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.
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Research Article|
March 10 2014
Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension
Dylan Burger
;
Dylan Burger
*Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
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Timothy L. Reudelhuber
;
Timothy L. Reudelhuber
†Clinical Research Institute of Montreal, Montreal, Canada
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Aman Mahajan
;
Aman Mahajan
‡Department of Chemistry and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, South Africa
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Kelly Chibale
;
Kelly Chibale
‡Department of Chemistry and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, South Africa
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Edward D. Sturrock
;
§Institute of Infectious Diseases and Molecular Medicine and Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
Correspondence: Professor Edward D. Sturrock (email Edward.Sturrock@uct.ac.za).
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Rhian M. Touyz
Rhian M. Touyz
*Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
∥BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, U.K.
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Clin Sci (Lond) (2014) 127 (1): 57–63.
Article history
Received:
December 10 2013
Revision Received:
January 31 2014
Accepted:
February 10 2014
Accepted Manuscript online:
February 10 2014
Citation
Dylan Burger, Timothy L. Reudelhuber, Aman Mahajan, Kelly Chibale, Edward D. Sturrock, Rhian M. Touyz; Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension. Clin Sci (Lond) 1 July 2014; 127 (1): 57–63. doi: https://doi.org/10.1042/CS20130808
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