Jens Georg Leipziger

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

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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 the H(+)-ATPase in α-intercalated (α-IC) cells. The inability to acidify urine in response to furosemide serves to diagnose distal renal tubular acidosis (dysfunction of α-IC). Since TAL is important for acid/base regulation, we speculated that it is involved in furosemide-induced urinary acidification. Luminal furosemide (100μM) caused a major, stable and reversible intracellular alkalization (7.27±0.06 to 7.6±0.04) in isolated perfused murine medullary TAL (mTAL) and a pronounced H(+) secretion. This H(+) secretion was fully inhibited with luminal amiloride (1mM) and the Na(+)/H(+) exchanger3 (NHE3) specific antagonist #4167 (1μM). Moreover, furosemide triggered a substantial drop of intracellular [Na(+)] in the mTAL. These results suggest that the furosemide-induced H(+) secretion is a consequence of a drop in [Na(+)]i increasing the driving force for NHE3. Intriguingly, in whole animal experiments, furosemide-induced urinary acidification and net acid excretion was markedly reduced by specific NHE3 inhibition. Furthermore, the furosemide-induced urinary acidification was preserved during ENaC 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.

Original languageEnglish
JournalAmerican Journal of Physiology: Renal Physiology
Pages (from-to)F146-F153
Number of pages8
Publication statusPublished - 20 May 2015

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