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

Abstract

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 endothelin type A receptor (ET_A) antagonist (TA-0201, 0.1 mg/kg/day, ED+ET_A group), while neither ED nor administration of ET_A 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 μg/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+ET_A 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 ET_A receptor antagonist is effective to prevent coronary microvascular spasm.