A nonpeptide, piperidine renin inhibitor provides renal and cardiac protection in double-transgenic mice expressing human renin and angiotensinogen genes.
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.
Major
Terry C
TC
Cardiovascular and Atherosclerosis Biology, Pfizer Global Research & Development, Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, MI 48105, USA. tcmajor@umich.edu
Olszewski
Bronia
B
Rosebury
Wendy
W
Okerberg
Carlin
C
Carlson
Tage
T
Ostroski
Robert
R
Schroeder
Richard
R
Kowala
Mark C
MC
Leadley
Robert
R
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
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