Additive renoprotective effect of candesartan and tetrahydrobiopterin in rats after 5/6 nephrectomy.
BACKGROUND
Chronic treatment with candesartan cilexetil (C) improves the outcome of rats after 5/6 nephrectomy (Nx). Tetrahydrobiopterin (BH4), an essential cofactor for appropriate endothelial nitric oxide synthase (eNOS) activity, prevents an increase in blood pressure (BP) in Nx rats when given immediately after surgery. In the present study, we evaluated the renoprotective effect of a combined treatment.


METHODS
Five groups of rats were studied: SHAM (sham-operated rats, n=12); SNx (untreated 5/6 nephrectomized rats, n=15); C (SNx rats treated with candesartan cilexetil, 5 mg/kg/day per os, n=11); C+BH4 (SNx rats treated with candesartan cilexetil and BH4, 10 mg/kg/day intraperitoneally, n=11); and BH4 (SNx rats treated with BH4, 10 mg/kg/day intraperitoneally, n=11). Treatment began 30 days after surgery, when hypertension and renal insufficiency have developed. This day was considered as day 1 of treatment for statistical comparisons. The study was continued until 50% mortality was achieved in the SNx rats (4 months after surgery).


RESULTS
The survival rates were 100% for SHAM, 47% for SNx, 50% for BH4, 64% for C and 80% for C+BH4 (P<0.05 vs all). Untreated Nx rats developed hypertension, proteinuria (UP) and severe renal insufficiency. Mortality was associated with a lower renal function and increased urine protein excretion. In C and C+BH4 rats, systolic blood pressure (SBP) decreased significantly. BH4 alone had a mild non-significant effect on SBP. C and C+BH4 treatments attenuated significantly the increase in proteinuria found in SNx animals. The weight of the remnant kidneys as well as the severity of glomerulosclerosis were significantly lower in the C+BH4 rats.


CONCLUSIONS
This study shows that in subnephrectomized rats, addition of BH4 to a treatment with candesartan had an additive renoprotective effect. The mechanism of such action may include a better control of BP associated with a blockade of actions of angiotensin II (Ag II), an improvement in nitric oxide synthesis and a balanced redox.
Podjarny
Eduardo
E
Department of Nephrology & Hypertension, Laboratory of Renal Physiology, Sapir Medical Center, Kfar-Saba, Sackler Faculty of Medicine, University of Tel Aviv, and Meir Hospital, Israel. podjarny@post.tau.ac.il
Bernheim
Joelle
J
Hasdan
Galit
G
Karsh
Dorit
D
Rashid
Gloria
G
Green
Janice
J
Katz
Bernardo
B
Bernheim
Jacques
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019610:Cytoprotection; D004357:Drug Synergism; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy / Q000379:methods*; D011184:Postoperative Period; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D013599:Systole; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D001708:Biopterins; C003402:sapropterin; C077793:candesartan cilexetil