TY - JOUR
T1 - Vasopeptidase inhibition attenuates the progression of renal injury in subtotal nephrectomized rats
AU - Cao, Zemin
AU - Burrell, Louise M.
AU - Tikkanen, Ilkka
AU - Bonnet, Fabrice
AU - Cooper, Mark E.
AU - Gilbert, Richard E.
PY - 2001/8
Y1 - 2001/8
N2 - 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.
AB - 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.
KW - ACE inhibition
KW - Cardiovascular therapy
KW - Heart failure
KW - Hypertension
KW - Neutral endopeptidases
KW - Progressive renal failure
UR - http://www.scopus.com/inward/record.url?scp=0034921566&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.2001.060002715.x
DO - 10.1046/j.1523-1755.2001.060002715.x
M3 - Article
C2 - 11473654
AN - SCOPUS:0034921566
SN - 0085-2538
VL - 60
SP - 715
EP - 721
JO - Kidney International
JF - Kidney International
IS - 2
ER -