Elucidation of roles of Na^+-driven cation transporter in blood pressure control and arterial lesions

盐摄入量过多是高血压的主要危险因素。在这里，我们通过SEA0400(一种通过NCX1进入Ca^&lt；2+&gt；的特异性抑制剂)和基因工程小鼠来确定Na^+/Ca^&gt；2+&gt；交换器1(NCX1)在盐敏感型高血压中的作用。SEA0400可降低盐依赖高血压大鼠模型的动脉血压，但对正常血压大鼠或其他类型的高血压大鼠无效。盐依赖型高血压大鼠股动脉注入SEA0400可增加动脉血流量，表明外周血管扩张。SEA0400可逆转哇巴因引起的动脉内钙升高和血管收缩。此外，杂合子NCX1缺失的小鼠对盐的敏感性很低，而在平滑肌中特异表达NCX1.3的转基因小鼠对盐高度敏感，SEA0400表达NCX1.3的转基因小鼠显著降低了盐依赖型高血压小鼠的血压，但在SEA0400不敏感的NCX1.3突变体中却没有。这些发现表明盐敏感型高血压是通过NCX1进入动脉平滑肌而触发的，提示NCX1抑制剂在治疗上可能是有用的。

Excessive salt intake is a major risk factor for hypertension Here we identify the role of Na^+/Ca^<2+> exchanger type 1 (NCX1) in salt-sensitive hypertension using SEA0400, a specific inhibitor for Ca^<2+> entry via NCX1, and genetically engineered mice. SEA0400 lowers arterial blood pressure in salt-dependent hypertensive rat models, but not in normotensive rats or other types of hypertensive rats. Infusion of SEA0400 into the femoral artery in salt-dependent hypertensive rats increases arterial blood flow indicating peripheral vasodilation. SEA0400 reverses ouabain-induced cytosolic Ca^<2+> elevation and vasoconstriction in arteries. Furthermore, heterozygous NCX1-deflcient mice have low salt-sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle are hypersensitive to salt SEA0400 significantly lowers the blood pressure in salt-dependent hypertensive mice expressing NCX1.3, but not in SEA0400-insensitive NCX1.3 mutants. These findings indicate that salt-sensitive hypertension is triggered by Ca^<2+> entry via NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically.