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

盐摄入过多是高血压的主要危险因素。在此，我们使用SEA 0400（一种Ca^2+通过NCX 1进入的特异性抑制剂）和基因工程小鼠，确定了Na^+/Ca^2+交换体1（NCX 1）在盐敏感性高血压中的作用。SEA 0400降低盐依赖性高血压大鼠模型的动脉血压，但不降低正常血压大鼠或其他类型的高血压大鼠的动脉血压。将SEA 0400输注到盐依赖性高血压大鼠的股动脉中增加了动脉血流量，表明外周血管舒张。SEA 0400逆转哇巴因诱导的细胞内Ca^2+升高和动脉血管收缩。此外，杂合NCX 1缺陷小鼠具有低盐敏感性，而在平滑肌中特异性表达NCX1.3的转基因小鼠对盐过敏，SEA 0400显著降低表达NCX1.3的盐依赖性高血压小鼠的血压，但不降低SEA 0400不敏感的NCX1.3突变体的血压。这些发现表明，盐敏感性高血压是由动脉平滑肌中通过NCX 1的Ca^2+进入触发的，并表明NCX 1抑制剂可能在治疗上有用。

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.