RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc Natl Acad Sci U S A 1997; 94: 14389-93.
• 7 Yan Y, Chi PP, Bourne HR. RGS4 inhibits Gq-mediated activation of mitogen-activated protein kinase and phosphoinositide synthesis. J Biol Chem 1997; 272: 11924-7.
• 8 Scheschonka A, Dessauer CW, Sinnarajah S. et al. RGS3 is a GTPase-activating protein for g(ialpha) and g(qalpha) and a potent inhibitor of signaling by GTPase-deficient forms of g(qalpha) and g(11alpha). Mol Pharmacol 2000; 58: 719-28.
• 9 Kawasaki T, Suzuki M, Katoh M. et al. Pharmacological action of and clinical experience with pamiteplase, a novel, modified, tissue-type plasminogen activator. In: New Therapeutic Agents in Thrombosis and Thrombolysis. 2nd edition. Sasahara AA, Loscalzo J. eds New York: Marcel Dekker Inc; 2002
• 10 Hladovec J. Experimental arterial thrombosis in rats with continuous registration. Thromb Diath Haemorrh 1971; 26: 407-10.
• 11 Kawasaki T, Kawamura S, Katoh S. et al. Experimental model of carotid artery thrombosis in rats and the thrombolytic activity of YM866, a novel modified tissue-type plasminogen activator. Jpn J Pharmacol 1993; 63: 135-42.
• 12 Schumacher WA, Steinbacher TE, Heran CL. et al. Effects of antithrombotic drugs in a rat model of aspirin-insensitive arterial thrombosis. Thromb Haemost 1993; 69: 509-14.
• 13 Kawasaki T, Sato K, Sakai Y. et al. Comparative studies of an orally-active factor Xa inhibitor, YM-60828, with other antithrombotic agents in a rat model of arterial thrombosis. Thromb Haemost 1998; 79: 410-6.
• 14 Kawasaki T, Kaku S, Kohinata T. et al. Inhibition by aurintricarboxylic acid of von Willebrand factor binding to platelet GPIb, platelet retention, and thrombus formation in vivo. Am J Hematol 1994; 47: 6-15.
• 15 Kawasaki T, Sato K, Hirayama F. et al. Effect of a synthetic factor Xa inhibitor, YM-60828, on blood vessel patency in combination with a thrombolytic agent and on blood loss from the operation site in a rat model of arterial thrombosis. Thromb Haemost 1998; 79: 859-64.
• 16 Kaida T, Matsuno H, Niwa M. et al. Antiplatelet effect of FK633, a platelet glyco-protein IIb/IIIa antagonist, on thrombus formation and vascular patency after thrombolysis in the injured hamster carotid artery. Thromb Haemost 1997; 77: 562-7.
• 17 Aoki T, Cox D, Senzaki K. et al. Comparison of the antithrombotic effects of FK633, GPIIb/IIIa antagonist, and aspirin in a guinea pig thrombosis model. Thromb Res 1998; 89: 129-36.
• 18 Ishii-Watabe A, Uchida E, Mizuguchi H. et al. On the mechanism of plasmin-induced platelet aggregation. Implications of the dual role of granule ADP. Biochem Pharmacol 2000; 59: 1345-55.
• 19 Offermanns S, Zhao LP, Gohla A. et al. Embryonic cardiomyocyte hypoplasia and craniofacial defects in G alpha q/G alpha 11-mutant mice. EMBO J 1998; 17: 4304-12.
• 20 Wilkie TM, Scherle PA, Strathmann MP. et al. Characterization of G-protein alpha subunits in the Gq class: expression in murine tissues and in stromal and hematopoietic cell lines. Proc Natl Acad Sci U S A 1991; 88: 10049-53.