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 language | English |
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Journal | American journal of physiology. Renal physiology |
Volume | 326 |
Issue | 1 |
Pages (from-to) | F143-F151 |
ISSN | 1931-857X |
DOIs | |
Publication status | Published - 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