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Article
Nature Medicine 10, 1193 - 1199 (2004)
Published online: 10 October 2004 | doi:10.1038/nm1118
Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle
Takahiro Iwamoto1,3, Satomi Kita1,5, Jin Zhang2, Mordecai P Blaustein2, Yuji Arai4, Shigeru Yoshida5, Koji Wakimoto6, Issei Komuro7 & Takeshi Katsuragi1
Abstract
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.
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