title: A nonpeptide, piperidine renin inhibitor provides renal and cardiac protection in double-transgenic mice expressing human renin and angiotensinogen genes.
abstract: BACKGROUND
  Controlling hypertension by angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), mechanisms that inhibit later pathway steps in the renin-angiotensin system (RAS), have clinically afforded protection against cardiac and renal disease.
  
  
  METHODS
  In order to determine if blocking the RAS rate-limiting step of angiotensin II generation via renin inhibition could afford similar end organ protection in a human-relevant preclinical model, this study investigated the cardiac and renal effects of a nonpeptide, piperidine renin inhibitor (RI; 100 mg/kg/day PO) in double transgenic mice (dTGM) which express both human renin and angiotensinogen genes. RI was compared to the ARB, candesartan (3 mg/kg/day PO), and to the ACEI, enalapril (60 mg/kg/day PO) in a 4-week dosing paradigm. These doses of RI, ACEI and ARB were previously found to normalize mean blood pressure (MBP) to 110 + 3, 109 + 7 and 107 + 6 mmHg, respectively, after 1 day of treatment.
  
  
  CONCLUSIONS
  In the dTGM, PRA, plasma aldosterone, GFR, microalbuminuria and left ventricular free wall thickness (LVH) were higher than in the wild type C57BL/6 mice. Microalbuminuria and LVH were significantly reduced by 93% and 9% for the RI, 83% and 13% for enalapril and 73% and 6% for candesartan, respectively. PRA and aldosterone were reduced by the RI 56% and 23%, respectively. These results suggest that the RI provides protection against cardiac and renal disease, similar to ARB and ACEI.
authors.affiliation: Cardiovascular and Atherosclerosis Biology, Pfizer Global Research & Development, Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, MI 48105, USA. tcmajor@umich.edu
authors.forename: Terry C
authors.initials: TC
authors.lastname: Major
authors.forename: Bronia
authors.initials: B
authors.lastname: Olszewski
authors.forename: Wendy
authors.initials: W
authors.lastname: Rosebury
authors.forename: Carlin
authors.initials: C
authors.lastname: Okerberg
authors.forename: Tage
authors.initials: T
authors.lastname: Carlson
authors.forename: Robert
authors.initials: R
authors.lastname: Ostroski
authors.forename: Richard
authors.initials: R
authors.lastname: Schroeder
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kowala
authors.forename: Robert
authors.initials: R
authors.lastname: Leadley
mesh_terms: D000284:Administration, Oral; D000419:Albuminuria / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology; D000450:Aldosterone / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004656:Enalapril / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use*; D011804:Quinolines / Q000737:chemistry / Q000627:therapeutic use*; D012083:Renin / Q000097:blood / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014463:Ultrasonography; D000092502:Renin Inhibitors
chemical_list: D000450:Aldosterone; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D004656:Enalapril; D010880:Piperidines; D011804:Quinolines; D012083:Renin; D013777:Tetrazoles; D000092502:Renin Inhibitors; C077793:candesartan cilexetil