Best P J, McKenna C J, Hasdai D, Holmes D R, Lerman A
Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
Circulation. 1999 Apr 6;99(13):1747-52. doi: 10.1161/01.cir.99.13.1747.
Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.
Acetylcholine (10(-6) to 10(-4) mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: -41.6%+/-10.7%, group 2: -4.7%+/-11.9%, group 3: 11.4%+/-7.4%).
Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. This study supports the role for ET-1 in the pathogenesis of endothelial function. Moreover, endothelin receptor antagonists may have a therapeutic role by maintaining coronary endothelial function in pathophysiological states.
内皮素-1（ET-1）是一种内皮源性肽，可通过刺激ET-A和ET-B受体使冠状动脉血管收缩。实验性猪高胆固醇血症与冠状动脉内皮功能受损及ET-1浓度升高有关。本研究旨在验证慢性内皮素受体拮抗作用可在实验性高胆固醇血症中保留冠状动脉内皮功能这一假说。
在基线时以及给予高胆固醇饮食12周后，将乙酰胆碱（10⁻⁶至10⁻⁴mol/L）依次注入猪的左前降支冠状动脉。在此期间，将动物随机分为3组：第1组不接受治疗，第2组接受每天3mg/kg的RO 48-5695（一种ET-A/ET-B受体联合拮抗剂），第3组接受每天4mg/kg的ABT-627（一种选择性ET-A受体拮抗剂）。根据定量冠状动脉造影和冠状动脉内多普勒检查计算冠状动脉直径、冠状动脉血流量和冠状动脉血管阻力的变化百分比。12周时，所有组的总胆固醇均显著且相似地升高。慢性内皮素受体拮抗作用在12周时显著增加了乙酰胆碱刺激后的冠状动脉血流量（第1组：-41.6%±10.7%，第2组：-4.7%±11.9%，第3组：11.4%±7.4%）。
慢性内皮素受体拮抗作用可在实验性高胆固醇血症中保留冠状动脉内皮功能。本研究支持ET-1在内皮功能发病机制中的作用。此外，内皮素受体拮抗剂可能通过在病理生理状态下维持冠状动脉内皮功能而具有治疗作用。
