Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage.
BACKGROUND
Chronic renal disease is associated with oxidative stress and reduced nitric oxide availability which, in turn, promotes hypertension and further progression of renal damage. Most actions of nitric oxide are mediated by cyclic 3',5' guanosine monophosphate (cGMP) which is rapidly degraded by phosphodiesterases (PDE). Therefore, we investigated if inhibition of PDE-5 would retard the progression of chronic renal failure.


METHODS
We studied rats with 5/6 nephrectomy treated with sildenafil (2.5 mg/kg(-1)/day(-1)) in two experimental protocols. In the first protocol, we started sildenafil therapy immediately after renal ablation and continued treatment for 8 weeks. Control groups consisted of rats with renal ablation treated with drug-free vehicle and sham-operated rats with and without sildenafil treatment.


RESULTS
In these studies, sildenafil treatment prevented hypertension and deterioration of renal function, reduced histologic damage, inflammation and apoptosis, delayed the onset of proteinuria, and preserved renal capillary integrity. In the second protocol we compared sildenafil with losartan (7.5 mg/kg(-1)/day(-1)) and the combination of both drugs in established renal disease, starting these drugs 4 weeks after 5/6 nephrectomy. Delayed sildenafil treatment failed to improve proteinuria and glomerulosclerosis but ameliorated hypertension and azotemia.


CONCLUSIONS
These observations suggest that currently available PDE-5 inhibitors have potential clinical value in the treatment of chronic renal disease.
Rodríguez-Iturbe
Bernardo
B
Renal Service, Hospital Universitario, Universidad del Zulia, Instituto de Investigaciones Biomédicas (INBIOMED) Maracaibo, Venezuela. bernardori@telcel.net.ve
Ferrebuz
Atilio
A
Vanegas
Valentina
V
Quiroz
Yasmir
Y
Espinoza
Fabiana
F
Pons
Hector
H
Vaziri
Nosratola D
ND
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068677:Sildenafil Citrate; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP