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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension
Clinical Science, Volume 127, No. 1, Year 2014
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Description
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. © The Authors Journal compilation. 2014 Biochemical Society.
Authors & Co-Authors
Burger, Dylan E.
Canada, Ottawa
Ottawa Hospital Research Institute
Reudelhuber, Timothy L.
Canada, Montreal
Institut de Recherches Cliniques de Montréal
Mahajan, Aman
South Africa, Cape Town
University of Cape Town
Chibale, Kelly
South Africa, Cape Town
University of Cape Town
Sturrock, Edward D.
South Africa, Cape Town
University of Cape Town
Touyz, Rhian M.
Canada, Ottawa
Ottawa Hospital Research Institute
United Kingdom, Glasgow
Glasgow Cardiovascular Research Centre
Statistics
Citations: 29
Authors: 6
Affiliations: 4
Identifiers
Doi:
10.1042/CS20130808
ISSN:
01435221
Research Areas
Noncommunicable Diseases