Article open access publication

Furosemide-induced urinary acidification is caused by pronounced H+ secretion in the thick ascending limb

American Journal of Physiology. Renal physiology, American Physiological Society, ISSN 0363-6127

Volume 309, 2, 2015

DOI:10.1152/ajprenal.00154.2015, Dimensions: pub.1011822438, PMID: 25995110,

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  1. (1) Aarhus University, grid.7048.b, AU
  2. (2) Kiel University, grid.9764.c

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Germany

Denmark

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Europe

Description

The loop diuretic furosemide inhibits NaCl reabsorption in the thick ascending limb (TAL). In addition, furosemide acidifies the urine, which is traditionally explained by increased Na+ loading to the distal tubule causing an activation of H+ secretion via H+-ATPase in α-intercalated cells. The inability to acidify urine in response to furosemide serves to diagnose distal renal tubular acidosis (dysfunction of α-intercalated cells). Since the TAL is important for acid/base regulation, we speculated that it is involved in furosemide-induced urinary acidification. Luminal furosemide (100 μM) caused major, stable, and reversible intracellular alkalization (7.27 ± 0.06 to 7.6 ± 0.04) in isolated perfused murine medullary TAL and pronounced H+ secretion. This H+ secretion was fully inhibited with luminal amiloride (1 mM) and the Na+/H+ exchanger (NHE)3-specific antagonist #4167 (1 μM). Moreover, furosemide triggered a substantial drop of intracellular Na+ concentration in the medullary TAL. These results suggest that the furosemide-induced H+ secretion is a consequence of a drop in intracellular Na+ concentration, increasing the driving force for NHE3. Intriguingly, in whole animal experiments, furosemide-induced urinary acidification and net acid excretion were markedly reduced by specific NHE3 inhibition. Furthermore, the furosemide-induced urinary acidification was partially preserved during epithelial Na+ channel inhibition with benzamil. These results provide new insights in the mechanism of furosemide-induced urinary acidification and emphasize the role of the TAL in renal acid/base handling.

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Times Cited: 21

Field Citation Ratio (FCR): 10.19

Relative Citation ratio (RCR): 1.31

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Green, Submitted