Jens Georg Leipziger

Hydrochlorothiazide and acute urinary acidification: The 'voltage hypothesis' of ENaC-dependent H+ secretion refuted

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AIM: The 'voltage hypothesis' of H+ secretion states that urinary acidification following increased Na+ delivery to the collecting duct (CD) is ENaC-dependent leading to transepithelial voltage-dependent increase in H+ secretion. We recently showed that furosemide acidifies the urine independently of ENaC activity. If the voltage hypothesis holds, hydrochlorothiazide (HCT) must acidify the urine. We here tested the acute effect of HCT on urine pH under normal and high ENaC expression.

METHODS: Mice subjected to a control or a low-Na+ diet were anesthetized and infused (0.5 ml h-1 ) with saline. Catheterization of the urinary bladder allowed real-time measurement of diuresis and urine pH. Mice received either HCT (1mg ml-1 ) or vehicle. Urinary Na+ and K+ excretions were determined by flame photometry. ENaC expression levels were measured by semi-quantitive Western Blotting.

RESULTS: (1) HCT increased diuresis and natriuresis in both diet groups. (2) K+ excretion rates increased after HCT administration from 18.6±1.3 to 31.7±2.5 μmol h-1 in the control diet group and from 23.0±1.3 to 48.7±3.0 μmol h-1 in the low-Na+ diet group. (3) Mice fed a low-Na+ diet showed a marked upregulation of ENaC. (4) Importantly, no acute changes in urine pH were observed after the administration of HCT in either group.

CONCLUSION: Acute administration of HCT has no effect on urine pH. Similarly, substantial functional and molecular up-regulation of ENaC did not cause HCT to acutely change urine pH. Thus, an increased Na+ load to the CD does not alter urine pH. This supports our previous finding and likely falsifies the voltage hypothesis of H+ secretion. This article is protected by copyright. All rights reserved.

Original languageEnglish
Article numbere13013
JournalActa Physiologica
Number of pages8
Publication statusPublished - May 2018

Bibliographical note

© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

    Research areas

  • Na , Cl cotransporter, acid excretion, distal convoluted tubule, epithelial Na channel

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