Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension

Clin Sci (Lond). 2014 Jul;127(1):57-63. doi: 10.1042/CS20130808.

Abstract

The somatic isozyme of ACE (angiotensin I-converting enzyme) comprises two distinct zinc-dependent catalytic domains with different substrate specificities for angiotensin I (cleaved selectively by the C-domain) and bradykinin (cleaved equally efficiently by both the N- and C-domains). Classical ACEIs (ACE inhibitors) target both domains, with side effects such as cough and angio-oedema being attributed, in part, to N-domain inhibition, probably through bradykinin accumulation. We questioned whether a novel C-domain-selective ACEI (lisW-S) has anti-hypertensive effects without influencing bradykinin status. AngII (angiotensin II)-dependent hypertension was studied in mice that express active human renin in the liver (TtRhRen). Compared with wild-type littermates, TtRhRen mice displayed cardiac hypertrophy and had significantly elevated SBP [systolic BP (blood pressure)] as determined by tail cuff sphygmomanometry (150±3 compared with 112±5 mmHg; P<0.05) and telemetry (163±3 compared with 112±2 mmHg; P<0.01). Treatment with the non-selective ACEI lisinopril (1 mg/kg of body weight per day via an osmotic mini-pump for 2 weeks) reduced SBP (127±3 compared with. 154±6; P<0.05). Similarly, treatment with the C-domain selective ACEI lisW-S (lisinopril-tryptophan; 3.6 mg/kg of body weight per day via an osmotic mini-pump for 2 weeks) reduced BP. Treatment with lisinopril or lisW-S significantly reduced levels of AngII in kidneys (~4-fold; P<0.001). Ang-(2-8) [angiotensin-2-8)] was significantly reduced by lisinopril, but not by lisW-S. Plasma bradykinin levels were significantly increased only in the lisinopril group. These data suggest that C-domain-selective ACEIs reduce BP and AngII levels similarly to classical ACEIs. C-domain-selective ACEIs have the potential to avoid undesirable effects on the bradykinin system common to classic ACEIs and may represent a novel approach to the treatment of hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism
  • Angiotensin II / physiology*
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Animals
  • Antihypertensive Agents / therapeutic use*
  • Blood Pressure / drug effects
  • Bradykinin / blood
  • Bradykinin / metabolism
  • Cardiomegaly / etiology
  • Cardiomegaly / prevention & control
  • Chronic Disease
  • Disease Models, Animal
  • Drug Evaluation, Preclinical / methods
  • Hypertension / complications
  • Hypertension / drug therapy*
  • Hypertension / physiopathology
  • Hypertrophy
  • Kidney / metabolism
  • Kidney / pathology
  • Lisinopril / analogs & derivatives
  • Lisinopril / therapeutic use
  • Mice
  • Mice, Transgenic

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Angiotensin II
  • Lisinopril
  • Bradykinin