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

The somatic isozyme of ACE (angiotensin l-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.