The human
renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human
renin. The
intravenous infusion of recombinant human
renin (2.4 microg x kg(-1) x min(-1)) in the
ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by
captopril,
enalkiren, and
losartan in a dose-dependent manner following
oral administration, with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A series of
peptidomimetic P2-P3 butanediamide
renin inhibitors inhibited purified recombinant human
renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of
renin inhibitors, the pressor response to infused human
renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 microg/kg. The in vivo inhibition of human
renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human
renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5).
Oral administration of
renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human
renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six
renin inhibitors with an oral potency of <1 mg/kg. The ED50 of
renin inhibitors for inhibition of
angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following
oral administration of the butanediamide series of
renin inhibitors.