Renoprotection by nitric oxide donor and lisinopril in the remnant kidney model.
Previous studies showed a renoprotective effect of l-arginine in experimental uremia. Whether this was caused by an increased nitric oxide (NO) release or depended on l-arginine per se is not clear. Here, we evaluated whether chronic administration of an NO donor, molsidomine, controlled systemic blood pressure and renal disease progression and prolonged survival in rats with renal mass reduction (RMR). Rats with RMR received the following daily in the drinking water: group 1 (n = 21), no specific therapy (vehicle); group 2 (n = 12), molsidomine, 120 mg/L; group 3 (n = 9), lisinopril, 25 mg/L; and group 4 (n = 12), reserpine, 5 mg/L, hydralazine, 80 mg/L, and hydrochlorothiazide, 25 mg/L, from day 21 after surgery, when rats had hypertension and proteinuria, until the death of the vehicle-treated rats. Molsidomine normalized systemic hypertension, only partially reduced proteinuria and serum creatinine levels, but significantly prolonged animal survival, particularly in the early stage of the disease. Lisinopril at a similar systemic blood pressure was even better than molsidomine in limiting proteinuria, preserving renal function, and prolonging survival, but triple therapy, despite being effective on blood pressure, offered no renoprotection or prolonged survival. Endothelin-1 (ET-1) levels, formed in excessive amounts by the kidneys of these animals, were reduced by molsidomine and lisinopril, but not by triple therapy. The prolongation of survival by NO donor could be attributed to its effect of reducing ET levels, which in turn may limit the smooth muscle cell proliferation and matrix accumulation responsible for organ and, especially, myocardial fibrosis in uremia.
Benigni
A
A
Mario Negri Institute for Pharmacological Research, Unit of Nephrology and Dialysis, Bergamo, Italy. abenigni@irfmn.mnegri.it
Zoja
C
C
Noris
M
M
Corna
D
D
Benedetti
G
G
Bruzzi
I
I
Todeschini
M
M
Remuzzi
G
G
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D004435:Eating / Q000187:drug effects; D019332:Endothelin-1 / Q000652:urine; D006830:Hydralazine / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects*; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D008981:Molsidomine / Q000494:pharmacology*; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009609:Nitrous Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D020030:Nitric Oxide Donors; D006852:Hydrochlorothiazide; D006830:Hydralazine; D009569:Nitric Oxide; D012110:Reserpine; D003404:Creatinine; D008981:Molsidomine; D017706:Lisinopril; D009609:Nitrous Oxide