2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and Thromboembolism

The process of rejection of skin first-set-allograft transplantation was pursued by observing the microcirculation of living mice, in comparison with that of the isograft transplantation (BALB/C vs. BALB/C). The vascular connection of the skin allograft between the host (BALB/C) and graft (R III) was established on day 8, in just the same pattern as in isograft skin, but the blood flow slowed down on day 9, and the formation of microthrombi was observed in the arterioles and later in the venules and capillaries at the sites slightly inside the graft from the margin on day 10. Thereafter each small vessel of the host formed a loop and the blood flow from the host did not enter the graft. The thrombus formation was confirmed by light and electron microscopy. The importance of the thrombus formation in the rejection process was further strengthened by prolongation of the cessation of the blood flow at the boundary from day 10 to days 14-15, after daily administration from days 2 to 9 of OKY-1581 (0.4 mg/g i.p.), a selective thromboxane synthetase inhibitor, or ticlopidine (0.3 mg/10 g p.o.), an inhibitor of platelet aggregation, in combination with a subthreshold dose (0.4 mg/10 g i.p.) of azathioprine. None of these drugs alone significantly prolonged the survival time.

Topics: Acrylates; Animals; Arterioles; Azathioprine; Blood Platelets; Capillaries; Graft Occlusion, Vascular; Graft Rejection; Graft Survival; Male; Methacrylates; Mice; Mice, Inbred BALB C; Microscopy, Electron; Skin; Skin Transplantation; Thiophenes; Thromboembolism; Thromboxane-A Synthase; Ticlopidine; Transplantation, Homologous; Transplantation, Isogeneic; Venules

We present a simple method for screening antithrombotic agents. When male Swiss-Webster mice (25-34 g; N = 143) were given an i.v. injection of 0.1 ml of a mixture of collagen (dose, 15 micrograms/mouse) and epinephrine (dose, 1.8 micrograms/mouse), 94% died within 5 min or remained paralyzed for more than 15 min. Examples of the use of the system for the study of antithrombotic agents are given. Solutions of agents were administered to the animals i.p. about 1 hr before the thrombotic challenge. Aspirin (20 mg/kg), OKY-1581 (30 mg/kg) and ethanol (2 gm/kg), administered as single agents in aqueous medium, protected (P less than .01, chi 2 test) 40, 50 and 35% of the animals, respectively. Heparin (150 U/kg) was ineffective. Combinations of ethanol with indomethacin or indobufen provided complete protection, whereas ethanol plus aspirin protected 84% of the animals and ethanol plus OKY-1581 protected 70% of the animals. Dipyridamole alone (3 mg/kg), dipyridamole (1.65 mg/kg) plus ethanol or dipyridamole (1.65 mg/kg) plus aspirin were ineffective. The method appears well suited for screening potential antithrombotic agents which act primarily against platelet thromboembolism.

Topics: Adenosine Triphosphate; Animals; Aspirin; Collagen; Disease Models, Animal; Drug Synergism; Epinephrine; Ethanol; Fibrinolytic Agents; Male; Methacrylates; Mice; Platelet Aggregation; Thromboembolism