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The purpose of the present study was to determine how the inhibition of basolateral K<jats:sub>ir<\/jats:sub>4.1\/K<jats:sub>ir<\/jats:sub>5.1 heteromeric K<jats:sup>+<\/jats:sup> channel affects epithelial sodium channel (ENaC)\u2010mediated Na<jats:sup>+<\/jats:sup> transport in the principal cells of cortical collecting duct (CCD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The effect of fluoxetine, amitriptyline and recently developed K<jats:sub>ir<\/jats:sub> inhibitor, VU0134992, on the activity of K<jats:sub>ir<\/jats:sub>4.1, K<jats:sub>ir<\/jats:sub>4.1\/K<jats:sub>ir<\/jats:sub>5.1 and ENaC were tested using electrophysiological approaches in CHO cells transfected with respective channel subunits, cultured polarized epithelial mCCD<jats:sub>cl1<\/jats:sub> cells and freshly isolated rat and human CCD tubules. To test the effect of pharmacological K<jats:sub>ir<\/jats:sub>4.1\/K<jats:sub>ir<\/jats:sub>5.1 inhibition on electrolyte homeostasis in vivo and corresponding changes in distal tubule transport, Dahl salt\u2010sensitive rats were injected with amitriptyline (15\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>) for 3\u2009days.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We found that inhibition of K<jats:sub>ir<\/jats:sub>4.1\/K<jats:sub>ir<\/jats:sub>5.1, but not the K<jats:sub>ir<\/jats:sub>4.1 channel, depolarizes the cell membrane, induces the elevation of intracellular Ca<jats:sup>2+<\/jats:sup> concentration and suppresses ENaC activity. Furthermore, we demonstrate that amitriptyline administration leads to a significant drop in plasma K<jats:sup>+<\/jats:sup> level, triggering sodium excretion and diuresis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The present data uncover a specific role of the K<jats:sub>ir<\/jats:sub>4.1\/K<jats:sub>ir<\/jats:sub>5.1 channel in the modulation of ENaC activity and emphasize the potential for using K<jats:sub>ir<\/jats:sub>4.1\/K<jats:sub>ir<\/jats:sub>5.1 inhibitors to regulate electrolyte homeostasis and BP.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15779","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T08:17:07Z","timestamp":1639469827000},"page":"2953-2968","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Crosstalk between epithelial sodium channels (<scp>ENaC)<\/scp> and basolateral potassium channels (K<sub>ir<\/sub>4.1\/K<sub>ir<\/sub>5.1) in the cortical collecting duct"],"prefix":"10.1111","volume":"179","author":[{"given":"Elena","family":"Isaeva","sequence":"first","affiliation":[{"name":"Department of Physiology Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Cellular Membranology Bogomoletz Institute of Physiology  Kyiv Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruslan","family":"Bohovyk","sequence":"additional","affiliation":[{"name":"Department of Physiology Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Cellular Membranology Bogomoletz Institute of Physiology  Kyiv Ukraine"},{"name":"Department of Molecular Pharmacology and Physiology University of South Florida  Tampa Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mykhailo","family":"Fedoriuk","sequence":"additional","affiliation":[{"name":"Department of Physiology Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Cellular Membranology Bogomoletz Institute of Physiology  Kyiv Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexey","family":"Shalygin","sequence":"additional","affiliation":[{"name":"Department of Physiology Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Molecular and Cellular Physiology Institute of Cytology of the Russian Academy of Sciences  St. Petersburg Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine A.","family":"Klemens","sequence":"additional","affiliation":[{"name":"Department of Physiology Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Molecular Pharmacology and Physiology University of South Florida  Tampa Florida USA"},{"name":"Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Zietara","sequence":"additional","affiliation":[{"name":"Department of Physiology Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Molecular Pharmacology and Physiology University of South Florida  Tampa Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladislav","family":"Levchenko","sequence":"additional","affiliation":[{"name":"Department of Physiology Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Molecular Pharmacology and Physiology University of South Florida  Tampa Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerod S.","family":"Denton","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pharmacology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5190-8356","authenticated-orcid":false,"given":"Alexander","family":"Staruschenko","sequence":"additional","affiliation":[{"name":"Department of Physiology Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Molecular Pharmacology and Physiology University of South Florida  Tampa Florida USA"},{"name":"Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Clement J. 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