Sildenafil reduces polyuria in rats with lithium-induced NDI.
Lithium (Li)-treated patients often develop urinary concentrating defect and polyuria, a condition known as nephrogenic diabetes insipidus (NDI). In a rat model of Li-induced NDI, we studied the effect that sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, has on renal expression of aquaporin-2 (AQP2), urea transporter UT-A1, Na(+)/H(+) exchanger 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (NKCC2), epithelial Na channel (ENaC; α-, β-, and γ-subunits), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase. We also evaluated cGMP levels in medullary collecting duct cells in suspension. For 4 wk, Wistar rats received Li (40 mmol/kg food) or no treatment (control), some receiving, in weeks 2-4, Sil (200 mg/kg food) or Li and Sil (Li+Sil). In Li+Sil rats, urine output and free water clearance were markedly lower, whereas urinary osmolality was higher, than in Li rats. The cGMP levels in the suspensions of medullary collecting duct cells were markedly higher in the Li+Sil and Sil groups than in the control and Li groups. Semiquantitative immunoblotting revealed the following: in Li+Sil rats, AQP2 expression was partially normalized, whereas that of UT-A1, γ-ENaC, and eNOS was completely normalized; and expression of NKCC2 and NHE3 was significantly higher in Li rats than in controls. Inulin clearance was normal in all groups. Mean arterial pressure and plasma arginine vasopressin did not differ among the groups. Sil completely reversed the Li-induced increase in renal vascular resistance. We conclude that, in experimental Li-induced NDI, Sil reduces polyuria, increases urinary osmolality, and decreases free water clearance via upregulation of renal AQP2 and UT-A1.
Nephrology Dept., Univ. of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 3° andar, sala 3310, CEP 01246-903, São Paulo, Brazil.
Talita Rojas
TR
Sanches
Rildo Aparecido
RA
Volpini
Maria H
MH
Massola Shimizu
Ana Carolina de
AC
Bragança
Fabíola
F
Oshiro-Monreal
Antonio Carlos
AC
Seguro
Lúcia
L
Andrade
D000818:Animals; D051399:Aquaporin 2 / Q000096:biosynthesis; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000096:biosynthesis; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000503:physiopathology*; D004326:Drinking / Q000187:drug effects; D053503:Epithelial Sodium Channels / Q000096:biosynthesis; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D007679:Kidney Medulla / Q000201:enzymology; D018020:Lithium Compounds / Q000009:adverse effects*; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D010879:Piperazines / Q000627:therapeutic use*; D011141:Polyuria / Q000188:drug therapy*; D011687:Purines / Q000627:therapeutic use; D051381:Rats; D000068677:Sildenafil Citrate; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis; D028021:Sodium-Potassium-Chloride Symporters / Q000096:biosynthesis; D064466:Solute Carrier Family 12, Member 1; D013450:Sulfones / Q000627:therapeutic use*; D000096982:Urea Transporters
D051399:Aquaporin 2; D006152:Cyclic GMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D053503:Epithelial Sodium Channels; D018020:Lithium Compounds; D026901:Membrane Transport Proteins; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010879:Piperazines; D011687:Purines; D000068677:Sildenafil Citrate; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D013450:Sulfones; D000096982:Urea Transporters; C578716:Slc12a1 protein, rat; C000613387:Slc9a3 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat