Angiotensin-converting Enzyme 2-independent Action of Presumed Angiotensin-Converting Enzyme 2 Activators: Studies in Vivo, Ex Vivo, and in Vitro

Hypertension. 2014 Apr;63(4):774-82. doi: 10.1161/HYPERTENSIONAHA.113.02856. Epub 2014 Jan 20.

Abstract

Angiotensin (Ang)-converting enzyme 2 (ACE2) is a key enzyme in the metabolism of Ang II. XNT (1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one) and diminazene have been reported to exert various organ-protective effects, which are attributed to the activation of ACE2. To test the effect of these compounds, we studied Ang II degradation in vivo and in vitro as well as their effect on ACE2 activity in vivo and in vitro. In a model of Ang II-induced acute hypertension, blood pressure (BP) recovery was markedly enhanced by XNT (slope with XNT, -3.26±0.2 versus -1.6±0.2 mm Hg/min without XNT; P<0.01). After Ang II infusion, neither plasma nor kidney ACE2 activity was affected by XNT. Plasma Ang II and Ang (1-7) levels also were not significantly affected by XNT. The BP-lowering effect of XNT seen in wild-type animals was also observed in ACE2 knockout mice (slope with XNT, -3.09±0.30 versus -1.28±0.22 mm Hg/min without XNT; P<0.001). These findings show that the BP-lowering effect of XNT in Ang II-induced hypertension cannot be because of the activation of ACE2. In vitro and ex vivo experiments in both mice and rat kidney confirmed a lack of enhancement of ACE2 enzymatic activity by XNT and diminazene. Moreover, Ang II degradation in vitro and ex vivo was unaffected by XNT and diminazene. We conclude that the biological effects of these compounds are ACE2-independent and should not be attributed to the activation of this enzyme.

Keywords: 1-((2-dimethylamino)ethylamino)-4-(hydroxymethyl)-7-((4-methylphenyl)sulfonyloxy)-9H-xanthene-9-one; diminazene; hypertension; renin-angiotensin system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / metabolism
  • Angiotensin II / adverse effects
  • Angiotensin II / drug effects
  • Angiotensin II / metabolism*
  • Animals
  • Blood Pressure / drug effects*
  • Blood Pressure / physiology
  • Diminazene / pharmacology*
  • Diminazene / therapeutic use
  • Disease Models, Animal
  • Glutamyl Aminopeptidase / metabolism
  • Hypertension / chemically induced
  • Hypertension / drug therapy
  • Hypertension / metabolism*
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Kidney / drug effects
  • Kidney / metabolism
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptide Fragments / metabolism
  • Peptidyl-Dipeptidase A / deficiency
  • Peptidyl-Dipeptidase A / drug effects*
  • Peptidyl-Dipeptidase A / metabolism*
  • Rats
  • Xanthones / pharmacology*
  • Xanthones / therapeutic use

Substances

  • 1-((2-dimethylamino)ethylamino)-4-(hydroxymethyl)-7-((4-methylphenyl)sulfonyloxy)-9H-xanthene-9-one
  • 2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid
  • Imidazoles
  • Peptide Fragments
  • Xanthones
  • Angiotensin II
  • Angiotensin I
  • Glutamyl Aminopeptidase
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2
  • Leucine
  • angiotensin I (1-7)
  • Diminazene