TY - JOUR
T1 - Additive renoprotective effect of candesartan and tetrahydrobiopterin in rats after 5/6 nephrectomy
AU - Podjarny, Eduardo
AU - Bernheim, Joelle
AU - Hasdan, Galit
AU - Karsh, Dorit
AU - Rashid, Gloria
AU - Green, Janice
AU - Katz, Bernardo
AU - Bernheim, Jacques
N1 - Funding Information:
Conflict of interest statement. This study was supported by a grant from Astra-Zeneca.
PY - 2007/7
Y1 - 2007/7
N2 - 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, 10mg/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. Conclusion. 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.
AB - 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, 10mg/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. Conclusion. 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.
KW - Angiotensin receptor antagonist
KW - Hypertension
KW - Nitric oxide
KW - Proteinuria
KW - Renal failure
KW - Tetrahydrobiopterin
UR - http://www.scopus.com/inward/record.url?scp=34547830283&partnerID=8YFLogxK
U2 - 10.1093/ndt/gfm129
DO - 10.1093/ndt/gfm129
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AN - SCOPUS:34547830283
VL - 22
SP - 1864
EP - 1872
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
SN - 0931-0509
IS - 7
ER -