Endothelin-1 production in coronary circulation in a new canine model of coronary thrombosis

Objective: The purpose of this study was to investigate whether endogenous endothelin-1 (ET-1) production in coronary circulation is associated with acute coronary thrombotic events in vivo. To achieve this goal, we have designed a new experimental canine model of coronary thrombosis. Methods: In vivo occlusive thrombus was induced by the intracoronary application of radiofrequency energy (660 kHz, 50 W) in closed-chest dogs. Pathological and immunohistochemical examinations of thrombosed coronary artery were performed. In 12 dogs, plasminogen activator was administered intravenously and serial measurements of ET-1, thromboxane B2 (TXB2) and thrombin-antithrombin HI complex (TAT) levels in plasma from the coronary sinus, aortic root and inferior vena cava were examined. Results: Occlusive platelet-rich thrombi were attached to the deeply injured intimal surface. TAT and TXB2 increased rapidly soon after the intimal injury and declined after successful thrombolysis. In contrast, ET-1 in the coronary sinus was elevated after reperfusion and was significantly higher than in the aorta. Net ET-1 production in the coronary circulation showed a significant positive correlation with the peak TAT levels ( r = 0.69, P < 0.05), but not with TXBf2 or total occlusion time as an index of ischemic severity. Conclusions: Deep intimal injury leads to occlusive coronary thrombus. Thrombus formation and its subsequent lysis is associated with the activation and deactivation, respectively, of the coagulation cascade and platelets. Thrombin generation may stimulate ET-1 production in the coronary endothelium in acute coronary thrombotic events.