A Nonpeptide, Piperidine Renin Inhibitor Provides Renal and Cardiac Protection in Double-Transgenic Mice Expressing Human Renin and Angiotensinogen Genes

  • Terry C. Major
  • Bronia Olszewski
  • Wendy Rosebury
  • Carlin Okerberg
  • Tage Carlson
  • Robert Ostroski
  • Richard Schroeder
  • Mark C. Kowala
  • Robert Leadley
Article

Abstract

Introduction

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.

Materials and 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.

Results and discussion

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.

Key words

Cardioprotection Renoprotection Hypertensive Double Transgenic Mice Enalapril Candesartan Renin Inhibitor Left Ventricular Hypertrophy and Microalbuminuria 

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Terry C. Major
    • 1
    • 3
  • Bronia Olszewski
    • 1
  • Wendy Rosebury
    • 1
  • Carlin Okerberg
    • 2
  • Tage Carlson
    • 2
  • Robert Ostroski
    • 1
  • Richard Schroeder
    • 1
  • Mark C. Kowala
    • 1
  • Robert Leadley
    • 1
  1. 1.Cardiovascular and Atherosclerosis BiologyPfizer Global Research & Development, Pfizer, Inc.Ann ArborUSA
  2. 2.Drug Safety Research and DevelopmentPfizer Global Research & Development, Pfizer, Inc.Ann ArborUSA
  3. 3.Robert Bartlett Extracorporeal Life Support Laboratory, Department of General SurgeryUniversity of Michigan Health SystemAnn ArborUSA

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