Vasopeptidase inhibition attenuates the progression of renal injury in subtotal nephrectomized rats

Zemin Cao, Louise M. Burrell, Ilkka Tikkanen, Fabrice Bonnet, Mark E. Cooper, Richard E. Gilbert

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72 Citations (Scopus)

Abstract

Background. Vasopeptidase inhibitors are a new class of cardiovascular compounds that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of the present study was to explore the effects of omapatrilat, a vasopeptidase inhibitor, on renal function and pathology in subtotally nephrectomized (STNx) rats. Methods. STNx rats were randomized to four groups and treated for 12 weeks: no treatment (N = 14); omapatrilat at a low dose of 10 mg/kg (L, N = 12) and at a high dose of 40 mg/kg (H, N = 10); or an ACE inhibitor, fosinopril, at a dose of 10 mg/kg (N = 12). Sham-operated rats were used as control animals (N = 12). Results. Elevated blood pressure in STNx rats (174 ± 9 mm Hg) was reduced by omapatrilat in a dose-dependent manner (L, 121 ± 3 mm Hg; H, 110 ± 3 mm Hg) and by fosinopril (149 ± 5 mm Hg). Proteinuria in STNx rats (246 ± 73 mg/day) was reduced by treatment with fosinopril (88 ± 21 mg/day) and was normalized by treatment with omapatrilat (L, 30 ± 4 mg/day; H, 20 ± 2 mg/day vs. control 25 ± 1 mg/day). Decreased glomerular filtration rates, elevated plasma urea and creatinine and glomerulosclerosis, and tubulointerstitial fibrosis were ameliorated by omapatrilat and fosinopril to a similar degree. Compared with fosinopril, omapatrilat treatment was associated with increased plasma renin activity and decreased renal ACE and NEP binding in a dose-dependent manner. Conclusion. These findings suggest that vasopeptidase inhibition may provide a useful strategy for the treatment of progressive renal disease.

Original languageEnglish
Pages (from-to)715-721
Number of pages7
JournalKidney International
Volume60
Issue number2
DOIs
Publication statusPublished - Aug 2001
Externally publishedYes

Keywords

  • ACE inhibition
  • Cardiovascular therapy
  • Heart failure
  • Hypertension
  • Neutral endopeptidases
  • Progressive renal failure

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