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O-071 Salt-sparing Diuretic Action Of A Urea Analogue Inhibitor Of Urea Transporters Ut-a And Ut-b In Rats
  1. O Cil1,
  2. C Esteva-Font2,
  3. ST Tas3,
  4. S Lee2,
  5. M Ertunc3,
  6. AS Verkman2
  1. 1Depatment of Pediatrics, Hacettepe University, Faculty of Medicine, Ankara, Turkey
  2. 2Departments of Medicine and Physiology, University of California San Francisco, San Francisco, USA
  3. 3Depatment of Pharmacology, Hacettepe University, Faculty of Medicine, Ankara, Turkey

Abstract

Background and aims Urea is end metabolite of protein metabolism and is crucial for generation of hypertonic renal medulla. Urea transport to medullary interstitium is facilitated by urea transporters (UT-A and UT-B). UT inhibitors have potential use as a novel class of salt-sparing diuretics.

Methods UT inhibitor effect of urea analogue dimethylthiourea (DMTU) was investigated and characterised in cell-based assays. Kidney function tests were investigated in both 1-day and 7-days DMTU-treated (500 mg/kg ip initially, then 125 mg/kg ip every 12h) rats. The effect of DMTU on maximum urine concentrating function was investigated in low (6%) and normal (20%) protein-fed rats.

Results DMTU non-competitively inhibited UT-A and UT-B with IC50 of ~3 mM. Following 500 mg/kg ip injection, plasma DMTU concentration was initially 10 mM (plasma elimination t1/2 ~10 h) and urine DMTU concentration was >20 mM for 12 h. DMTU-treated rats showed reversible, sustained reduction in urine osmolality (>60%) and 3-fold increased daily urine output. DMTU increased renal electrolyte-free water excretion without altering solute excretion. DMTU impaired maximum urinary concentrating function only in normal protein-fed rats. Methylurea, a non-UT inhibitor urea analogue, had no effect on either urine volume or osmolality. DMTU-treated rats had greater diuresis and much reduced urinary salt loss compared to that of furosemide-treated rats.

Conclusions These results establish a rat model of sustained UT inhibition and demonstrate remarkable diuretic efficacy of UT inhibition. Prominent effect of UT inhibitors on net renal water excretion implies a novel therapeutic strategy for treatment of oedema in hypervolemic diseases.

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