Z Cao1, L M Burrell, I Tikkanen, F Bonnet, M E Cooper, R E Gilbert. 1. University of Melbourne Department of Medicine at Austin and Repatriation Medical Centre, Heidelberg West, Victoria, Australia. cao@austin.unimelb.edu.au
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.
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:STNxrats 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 STNxrats (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 STNxrats (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.
Authors: Sabine Fredersdorf; Joachim Weil; Coskun Ulucan; Christoph Birner; Roland Büttner; Thomas Schubert; Carsten A Böger; Kurt Debl; Frank Muders; Günter A Riegger; Andreas Luchner Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2007-03-01 Impact factor: 3.000
Authors: B J Davis; C I Johnston; L M Burrell; W C Burns; E Kubota; Z Cao; M E Cooper; T J Allen Journal: Diabetologia Date: 2003-06-28 Impact factor: 10.122