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Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle

Nature Medicine volume 10, pages 1193–1199 (2004)Cite this article

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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Figure 1: NCX1 inhibition and antihypertensive effects of SEA0400.
Figure 2: Vascular responses to intrafemoral infusion of SEA0400 in anesthetized DOCA-salt hypertensive or uninephrectomized sham rats.
Figure 3: Effects of SEA0400 on ouabain-induced hypertension and vasoconstriction.
Figure 4: Effects of low-dose ouabain and SEA0400 on cytosolic Ca2+ level and myogenic tone (MT) in pressurized mouse small mesenteric arteries.
Figure 5: Prevention of DOCA-salt hypertension in Slc8a1+/− mice.
Figure 6: Enhanced salt-sensitivity in N1.3Tg/Tg or mN1.3Tg/Tg mice.

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Acknowledgements

We thank K. Takahashi and S. Okuyama (Taisho Pharmaceutical Co. Ltd.), K. Saku and H. Urata (Fukuoka University), J. Kimura (Fukushima Medical University) and Y. Matsumura (Osaka University of Pharmaceutical Sciences) for discussions, and W.G. Wier and R. Saunders (University of Maryland) for help in making the video clip. This work was supported by Grants-in-Aid for scientific research (14570097, 16590213) from the Ministry of Education, Science and Culture of Japan, a grant from the Salt Science Research Foundation (No.02), US National Institutes of Health grant HL-45215, and an American Heart Association Mid-Atlantic Affiliate Postdoctoral Fellowship.

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Authors and Affiliations

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

    Takahiro Iwamoto, Satomi Kita & Takeshi Katsuragi

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

    Jin Zhang & Mordecai P Blaustein

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

    Takahiro Iwamoto

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

    Yuji Arai

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

    Satomi Kita & Shigeru Yoshida

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

    Koji Wakimoto

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

    Issei Komuro

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Supplementary information

Supplementary Fig. 1

Expression levels and NCX activities in CCL39 fibroblasts overexpressing human NCX1 isoforms. (PDF 232 kb)

Supplementary Fig. 2

Effect of SEA0400 on the development of DOCA-salt hypertension in rats. (PDF 633 kb)

Supplementary Fig. 3

VSM-specific overexpression of NCX1.3 and its mutant in N1.3Tg/Tg and N1.3Tg/Tg mice. (PDF 233 kb)

Supplementary Fig. 4

Salt-insensitivity in transgenic mice with heart-specific overexpression of NCX1.1. (PDF 302 kb)

Supplementary Table 1

Effects of SEA0400 on morphological changes of thoracic aortas in DOCA-salt hypertensive rats (PDF 10 kb)

Supplementary Table 2

Effects of SEA0400 on creatinine clearance, urinary excretion of protein, and fractional excretion of sodium in DOCA-salt hypertensive rats (PDF 10 kb)

Supplementary Movie

Effects of ouabain and SEA0400 on cytosolic Ca2+ and myogenic tone in a small mesenteric artery. (MOV 2980 kb)

Supplementary Methods (PDF 23 kb)

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Iwamoto, T., Kita, S., Zhang, J. et al. Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle. Nat Med 10, 1193–1199 (2004). https://doi.org/10.1038/nm1118

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