Barton M, d'Uscio L V, Shaw S, Meyer P, Moreau P, Lüscher T F
Cardiology, University Hospital Zürich, Switzerland.
Hypertension. 1998 Jan;31(1 Pt 2):499-504. doi: 10.1161/01.hyp.31.1.499.
Sodium plays an important role in the pathogenesis and therapy of hypertension, a major risk factor for cardiovascular disease. This study investigated the involvement of endothelin in vascular alterations in salt-induced Dahl hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ET(A) receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied. In DS rats, a high-sodium diet increased systolic pressure (190+/-4 versus 152+/-2 mm Hg, P<.05) and aortic ET-1 protein content (4.2-fold, P<.0001) and induced aortic hypertrophy as assessed by tissue weight (P<.0001). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (49+/-4% versus 81+/-4%, P<.0001) and contractions to ET-1 (92+/-7 versus 136+/-8% of KCl, P=.0011). ET-1 tissue levels were highly and inversely correlated with endothelium-dependent relaxations (r=0.931, P<.0001) and contractions to ET (r=0.77, P=.0007). LU135252 treatment reduced systolic blood pressure only in part (168+/-3 versus 190+/-4 mm Hg, P<.05) but normalized sodium-induced changes of vascular reactivity, tissue ET-1 protein content, and vascular structure (P<.001 versus sodium). None of these effects were observed in DR rats. These results suggest that ET-1 acts as a local mediator of vascular dysfunction and aortic hypertrophy in Dahl salt-induced hypertension. ET(A) receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.
钠在高血压（心血管疾病的主要危险因素）的发病机制和治疗中起着重要作用。本研究调查了内皮素在盐诱导的Dahl高血压血管改变中的作用。将盐敏感（DS）和盐抵抗（DR）的Dahl大鼠用含或不含ET(A)受体拮抗剂LU135252的高钠饮食（NaCl 4%）处理两个月，并研究了这些处理对收缩压、血管内皮素-1（ET-1）蛋白含量、主动脉肥厚以及离体主动脉环血管反应性的影响。在DS大鼠中，高钠饮食增加了收缩压（190±4对152±2 mmHg，P<0.05）和主动脉ET-1蛋白含量（4.2倍，P<0.0001），并通过组织重量评估诱导了主动脉肥厚（P<0.0001）。高钠饮食显著降低了NO介导的对乙酰胆碱的内皮依赖性舒张（49±4%对81±4%，P<0.0001）以及对ET-1的收缩反应（92±7对KCl的136±8%，P=0.0011）。ET-1组织水平与内皮依赖性舒张（r=0.931，P<0.0001）以及对ET的收缩反应（r=0.77，P=0.0007）高度负相关。LU135252处理仅部分降低了收缩压（168±3对190±4 mmHg，P<0.05），但使钠诱导的血管反应性、组织ET-1蛋白含量和血管结构的变化恢复正常（与钠处理相比，P<0.001）。在DR大鼠中未观察到这些效应。这些结果表明，ET-1在Dahl盐诱导的高血压中作为血管功能障碍和主动脉肥厚的局部介质起作用。ET(A)受体拮抗作用可能具有降低血管ET-1含量、改善内皮功能以及预防盐敏感性高血压结构改变的治疗潜力。
