Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905, USA.
Circulation. 2010 Sep 7;122(10):958-66. doi: 10.1161/CIRCULATIONAHA.110.967406. Epub 2010 Aug 23.
Endothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET(A)) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis.
Forty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET(A) receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10(-6) to 10(-4) mol/L) in the left anterior descending coronary artery. N(G)-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus -2.22%, 95% confidence interval -27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N(G)-monomethyl-l-arginine were similar between the groups at baseline and at 6 months.
This study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.
内皮素（ET-1）是最强的血管收缩剂之一，在动脉粥样硬化的发病机制中起着重要作用。本研究旨在检验长期使用内皮素 A（ET(A)）受体拮抗剂是否能改善早期冠状动脉粥样硬化患者的冠状动脉内皮功能的假说。
47 名患有多种心血管危险因素、非阻塞性冠状动脉疾病和冠状动脉内皮功能障碍的患者被随机双盲分为 ET(A)受体拮抗剂阿曲生坦（10mg）组或安慰剂组，治疗 6 个月。通过在前降支冠状动脉内输注乙酰胆碱（10(-6)至 10(-4)mol/L）来检测冠状动脉内皮依赖性血管舒张功能。对亚组患者给予 N(G)-单甲基-L-精氨酸。通过冠状动脉内给予腺苷和硝酸甘油来检测内皮非依赖性冠状动脉血流储备。两组患者的基线特征和不良反应发生率相似。与安慰剂组相比，阿曲生坦组在 6 个月时乙酰胆碱引起的冠状动脉血流百分比变化有显著改善（39.67%，95%置信区间 23.23%至 68.21%，vs. -2.22%，95%置信区间 27.37%至 15.28%；P<0.001）。但两组间冠状动脉直径百分比变化或冠状动脉血流储备变化均无显著差异。两组在基线和 6 个月时的冠状动脉血流、冠状动脉直径和 N(G)-单甲基-L-精氨酸的作用均相似。
本研究表明，阿曲生坦治疗 6 个月可改善冠状动脉微血管内皮功能，并支持内源性内皮素系统在人类早期动脉粥样硬化中调节内皮功能的作用。临床试验注册信息- URL：http://www.clinicaltrials.gov。唯一标识符：NCT00271492。
