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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

1  Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.

2  Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

3  Department of Molecular Physiology, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan.

4  Department of Bioscience, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan.

5  Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama 330-8530, Japan.

6  Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka 532-8505, Japan.

7  Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.

Correspondence should be addressed to Takahiro Iwamoto tiwamoto@cis.fukuoka-u.ac.jp
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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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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