Early, but not late therapy with a vasopressin V1a-antagonist ameliorates the development of renal damage after 5/6 nephrectomy.
BACKGROUND
Vasopressin, mainly through the V1a-receptor, is thought to be a major player in the maintenance of hyperfiltration. Its inhibition could therefore lead to a decrease in progression of chronic renal failure. To this end, the effect of the vasopressin V1a-receptor-selective antagonist, YM218, was studied on proteinuria and focal glomerulosclerosis in early and late intervention after 5/6 nephrectomy in rats, and compared with an angiotensin-converting enzyme inhibitor (ACE-I).


METHODS
After 5/6 nephrectomy, early intervention was performed between week 2 and 10 thereafter with the V1a-receptor-selective antagonist (VRA, 10 mg/kg/day, n=10), enalapril (ACE-I, 10 mg/kg/day, n=9), or vehicle (n=8). Late intervention was performed in another group between week 6 and 12 with VRA (10 mg/kg/day, n=7), lisinopril (ACE-I, 5 mg/kg/day, n=7), or vehicle (n=7).


RESULTS
In early intervention, proteinuria and focal glomerulosclerosis were significantly decreased by VRA compared to vehicle (44+7% and 59+8% respectively). ACE-I significantly decreased proteinuria (67+7%) and a trend towards a decrease in focal glomerulosclerosis was observed (30+18%). In late intervention, VRA did not decrease proteinuria and focal glomerulosclerosis compared to vehicle (21+20% and 0%, respectively), ACE-I significantly lowered proteinuria (92+2%) and a focal glomerulosclerosis (69+1%) lowering trend was observed.


CONCLUSIONS
These results indicate that VRA may protect against early progression of renal injury after 5/6 nephrectomy, whereas its effectiveness seems limited in established renal damage.
Windt
Willemijn A K M
WA
Department of Clinical Pharmacology, Groningen Institute for Drug Evaluation (GUIDE), University Medical Center Groningen, Antonius Deusinglaan 1. NL-9713 AV Groningen NL-9713, The Netherlands.
Tahara
Atsua
A
Kluppel
Alex C A
AC
de Zeeuw
Dick
D
Henning
Robert H
RH
van Dokkum
Richard P E
RP
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000008:administration & dosage* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects; D008297:Male; D009392:Nephrectomy; D010880:Piperidines / Q000008:administration & dosage* / Q000627:therapeutic use; D011507:Proteinuria / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar
C501286:4'-(4,4-difluoro-5-(2-oxo-2-(4-piperidinopiperidino)ethylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl)-2-methyl-3-furanilide; D000806:Angiotensin-Converting Enzyme Inhibitors; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D010880:Piperidines; D004656:Enalapril