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Three FDA\u2010approved drugs against constipation\u2010prone irritable bowel syndrome were tested for their ability to increase luminal fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator (CFTR) null (<jats:italic>cftr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) and F508del mutant (<jats:italic>F508del<\/jats:italic><jats:sup>mut\/mut<\/jats:sup>) murine intestine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Guanylate cyclase C agonist linaclotide, PGE<jats:sub>1<\/jats:sub> analogue lubiprostone and intestine\u2010specific NHE3 inhibitor tenapanor were perfused through a ~3 cm jejunal, proximal or mid\u2010distal colonic segment in anaesthetized <jats:italic>cftr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>, <jats:italic>F508del<\/jats:italic><jats:sup>mut\/mut<\/jats:sup> and WT mice. Net fluid balance was determined gravimetrically and alkaline output by pH\u2010stat back titration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Basal jejunal fluid absorptive rates were significantly higher and basal HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> output was significantly lower in <jats:italic>cftr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>F508del<\/jats:italic><jats:sup>mut\/mut<\/jats:sup> compared to WT mice. In <jats:italic>cftr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>F508del<\/jats:italic><jats:sup>mut\/mut<\/jats:sup> mice, all three drugs significantly inhibited the fluid absorptive rate and increased alkaline output in the jejunum and tenapanor and lubiprostone, but not linaclotide, in the colon. After tenapanor pre\u2010incubation, linaclotide elicited a robust fluid secretory response in WT jejunum, while no further change in absorptive rates was observed in <jats:italic>cftr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>F508del<\/jats:italic><jats:sup>mut\/mut<\/jats:sup> jejunum, suggesting that the increase in gut fluidity and alkalinity by linaclotide in CF gut is mediated via NHE3 inhibition. Lubiprostone also inhibited fluid absorption in <jats:italic>cftr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>F508del<\/jats:italic><jats:sup>mut\/mut<\/jats:sup> jejunum via NHE3 inhibition but had a residual NHE3\u2010independent effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Linaclotide, lubiprostone and tenapanor reduced fluid absorption and increased alkaline output in the CF gut. Their application may ameliorate constipation and reduce obstructive episodes in CF patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15323","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T06:55:29Z","timestamp":1605164129000},"page":"1018-1036","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Inhibition of Na<sup>+<\/sup>\/H<sup>+<\/sup> exchanger isoform 3 improves gut fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator\u2010deficient and F508del mutant mice"],"prefix":"10.1111","volume":"178","author":[{"given":"Qinghai","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hanover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"di Stefano","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hanover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinjie","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hanover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiu","family":"Renjie","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hanover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dorothee","family":"R\u00f6mermann","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hanover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven R.","family":"Talbot","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Research Hannover Medical School  Hanover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9600-2769","authenticated-orcid":false,"given":"Ursula E.","family":"Seidler","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hanover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,2,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2017.06.013"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13299"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-012-2410-2"},{"issue":"1","key":"e_1_2_12_5_1","first-page":"S21","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: G protein\u2010coupled receptors","volume":"176","author":"Alexander S. 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