Trimethoprim inhibits renal H+/K+ ATPase in states of K+ depletion

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

1 Citation (Scopus)

Abstract

There is growing consensus that under physiological conditions, collecting duct H+ secretion is independent of epithelial Na+ channel (ENaC) activity. We have recently shown that the direct ENaC inhibitor benzamil acutely impairs H+ excretion by blocking renal H+-K+-ATPase. However, the question remains whether inhibition of ENaC per se causes alterations in renal H+ excretion. To revisit this question, we studied the effect of the antibiotic trimethoprim (TMP), which is well known to cause K+ retention by direct ENaC inhibition. The acute effect of TMP (5 lg/g body wt) was assessed in bladder-catheterized mice, allowing real-time measurement of urinary pH, electrolyte, and acid excretion. Dietary K+ depletion was used to increase renal H+- K+-ATPase activity. In addition, the effect of TMP was investigated in vitro using pig gastric H+-K+-ATPase-enriched membrane vesicles. TMP acutely increased natriuresis and decreased kaliuresis, confirming its ENaC-inhibiting property. Under control diet conditions, TMP had no effect on urinary pH or acid excretion. Interestingly, K+ depletion unmasked an acute urine alkalizing effect of TMP. This finding was corroborated by in vitro experiments showing that TMP inhibits H+-K+-ATPase activity, albeit at much higher concentrations than benzamil. In conclusion, under control diet conditions, TMP inhibited ENaC function without changing urinary H+ excretion. This finding further supports the hypothesis that the inhibition of ENaC per se does not impair H+ excretion in the collecting duct. Moreover, TMP-induced urinary alkalization in animals fed a low-K+ diet highlights the importance of renal H+-K+-ATPase-mediated H+ secretion in states of K+ depletion.

Original languageEnglish
JournalAmerican journal of physiology. Renal physiology
Volume326
Issue1
Pages (from-to)F143-F151
ISSN1931-857X
DOIs
Publication statusPublished - 1 Jan 2024

Keywords

  • Acidosis/metabolism
  • Animals
  • Anti-Bacterial Agents/pharmacology
  • Epithelial Sodium Channels/metabolism
  • H(+)-K(+)-Exchanging ATPase/metabolism
  • Kidney Tubules, Collecting/metabolism
  • Mice
  • Sodium/metabolism
  • Swine
  • Trimethoprim/pharmacology
  • metabolic acidosis
  • sulfamethoxazole
  • benzamil
  • epithelial Na+ channel

Fingerprint

Dive into the research topics of 'Trimethoprim inhibits renal H+/K+ ATPase in states of K+ depletion'. Together they form a unique fingerprint.

Cite this