Acute inhibition of NCC does not activate distal electrogenic Na+ reabsorption or kaliuresis

Am J Physiol Renal Physiol. 2014 Feb 15;306(4):F457-67. doi: 10.1152/ajprenal.00339.2013. Epub 2014 Jan 8.


Na(+) reabsorption from the distal renal tubule involves electroneutral and electrogenic pathways, with the latter promoting K(+) excretion. The relative activities of these two pathways are tightly controlled, participating in the minute-to-minute regulation of systemic K(+) balance. The pathways are interdependent: the activity of the NaCl cotransporter (NCC) in the distal convoluted tubule influences the activity of the epithelial Na(+) channel (ENaC) downstream. This effect might be mediated by changes in distal Na(+) delivery per se or by molecular and structural adaptations in the connecting tubule and collecting ducts. We hypothesized that acute inhibition of NCC activity would cause an immediate increase in Na(+) flux through ENaC, with a concomitant increase in renal K(+) excretion. We tested this using renal clearance methodology in anesthetized mice, by the administration of hydrochlorothiazide (HCTZ) and/or benzamil (BZM) to exert specific blockade of NCC and ENaC, respectively. Bolus HCTZ elicited a natriuresis that was sustained for up to 110 min; urinary K(+) excretion was not affected. Furthermore, the magnitude of the natriuresis was no greater during concomitant BZM administration. This suggests that ENaC-mediated Na(+) reabsorption was not normally limited by Na(+) delivery, accounting for the absence of thiazide-induced kaliuresis. After dietary Na(+) restriction, HCTZ elicited a kaliuresis, but the natiuretic effect of HCTZ was not enhanced by BZM. Our findings support a model in which inhibition of NCC activity does not increase Na(+) reabsorption through ENaC solely by increasing distal Na(+) delivery but rather by inducing a molecular and structural adaptation in downstream nephron segments.

Keywords: NaCl cotransporter; benzamil; epithelial Na+ channel; hydrochlorothiazide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiloride / analogs & derivatives
  • Amiloride / pharmacology
  • Animals
  • Diuretics / pharmacology
  • Hydrochlorothiazide / pharmacology
  • Ion Transport / drug effects*
  • Kidney Tubules, Distal / drug effects*
  • Kidney Tubules, Distal / metabolism
  • Mice
  • Natriuresis / drug effects
  • Sodium / metabolism*
  • Sodium Chloride Symporter Inhibitors / pharmacology*
  • Sodium Chloride Symporters / metabolism*


  • Diuretics
  • Sodium Chloride Symporter Inhibitors
  • Sodium Chloride Symporters
  • benzamil
  • Hydrochlorothiazide
  • Amiloride
  • Sodium