Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide

Nature. 1995 Nov 2;378(6552):65-8. doi: 10.1038/378065a0.


Around half of all humans with essential hypertension are resistant to salt (blood pressure does not change by more than 5 mm Hg when salt intake is high), and although various inbred strains of rats display salt-insensitive elevated blood pressure, a gene defect to account for the phenotype has not been described. Atrial natriuretic peptide (ANP) is released from the heart in response to atrial stretch and is thought to mediate its natriuretic and vaso-relaxant effects through the guanylyl cyclase-A receptor (GC-A). Here we report that disruption of the GC-A gene results in chronic elevations of blood pressure in mice on a normal salt diet. Unexpectedly, the blood pressure remains elevated and unchanged in response to either minimal or high salt diets. Aldosterone and ANP concentrations are not affected by the genotype. Therefore, mutations in the GC-A gene could explain some salt-resistant forms of essential hypertension and, coupled with previous work, further suggest that the GC-A signaling pathway dominates at the level of peripheral resistance, where it can operate independently of ANP.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenal Glands / metabolism
  • Animals
  • Atrial Natriuretic Factor / metabolism*
  • Base Sequence
  • Cell Line
  • DNA Primers
  • Diet
  • Female
  • Gene Targeting
  • Guanylate Cyclase / metabolism*
  • Humans
  • Hypertension / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Molecular Sequence Data
  • Myocardium / metabolism
  • Receptors, Atrial Natriuretic Factor*
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Sodium Chloride / pharmacology*


  • DNA Primers
  • Receptors, Cell Surface
  • Sodium Chloride
  • Atrial Natriuretic Factor
  • Guanylate Cyclase
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor A