Preventive Effect of Chronic Endothelin Type A Receptor Antagonist on Coronary Microvascular Spasm Induced by Repeated Epicardial Coronary Artery Endothelial Denudation in Pigs

Aim: We investigated the role of endothelin-1 (ET-1) in coronary microvascular spasm in a porcine model. Methods: A flowmeter was implanted around the left anterior descending coronary artery (LAD), and epicardial coronary artery endothelial denudation (ED) was performed just distal to the flowmeter every 2 weeks (W) until 6 W in 10 pigs (ED group). Ten pigs were chronically treated with endothelia type A receptor (ETA) antagonist (TA-0201, 0.1 mg/kg/day, ED + ETA group), while neither ED nor administration of ETA antagonist was performed in 12 pigs (Control group). We assessed changes in LAD blood flow and the denuded site diameter induced by acetylcholine (ACh, 0.05 mu g/kg i.c.). Results: In the ED group, administration of ACh to LAD induced zero flow without LAD diameter reduction at 8 W In the ED + ETA group, the decrease in LAD blood flow response to ACh was suppressed. Chronic administration of TA-0201 suppressed ROS generation in the myocardium. Decreases of eNOS and intimal thickening were smaller in the TA-0201 administration group than the non-TA-0201 administration group. Conclusion: Chronic administration of ETA receptor antagonist is effective to prevent coronary microvascular spasm.