y-20811 and Disease-Models--Animal

The effect of Y-20811, a selective thromboxane A2 synthetase inhibitor, was investigated on cerebral embolism using a new model of embolic cerebral infarction in rabbits. Most of cerebral infarctions were observed in the hemisphere, ipsilateral to the irradiated carotid artery. Cerebral infarction, ranging from 0.2 to 1.0 mm in size, appeared only on the surface of the cortex. The platelet emboli were identified in the carotid artery and cortex arteriole by light microscopy. In our study, 83% of the control group had cerebral infarction. Y-20811 significantly suppressed the infarction number and the incidence at doses of 1 mg/kg and 10 mg/kg (p.o.), respectively. Aspirin significantly inhibited the infarction number at a dose of 10 mg/kg, but its inhibitory effect decreased at 30 mg/kg. Ticlopidine showed no effect even at a dose of 300 mg/kg. These results indicate that Y-20811 may be useful in preventing embolic cerebral infarction and transient ischemic attacks.

Topics: Animals; Aspirin; Carotid Artery Thrombosis; Carotid Stenosis; Cerebral Infarction; Disease Models, Animal; Imidazoles; Intracranial Embolism and Thrombosis; Ligation; Male; Photochemistry; Platelet Aggregation; Rabbits; Rose Bengal; Thromboxane-A Synthase; Ticlopidine

We have already developed an arterial thrombosis model in the rat femoral artery which utilized photochemical reaction between systemically injected rose bengal and transillumination of a green light with 540 nm wave length from the outside of the vessel. In the present study, we applied this model to guinea-pigs in order to produce a more suitable thrombus model for evaluation of antithrombotic drugs which act on the prostaglandin cascade. In the guinea-pigs, the irradiated femoral artery was completely occluded in 7 min after the injection of rose bengal (10 mg/kg) in a similar manner to the rats. The processes of primary endothelial injury and the subsequent formation of thrombus during this manipulation were observed by the electron microscopy. Pretreatment with aspirin and Y-20811, a thromboxane synthetase inhibitor, significantly prolonged the time required for occlusion in the guinea-pigs, while these drugs were ineffective in the rats. The antithrombotic effect of vapiprost, a thromboxane A2 receptor antagonist, was more pronounced in the guinea-pigs than the rats. In conclusion, this model in guinea-pigs is more suitable for evaluating antithrombotic drugs, particularly, the action of which is exerted involving the prostaglandin cascade.

Topics: Animals; Aspirin; Biphenyl Compounds; Disease Models, Animal; Femoral Artery; Fibrinolytic Agents; Guinea Pigs; Heptanoic Acids; Imidazoles; Light; Male; Microscopy, Electron, Scanning; Photochemistry; Platelet Aggregation; Prostaglandins; Rats; Rats, Wistar; Rose Bengal; Thrombosis

The effects of Y-20811, a selective inhibitor of thromboxane A2 (TXA2) synthetase, on blood flow and local levels of immunoreactive thromboxane B2 (i-TXB2) and 6-keto prostaglandin F1 alpha (i-6-keto PGF1 alpha) in the coronary artery were investigated in the canine model of coronary thrombosis. Thrombosis was induced by applying an electric current to the intraluminal surface of the coronary artery. The plasma levels of i-TXB2 and i-6-keto PGF1 alpha were measured distal to the electrode. In the control group, coronary blood flow decreased and finally stopped 207 +/- 53 min (mean +/- S.E.M., n = 5) after the start of current application. The level of i-TXB2 rose before the coronary occlusion. Coronary blood flow did not change significantly in the Y-20811-treated group (1 mg/kg i.v.). The level of i-TXB2 decreased and remained significantly lower than that in the control group. The level of i-6-keto PGF1 alpha tended to increase slightly in the Y-20811-treated, but not in the control group. The weight of the thrombus in the Y-20811-treated group was significantly less than that in the control group (P less than 0.01). These results suggest that Y-20811 prevents coronary thrombosis by the inhibition of TXA2 production around the electrically injured lumen of the coronary artery.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Thrombosis; Disease Models, Animal; Dogs; Electric Stimulation; Imidazoles; Male; Thromboxane B2; Thromboxane-A Synthase