We examined the inhibitory effects of a novel antiplatelet aggregating agent, E-5510, on cyclic flow variations (CFVs) of coronary blood flow (CBF) in anesthetized open-chest pigs. These CFVs, which are characterized by progressive declines in CBF followed by sudden restoration of flow, were initiated by electrical stimulation of the intimal surface of the left circumflex coronary artery (LCX). A reduction in CBF to zero during CFVs was accompanied by ischemic changes in the surface electrocardiogram and regional segment shortening of the left ventricular wall. Occlusive thrombi were detected postmortem in the coronary arteries of the animals in which CFVs had occurred. After CFVs had been observed for 1 h, E-5510 (0.01 or 0.1 mg/kg) or saline was administered intravenously. Once CFVs were initiated, both the frequency and the severity (the mean of the three lowest nadirs of CBF) were unchanged by the administration of saline. E-5510 at 0.01 mg/kg decreased the frequency of CFVs from 7.7 ± 0.9 to 4.6 ± 1.1 CFVs/h (n =7, p < 0.05), and increased the mean lowest nadir from 13.5 ± 5.2% of the CBF level before electrical stimulation to 54.3 ± 11.1% (n = 7, p < 0.01). E-5510 at 0.1 mg/kg further decreased the frequency from 8.9 ± 0.7 to 2.4 ± 0.5 CFVs/h (n = 9, p < 0.01), and increased the mean lowest nadir from 14.3 ± 3.2% to 53.6 ± 10.8% (n = 9, p < 0.01). E-5510, however, showed no ameliorative effect on ischemia-induced myocardial dysfunction, as expressed by the decrease in regional myocardial shortening. Collagen-induced platelet aggregation was significantly (p < 0.01) inhibited in the platelet-rich plasma of the blood taken at 15 and 60 min after the administration of either dose of E-5510. These results indicate that E- 5510 had a potent antiplatelet aggregating effect in this in vivo model, and suggest its potential benefits in treating coronary artery thrombosis
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