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

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Abstract

BACKGROUND: There is growing consensus that under physiological conditions collecting duct H+ secretion is independent of epithelial sodium channel (ENaC) activity. We have recently shown that the direct ENaC inhibitor benzamil acutely impairs H+ excretion by blocking the 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), well known to cause K+ retention by direct ENaC inhibition.

METHODS: The acute effect of TMP (5 µg/g bw) 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. Additionally, the effect of TMP was investigated in vitro using pig gastric H+/K+ ATPase-enriched membrane vesicles.

RESULTS: 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.

CONCLUSIONS: 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.

OriginalsprogEngelsk
TidsskriftAmerican journal of physiology. Renal physiology
Vol/bind326
Nummer1
Sider (fra-til)F143-F151
ISSN1931-857X
DOI
StatusUdgivet - 1 jan. 2024

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