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Early, but not late therapy with a vasopressin V1a-antagonist ameliorates the development of renal damage after 5/6 nephrectomy

Department of Clinical Pharmacology, Groningen Institute for Drug Evaluation (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Atsua Tahara

Institute for Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan

Alex CA Kluppel

Department of Clinical Pharmacology, Groningen Institute for Drug Evaluation (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Dick de Zeeuw

Department of Clinical Pharmacology, Groningen Institute for Drug Evaluation (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Robert H Henning

Department of Clinical Pharmacology, Groningen Institute for Drug Evaluation (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Richard PE van Dokkum

Department of Clinical Pharmacology, Groningen Institute for Drug Evaluation (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, r.p.e.van.dokkum{at}med.umcg.nl

Introduction. Vasopressin, mainly through the V_1a-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).

Materials and methods. After 5/6 nephrectomy, early intervention was performed between week 2 and 10 thereafter with the V_1a-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.

Conclusion. 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.

Key Words: 5/6 nephrectomy • ACE-inhibition • glomerular hyperfiltration • focal glomerulosclerosis • proteinuria • vasopressin antagonism

Journal of Renin-Angiotensin-Aldosterone System, Vol. 7, No. 4, 217-224 (2006)
DOI: 10.3317/jraas.2006.041


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