The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors

Abstract

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 µg·kg-1·min-1) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47 ± 3 mmHg (1 mmHg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50values of 0.3 ± 0.1, 2.5 ± 0.9, and 5.2 ± 1.6 mg/kg, respectively. A series of peptidomimetic P2-P3butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50values (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 ED50values ranging from 4 to 600 µg/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 ED50values 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 ED50of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50for 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.Key words: renin-angiotensin system, recombinant human renin, rat, renin inhibitors.