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This study's purpose was to determine the co-ion that accompanies benzamil- and DIDS-sensitive Cl<jats:sup>\u2212<\/jats:sup>flux. Thus transepithelial voltage, V<jats:sub>T<\/jats:sub>, as well as total CO<jats:sub>2<\/jats:sub>(tCO<jats:sub>2<\/jats:sub>) and Cl<jats:sup>\u2212<\/jats:sup>flux were measured in CCDs from aldosterone-treated mice consuming a NaCl-replete diet. We reasoned that if stilbene inhibitors (DIDS) reduce conductive anion secretion they should reduce the lumen-negative V<jats:sub>T<\/jats:sub>. However, during ENaC blockade (benzamil, 3 \u03bcM), DIDS (100 \u03bcM) application to the perfusate reduced net H<jats:sup>+<\/jats:sup>secretion, which increased the lumen-negative V<jats:sub>T<\/jats:sub>. Conversely, ENaC blockade alone stimulated H<jats:sup>+<\/jats:sup>secretion, which reduced the lumen-negative V<jats:sub>T<\/jats:sub>. Application of an ENaC inhibitor to the perfusate reduced the lumen-negative V<jats:sub>T<\/jats:sub>, increased intercalated cell intracellular pH, and reduced net tCO<jats:sub>2<\/jats:sub>secretion. However, benzamil did not change tCO<jats:sub>2<\/jats:sub>flux during apical H<jats:sup>+<\/jats:sup>-ATPase blockade (bafilomycin, 5 nM). The increment in H<jats:sup>+<\/jats:sup>secretion observed with benzamil application contributes to the fall in V<jats:sub>T<\/jats:sub>observed with application of this diuretic. As such, ENaC blockade reduces the lumen-negative V<jats:sub>T<\/jats:sub>by inhibiting conductive Na<jats:sup>+<\/jats:sup>absorption and by stimulating H<jats:sup>+<\/jats:sup>secretion by type A intercalated cells. In conclusion, 1) in CCDs from aldosterone-treated mice, benzamil application stimulates HCl secretion mediated by the apical H<jats:sup>+<\/jats:sup>-ATPase and a yet to be identified conductive Cl<jats:sup>\u2212<\/jats:sup>transport pathway; 2) benzamil-induced HCl secretion is reversed with the application of stilbene inhibitors or H<jats:sup>+<\/jats:sup>-ATPase inhibitors to the perfusate; and 3) benzamil reduces V<jats:sub>T<\/jats:sub>not only by inhibiting conductive Na<jats:sup>+<\/jats:sup>absorption, but also by stimulating H<jats:sup>+<\/jats:sup>secretion.<\/jats:p>","DOI":"10.1152\/ajprenal.00120.2015","type":"journal-article","created":{"date-parts":[[2015,5,28]],"date-time":"2015-05-28T12:54:22Z","timestamp":1432817662000},"page":"F259-F268","source":"Crossref","is-referenced-by-count":9,"title":["ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. II. 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