Elsevier

Kidney International

Volume 60, Issue 2, August 2001, Pages 715-721
Kidney International

Vascular Biology – Hemodynamics – Hypertension
Vasopeptidase inhibition attenuates the progression of renal injury in subtotal nephrectomized rats

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

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.

Keywords

progressive renal failure
ACE inhibition
cardiovascular therapy
neutral endopeptidases
hypertension
heart failure

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1

Current address: Department of Medicine, University of Melbourne, St. Vincent's Hospital, Victoria Parade, Fitzroy VIC 3065, Australia