Hydrochlorothiazide Does Not Acutely Acidify Urine

Abstract

Urine acidification is fine‐tuned in the collecting duct. The α‐intercalated cells in this segment express the apical H+‐ATPase, which activity is assumed to be dependent on the transepithelial voltage (Vte). The lumen‐negative Vte generated by Na+ influx via the epithelial Na+ channel (ENaC) is believed to promote H+‐ATPase‐dependent H+ secretion. An increased Na+ delivery to the collecting duct would result in additional Na+ uptake through ENaC, increased lumen‐negative Vte, and thus, favor acid secretion via the H+‐ATPase. This mechanism has been the main explanation for the marked urine acidification by loop diuretics. However, we recently showed that urine acidification by furosemide occurs independent of ENaC activity. We demonstrated that furosemide directly stimulates H+ secretion in the thick ascending limb via the Na+/H+ exchanger NHE3. Here, we investigate whether hydrochlorothiazide, an inhibitor of Na+, Cl− cotransporter (NCC) in the distal convoluted tubule causes acute alterations of urine pH. NCC inhibition should similar to the loop diuretics lead to increased Na+ delivery to the collecting duct and, thus, cause urine acidification.Mice were anesthetizes and infused (0.5 ml/h) via a jugular vein catheter with control or hydrochlorothiazide (HCT) (30 mg/kg/h) and bladder was catheterized. Urine pH was measured directly in the outflow of bladder catheter and urine Na+ and K+ were measured using flame photometry.HCT increased urine flow rate from 8.1±1.8 to 15.8±2.6 μl/h/g BW (n=11). Na+ excretion was increased from 20.81±4.15 to 51.8±7.73 μmol/h, whereas no change in K+ excretion was observed. These results clearly demonstrate the diuretic properties of HCT. Interestingly, urine pH was unchanged during the entire infusion period of HCT (1h) compared to control (pH 6.13±0.23 vs 6.15±0.16).Hence, despite the natriuresis induced by HCT, an acute increased H+ secretion was not observed. These results therefore challenge the current understanding of loop‐diuretic‐induced urine acidification, because other means for increasing Na+ delivery to the collecting duct do not acidify urine. Thus, this study supports our previous finding that H+ secretion by furosemide takes place already in the thick ascending limb and will contribute to a better understanding of how the kidneys secrete acid.