title: 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 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.
authors.affiliation: Department of Biological Sciences, Boehringer Ingelheim (Canada) Limited, Bio-Méga Research Divisioin, Laval QC. gbolger@lav.boehringer-ingelheim.com
authors.forename: G
authors.initials: G
authors.lastname: Bolger
authors.forename: J C
authors.initials: JC
authors.lastname: Vigeant
authors.forename: F
authors.initials: F
authors.lastname: Liard
authors.forename: B
authors.initials: B
authors.lastname: Simoneau
authors.forename: D
authors.initials: D
authors.lastname: Thibeault
authors.forename: L
authors.initials: L
authors.lastname: Pilote
authors.forename: D
authors.initials: D
authors.lastname: Lamarre
authors.forename: G
authors.initials: G
authors.lastname: Jung
authors.forename: P
authors.initials: P
authors.lastname: Anderson
authors.forename: J
authors.initials: J
authors.lastname: Jaramillo
mesh_terms: D000284:Administration, Oral; D000803:Angiotensin I / Q000096:biosynthesis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005730:Ganglionic Blockers / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012083:Renin / Q000494:pharmacology; D013997:Time Factors; D000092502:Renin Inhibitors
chemical_list: D000803:Angiotensin I; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002216:Captopril; D004151:Dipeptides; D005730:Ganglionic Blockers; D019808:Losartan; D011994:Recombinant Proteins; D012083:Renin; D000092502:Renin Inhibitors; C056622:enalkiren