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Benzamil-mediated urine alkalization is caused by the inhibition of H+, K+ ATPases

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Benzamil-mediated urine alkalization is caused by the inhibition of H+, K+ ATPases. / Ayasse, Niklas; Berg, Peder; Andersen, Jesper Frank; Svendsen, Samuel Levi Svinth C; Sørensen, Mads Vaarby; Fedosova, Natalya; Wingo, Charles; Lynch, I. Jeanette; Leipziger, Jens Georg.

In: American Journal of Physiology: Renal Physiology, Vol. 320, No. 4, 04.2021, p. F596-F607.

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

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Ayasse, Niklas et al. "Benzamil-mediated urine alkalization is caused by the inhibition of H+, K+ ATPases". American Journal of Physiology: Renal Physiology. 2021, 320(4). F596-F607. https://doi.org/10.1152/ajprenal.00444.2020

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Ayasse, Niklas ; Berg, Peder ; Andersen, Jesper Frank ; Svendsen, Samuel Levi Svinth C ; Sørensen, Mads Vaarby ; Fedosova, Natalya ; Wingo, Charles ; Lynch, I. Jeanette ; Leipziger, Jens Georg. / Benzamil-mediated urine alkalization is caused by the inhibition of H+, K+ ATPases. In: American Journal of Physiology: Renal Physiology. 2021 ; Vol. 320, No. 4. pp. F596-F607.

Bibtex

@article{ab0e60e8b95e47b49ade9b0976a87e95,
title = "Benzamil-mediated urine alkalization is caused by the inhibition of H+, K+ ATPases",
abstract = "Epithelial Na+ channel (ENaC) blockers elicit acute and substantial increases of urinary pH. The underlying mechanism remains to be understood. Here, we evaluated if benzamil-induced urine alkalization is mediated by an acute reduction in H+ secretion via renal H+-K+-ATPases (HKAs). Experiments were performed in vivo on HKA double-knockout and wild-type mice. Alterations in dietary K+ intake were used to change renal HKA and ENaC activity. The acute effects of benzamil (0.2 µg/g body wt, sufficient to block ENaC) on urine flow rate and urinary electrolyte and acid excretion were monitored in anesthetized, bladder-catheterized animals. We observed that benzamil acutely increased urinary pH (ΔpH: 0.33 ± 0.07) and reduced NH4+ and titratable acid excretion and that these effects were distinctly enhanced in animals fed a low-K+ diet (ΔpH: 0.74 ± 0.12), a condition when ENaC activity is low. In contrast, benzamil did not affect urine acid excretion in animals kept on a high-K+ diet (i.e., during high ENaC activity). Thus, urine alkalization appeared completely uncoupled from ENaC function. The absence of benzamil-induced urinary alkalization in HKA double-knockout mice confirmed the direct involvement of these enzymes. The inhibitory effect of benzamil was also shown in vitro for the pig α1-isoform of HKA. These results suggest a revised explanation of the benzamil effect on renal acid-base excretion. Considering the conditions used here, we suggest that it is caused by a direct inhibition of HKAs in the collecting duct and not by inhibition of the ENaC function.NEW & NOTEWORTHY Bolus application of epithelial Na+ channel (EnaC) blockers causes marked and acute increases of urine pH. Here, we provide evidence that the underlying mechanism involves direct inhibition of the H+-K+ pump in the collecting duct. This could provide a fundamental revision of the previously assumed mechanism that suggested a key role of ENaC inhibition in this response.",
keywords = "acid excretion, acid secretion, aldosterone-sensitive distal nephron, benzamil, epithelial Na+ channel",
author = "Niklas Ayasse and Peder Berg and Andersen, {Jesper Frank} and Svendsen, {Samuel Levi Svinth C} and S{\o}rensen, {Mads Vaarby} and Natalya Fedosova and Charles Wingo and Lynch, {I. Jeanette} and Leipziger, {Jens Georg}",
year = "2021",
month = apr,
doi = "10.1152/ajprenal.00444.2020",
language = "English",
volume = "320",
pages = "F596--F607",
journal = "American Journal of Physiology: Renal Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "4",

}

RIS

TY - JOUR

T1 - Benzamil-mediated urine alkalization is caused by the inhibition of H+, K+ ATPases

AU - Ayasse, Niklas

AU - Berg, Peder

AU - Andersen, Jesper Frank

AU - Svendsen, Samuel Levi Svinth C

AU - Sørensen, Mads Vaarby

AU - Fedosova, Natalya

AU - Wingo, Charles

AU - Lynch, I. Jeanette

AU - Leipziger, Jens Georg

PY - 2021/4

Y1 - 2021/4

N2 - Epithelial Na+ channel (ENaC) blockers elicit acute and substantial increases of urinary pH. The underlying mechanism remains to be understood. Here, we evaluated if benzamil-induced urine alkalization is mediated by an acute reduction in H+ secretion via renal H+-K+-ATPases (HKAs). Experiments were performed in vivo on HKA double-knockout and wild-type mice. Alterations in dietary K+ intake were used to change renal HKA and ENaC activity. The acute effects of benzamil (0.2 µg/g body wt, sufficient to block ENaC) on urine flow rate and urinary electrolyte and acid excretion were monitored in anesthetized, bladder-catheterized animals. We observed that benzamil acutely increased urinary pH (ΔpH: 0.33 ± 0.07) and reduced NH4+ and titratable acid excretion and that these effects were distinctly enhanced in animals fed a low-K+ diet (ΔpH: 0.74 ± 0.12), a condition when ENaC activity is low. In contrast, benzamil did not affect urine acid excretion in animals kept on a high-K+ diet (i.e., during high ENaC activity). Thus, urine alkalization appeared completely uncoupled from ENaC function. The absence of benzamil-induced urinary alkalization in HKA double-knockout mice confirmed the direct involvement of these enzymes. The inhibitory effect of benzamil was also shown in vitro for the pig α1-isoform of HKA. These results suggest a revised explanation of the benzamil effect on renal acid-base excretion. Considering the conditions used here, we suggest that it is caused by a direct inhibition of HKAs in the collecting duct and not by inhibition of the ENaC function.NEW & NOTEWORTHY Bolus application of epithelial Na+ channel (EnaC) blockers causes marked and acute increases of urine pH. Here, we provide evidence that the underlying mechanism involves direct inhibition of the H+-K+ pump in the collecting duct. This could provide a fundamental revision of the previously assumed mechanism that suggested a key role of ENaC inhibition in this response.

AB - Epithelial Na+ channel (ENaC) blockers elicit acute and substantial increases of urinary pH. The underlying mechanism remains to be understood. Here, we evaluated if benzamil-induced urine alkalization is mediated by an acute reduction in H+ secretion via renal H+-K+-ATPases (HKAs). Experiments were performed in vivo on HKA double-knockout and wild-type mice. Alterations in dietary K+ intake were used to change renal HKA and ENaC activity. The acute effects of benzamil (0.2 µg/g body wt, sufficient to block ENaC) on urine flow rate and urinary electrolyte and acid excretion were monitored in anesthetized, bladder-catheterized animals. We observed that benzamil acutely increased urinary pH (ΔpH: 0.33 ± 0.07) and reduced NH4+ and titratable acid excretion and that these effects were distinctly enhanced in animals fed a low-K+ diet (ΔpH: 0.74 ± 0.12), a condition when ENaC activity is low. In contrast, benzamil did not affect urine acid excretion in animals kept on a high-K+ diet (i.e., during high ENaC activity). Thus, urine alkalization appeared completely uncoupled from ENaC function. The absence of benzamil-induced urinary alkalization in HKA double-knockout mice confirmed the direct involvement of these enzymes. The inhibitory effect of benzamil was also shown in vitro for the pig α1-isoform of HKA. These results suggest a revised explanation of the benzamil effect on renal acid-base excretion. Considering the conditions used here, we suggest that it is caused by a direct inhibition of HKAs in the collecting duct and not by inhibition of the ENaC function.NEW & NOTEWORTHY Bolus application of epithelial Na+ channel (EnaC) blockers causes marked and acute increases of urine pH. Here, we provide evidence that the underlying mechanism involves direct inhibition of the H+-K+ pump in the collecting duct. This could provide a fundamental revision of the previously assumed mechanism that suggested a key role of ENaC inhibition in this response.

KW - acid excretion

KW - acid secretion

KW - aldosterone-sensitive distal nephron

KW - benzamil

KW - epithelial Na+ channel

UR - http://www.scopus.com/inward/record.url?scp=85104160283&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00444.2020

DO - 10.1152/ajprenal.00444.2020

M3 - Journal article

C2 - 33554781

VL - 320

SP - F596-F607

JO - American Journal of Physiology: Renal Physiology

JF - American Journal of Physiology: Renal Physiology

SN - 1931-857X

IS - 4

ER -