Antithrombotic Activity of an Indolinone Derivative – a Soluble Guanylate Cyclase Stimulator

Abstract

Introduction. The article presents the results of studying the antithrombotic activity of a novel drug, a soluble guanylate cyclase stimulator (codename – GRS), in experimental models of arterial and venous thrombosis and thromboembolism.Aim. Study the antithrombotic action of GRS compound in comparison with clopidogrel and rivaroxaban in the following models: arterial thrombosis induced by iron chloride application to carotid artery wall in rats; thromboembolism induced by intravenous administration of thrombin solution in mice; venous thrombosis induced by the ligature of inferior vena cava in rats.Materials and methods. Arterial thrombosis was modelled in rats by applying a pad soaked in iron chloride (FeCl3) to the carotid artery, GRS compound was administered orally in median effective dose of 10 mg/kg once 3 hours before pad application. Blood flow in carotid arteries and blood clot mass were registered. Thromboembolism was induced in mice by intravenous administration of thrombin solution, GRS in dose 10 mg/kg or the reference drug clopidogrel were administered once orally daily for 3 days. Animal mortality, survival time and blood clot size were registered. Venous thrombosis was induced in rats by the ligature of inferior vena cava below renal veins, GRS in dose 10 mg/kg, reference drug rivaroxaban in 5 mg/kg dose or their combination in these doses were administered once orally 1 hour before vein ligature. The mass of dry and wet blood clots was registered.Results and discussion. In arterial thrombosis model GRS compound in 10 mg/kg, administered 3 hours before iron chloride application, increased the time to blood flow cessation in the carotid artery by 35 % and reduced the frequency of complete artery occlusion by 2 times compared to the control group (р < 0.05). 60 min after arterial thrombosis modelling complete occlusion was observed in 28 % of animals in GRS group and in 75 % of control animals, while after 24 hours the occlusion was observed in 14 % of animals in GRS group and in 50 % of control group animals (p < 0.05). In thrombin-induced thromboembolism model in mice GRS did not reduce the size of blood clots in pulmonary vessels, while clopidogrel reduced it by 48 %. In GRS group 80 % of animals died of thrombosis, compared to 30 % in clopidogrel group and 90 % in the control group. In ligature-induced venous thrombosis in rats GRS after single oral administration reduced the mass of dry blood clot, being as potent as rivaroxaban. Combined administration of GRS and rivaroxaban did not enhance their antithrombotic action.Conclusion. GRS after single oral administration in 10 mg/kg dose had potent antithrombotic action in models of arterial and venous thrombosis in rats, while not preventing pulmonary vessel thrombosis in mice after thrombin administration. Therapeutic action of GRS in experimental venous thrombosis was as potent as that of rivaroxaban. Antithrombotic action of GRS compound results not only from its antiplatelet action, but also from the alleviation of endothelial dysfunction in arteries and veins.

Keywords

• indolinone derivative
• guanylate cyclase stimulator
• rivaroxaban
• clopidogrel
• models of arterial and venous thrombosis and thromboembolism