Role of angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis in the hypotensive effect of azilsartan

Hypertens Res. 2014 Jul;37(7):616-20. doi: 10.1038/hr.2014.49. Epub 2014 Mar 6.


The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang-(1-7)/Mas axis against the ACE/Ang II/Ang II type 1 (AT1) receptor axis in blood pressure control has been previously described. We examined the possibility that this pathway might be involved in the anti-hypertensive effect of a newly developed AT1 receptor blocker (ARB), azilsartan, and compared azilsartan's effects with those of another ARB, olmesartan. Transgenic mice carrying the human renin and angiotensinogen genes (hRN/hANG-Tg) were given azilsartan or olmesartan. Systolic and diastolic blood pressure, as determined by radiotelemetry, were significantly higher in hRN/hANG-Tg mice than in wild-type (WT) mice. Treatment with azilsartan or olmesartan (1 or 5 mg kg(-1) per day) significantly decreased systolic and diastolic blood pressure, and the blood pressure-lowering effect of azilsartan was more marked than that of olmesartan. The urinary Na concentration decreased in an age-dependent manner in hRN/hANG-Tg mice. Administration of azilsartan or olmesartan increased urinary Na concentration, and this effect was weaker with olmesartan than with azilsartan. Azilsartan decreased ENaC-α mRNA expression in the kidney and decreased the ratio of heart to body weight. Olmesartan had a similar but less-marked effect. ACE2 mRNA expression was lower in the kidneys and hearts of hRN/hANG-Tg mice than in WT mice. This decrease in ACE2 mRNA expression was attenuated by azilsartan, but not by olmesartan. These results suggest that the hypotensive and anti-hypertrophic effects of azilsartan may involve activation of the ACE2/Ang-(1-7)/Mas axis with AT1 receptor blockade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / pharmacology*
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Benzimidazoles / pharmacology*
  • Blood Pressure / drug effects
  • Cardiomegaly / prevention & control
  • Epithelial Sodium Channels / genetics
  • Imidazoles / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxadiazoles / pharmacology*
  • Peptide Fragments / pharmacology*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / physiology*
  • Proto-Oncogene Proteins / physiology*
  • Receptors, G-Protein-Coupled / physiology*
  • Sodium / urine
  • Tetrazoles / pharmacology


  • Angiotensin II Type 1 Receptor Blockers
  • Antihypertensive Agents
  • Benzimidazoles
  • Epithelial Sodium Channels
  • Imidazoles
  • Oxadiazoles
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Tetrazoles
  • proto-oncogene proteins c-mas-1
  • olmesartan
  • Angiotensin I
  • Sodium
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • azilsartan
  • angiotensin I (1-7)