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.


CONCLUSIONS
These findings suggest that vasopeptidase inhibition may provide a useful strategy for the treatment of progressive renal disease.
Cao
Z
Z
University of Melbourne Department of Medicine at Austin and Repatriation Medical Centre, Heidelberg West, Victoria, Australia. cao@austin.unimelb.edu.au
Burrell
L M
LM
Tikkanen
I
I
Bonnet
F
F
Cooper
M E
ME
Gilbert
R E
RE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D017328:Fosinopril / Q000494:pharmacology; D005919:Glomerular Filtration Rate; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000201:enzymology; D008297:Male; D009392:Nephrectomy; D015260:Neprilysin / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009929:Organ Size; D007703:Peptidyl-Dipeptidase A / Q000032:analysis / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D012083:Renin / Q000097:blood; D013841:Thiazepines / Q000494:pharmacology*; D014508:Urea / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D014508:Urea; D003404:Creatinine; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D015260:Neprilysin; D017328:Fosinopril