Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle
Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle
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DOI：
10.1038/nm1118
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发表时间：
2004-11-01
期刊：
影响因子：
82.9
通讯作者：
Katsuragi, T
中科院分区：
文献类型：
--
作者：
Iwamoto, T;Kita, S;Katsuragi, T
盐摄入过多是高血压的主要危险因素。在这里，我们确定的作用Na+/Ca 2+交换器1型（NCX 1）在盐敏感性高血压使用SEA 0400，通过NCX 1的Ca 2+进入的特异性抑制剂，和基因工程小鼠。在盐依赖性高血压大鼠模型中，SEA 0400降低动脉血压，但在其他类型的高血压大鼠或血压正常的大鼠中不降低动脉血压。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质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可降低盐依赖性高血压小鼠表达NCX1.3的血压，但对SEA 0400不敏感的NCX1.3突变体没有影响。这些研究结果表明，盐敏感性高血压是由Ca 2+通过动脉平滑肌中的NCX 1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+/Ca2+ exchanger type 1 (NCX1) in salt-sensitive hypertension using SEA0400, a specific inhibitor of Ca2+ entry through NCX1, and genetically engineered mice. SEA0400 lowers arterial blood pressure in salt-dependent hypertensive rat models, but not in other types of hypertensive rats or in normotensive 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 Ca2+ elevation and vasoconstriction in arteries. Furthermore, heterozygous NCX1-deficient mice have low salt sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle are hypersensitive to salt. SEA0400 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 Ca2+ entry through NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically.