V1/V2 Vasopressin receptor antagonism potentiates the renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction.
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.
Perico
Norberto
N
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Zoja
Carla
C
Corna
Daniela
D
Rottoli
Daniela
D
Gaspari
Flavio
F
Haskell
Lloyd
L
Remuzzi
Giuseppe
G
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D004231:Diuresis / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004359:Drug Therapy, Combination; D004435:Eating / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009392:Nephrectomy; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013141:Spiro Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D015415:Biomarkers; D006727:Hormone Antagonists; C526925:RWJ-676070; D017483:Receptors, Vasopressin; D013141:Spiro Compounds; D004656:Enalapril; D019808:Losartan