| First Author | Ayasse N | Year | 2021 |
| Journal | Am J Physiol Renal Physiol | Volume | 320 |
| Issue | 4 | Pages | F596-F607 |
| PubMed ID | 33554781 | Mgi Jnum | J:344202 |
| Mgi Id | MGI:7574183 | Doi | 10.1152/ajprenal.00444.2020 |
| Citation | Ayasse N, et al. (2021) Benzamil-mediated urine alkalization is caused by the inhibition of H(+)-K(+)-ATPases. Am J Physiol Renal Physiol 320(4):F596-F607 |
| abstractText | 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 microg/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 (DeltapH: 0.33 +/- 0.07) and reduced NH(4)(+) and titratable acid excretion and that these effects were distinctly enhanced in animals fed a low-K(+) diet (DeltapH: 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 alpha(1)-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. |
