title: Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension.
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.
authors: *Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada.
authors: Dylan
authors: D
authors: Burger
authors: †Clinical Research Institute of Montreal, Montreal, Canada.
authors: Timothy L
authors: TL
authors: Reudelhuber
authors: ‡Department of Chemistry and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, South Africa.
authors: Aman
authors: A
authors: Mahajan
authors: ‡Department of Chemistry and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, South Africa.
authors: Kelly
authors: K
authors: Chibale
authors: §Institute of Infectious Diseases and Molecular Medicine and Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.
authors: Edward D
authors: ED
authors: Sturrock
authors: Rhian M
authors: RM
authors: Touyz
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000097:blood / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control; D002908:Chronic Disease; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006984:Hypertrophy; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D017706:Lisinopril / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D000804:Angiotensin II; D017706:Lisinopril; D001920:Bradykinin