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

Nat Med. 2004 Nov;10(11):1193-9. doi: 10.1038/nm1118. Epub 2004 Oct 10.

Abstract

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 of Ca(2+) 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 Ca(2+) 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 Ca(2+) entry through NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing / genetics
  • Alternative Splicing / physiology
  • Aniline Compounds / pharmacology*
  • Animals
  • Blood Pressure / drug effects*
  • Calcium / metabolism
  • Hypertension / etiology*
  • Hypertension / metabolism
  • Immunoblotting
  • Immunohistochemistry
  • Male
  • Mesenteric Arteries / drug effects
  • Mice
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / drug effects*
  • Ouabain / metabolism
  • Phenyl Ethers / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Chloride, Dietary / metabolism
  • Sodium-Calcium Exchanger / antagonists & inhibitors
  • Sodium-Calcium Exchanger / metabolism*
  • Vasoconstriction / drug effects

Substances

  • Aniline Compounds
  • Phenyl Ethers
  • SEA 0400
  • Sodium Chloride, Dietary
  • Sodium-Calcium Exchanger
  • sodium-calcium exchanger 1
  • Ouabain
  • Calcium