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.