{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:00:03Z","timestamp":1791273603270,"version":"4.1.0"},"reference-count":25,"publisher":"American Physiological Society","issue":"6","funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK52766"],"award-info":[{"award-number":["DK52766"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK57061"],"award-info":[{"award-number":["DK57061"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2015,9,15]]},"abstract":"<jats:p> Human jejunum smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs) express the SCN5A-encoded voltage-gated, mechanosensitive sodium channel Na<jats:sub>V<\/jats:sub>1.5. Na<jats:sub>V<\/jats:sub>1.5 contributes to small bowel excitability, and Na<jats:sub>V<\/jats:sub>1.5 inhibitor ranolazine produces constipation by an unknown mechanism. We aimed to determine the presence and molecular identity of Na<jats:sup>+<\/jats:sup> current in the human colon smooth muscle and to examine the effects of ranolazine on Na<jats:sup>+<\/jats:sup> current, mechanosensitivity, and smooth muscle contractility. Inward currents were recorded by whole cell voltage clamp from freshly dissociated human colon SMCs at rest and with shear stress. SCN5A mRNA and Na<jats:sub>V<\/jats:sub>1.5 protein were examined by RT-PCR and Western blots, respectively. Ascending human colon strip contractility was examined in a muscle bath preparation. SCN5A mRNA and Na<jats:sub>V<\/jats:sub>1.5 protein were identified in human colon circular muscle. Freshly dissociated human colon SMCs had Na<jats:sup>+<\/jats:sup> currents (\u22121.36 \u00b1 0.36 pA\/pF), shear stress increased Na<jats:sup>+<\/jats:sup> peaks by 17.8 \u00b1 1.8% and accelerated the time to peak activation by 0.7 \u00b1 0.3 ms. Ranolazine (50 \u03bcM) blocked peak Na<jats:sup>+<\/jats:sup> current by 43.2 \u00b1 9.3% and inhibited shear sensitivity by 25.2 \u00b1 3.2%. In human ascending colon strips, ranolazine decreased resting tension (31%), reduced the frequency of spontaneous events (68%), and decreased the response to smooth muscle electrical field stimulation (61%). In conclusion, SCN5A-encoded Na<jats:sub>V<\/jats:sub>1.5 is found in human colonic circular smooth muscle. Ranolazine blocks both peak amplitude and mechanosensitivity of Na<jats:sup>+<\/jats:sup> current in human colon SMCs and decreases contractility of human colon muscle strips. Our data provide a likely mechanistic explanation for constipation induced by ranolazine. <\/jats:p>","DOI":"10.1152\/ajpgi.00051.2015","type":"journal-article","created":{"date-parts":[[2015,7,16]],"date-time":"2015-07-16T21:54:35Z","timestamp":1437083675000},"page":"G506-G512","source":"Crossref","is-referenced-by-count":33,"title":["Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells"],"prefix":"10.1152","volume":"309","author":[{"given":"Leila","family":"Neshatian","sequence":"first","affiliation":[{"name":"Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, Minnesota;"},{"name":"Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R.","family":"Strege","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, Minnesota;"},{"name":"Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poong-Lyul","family":"Rhee","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Kraichely","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, Minnesota;"},{"name":"Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Mazzone","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, Minnesota;"},{"name":"Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl E.","family":"Bernard","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, Minnesota;"},{"name":"Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert R.","family":"Cima","sequence":"additional","affiliation":[{"name":"Department of Colon and Rectal Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Larson","sequence":"additional","affiliation":[{"name":"Department of Colon and Rectal Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Dozois","sequence":"additional","affiliation":[{"name":"Department of Colon and Rectal Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal F.","family":"Kline","sequence":"additional","affiliation":[{"name":"The Dorothy M. 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