V1/V2 Vasopressin receptor antagonism potentiates the renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction

Kidney Int. 2009 Nov;76(9):960-7. doi: 10.1038/ki.2009.267. Epub 2009 Jul 22.


Blockade of the renin-angiotensin system (RAS), the standard treatment for chronic proteinuric nephropathy, slows but may not halt progression of the disease, particularly when therapy is started late. Because vasopressin may also play a role in the progression of renal disease, we measured the effect of a dual V(1a) and V(2) vasopressin receptor antagonist (RWJ-676070) alone or combined with angiotensin-converting enzyme inhibition or angiotensin II type 1 receptor blockade on proteinuria and renal disease progression during overt nephropathy. Twenty-one days after renal mass reduction, a time of established injury, rats were given vehicle, RWJ-676070, enalapril, losartan, RWJ-676070 plus enalapril, or losartan in drinking water for an additional 39 days. RWJ-676070 returned the blood pressure to pre-treatment levels, which were significantly lower than those in vehicle-treated rats. Enalapril, losartan, and the combined therapies reduced blood pressure to a greater extent. RWJ-676070 afforded a partial antiproteinuric effect, which was enhanced by the addition of enalapril or losartan. Renal functional impairment, and glomerular and tubular changes were partially ameliorated by RWJ-676070; parameters significantly improved with either enalapril or losartan alone and improved to a greater extent with the combined therapies. Our findings suggest that vasopressin receptor antagonists could be of additional therapeutic value in the treatment of chronic proteinuric nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Antidiuretic Hormone Receptor Antagonists*
  • Benzazepines / blood
  • Benzazepines / pharmacokinetics
  • Benzazepines / pharmacology*
  • Biomarkers / blood
  • Biomarkers / urine
  • Blood Pressure / drug effects
  • Body Weight / drug effects
  • Chronic Disease
  • Disease Models, Animal
  • Disease Progression
  • Diuresis / drug effects
  • Drinking / drug effects
  • Drug Therapy, Combination
  • Eating / drug effects
  • Enalapril / pharmacology*
  • Hormone Antagonists / blood
  • Hormone Antagonists / pharmacokinetics
  • Hormone Antagonists / pharmacology*
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Kidney Diseases / physiopathology
  • Losartan / pharmacology*
  • Male
  • Nephrectomy
  • Proteinuria / drug therapy
  • Proteinuria / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Vasopressin / metabolism
  • Renin-Angiotensin System / drug effects*
  • Spiro Compounds / blood
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology*
  • Time Factors


  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Antidiuretic Hormone Receptor Antagonists
  • Benzazepines
  • Biomarkers
  • Hormone Antagonists
  • RWJ-676070
  • Receptors, Vasopressin
  • Spiro Compounds
  • Enalapril
  • Losartan