Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells

Leila Neshatian, Peter R Strege, Poong-Lyul Rhee, Robert E Kraichely, Amelia Mazzone, Cheryl E Bernard, Robert R Cima, David W Larson, Eric J Dozois, Crystal F Kline, Peter J Mohler, Arthur Beyder, Gianrico Farrugia

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Human jejunum smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs) express the SCN5A-encoded voltage-gated, mechanosensitive sodium channel NaV1.5. NaV1.5 contributes to small bowel excitability, and NaV1.5 inhibitor ranolazine produces constipation by an unknown mechanism. We aimed to determine the presence and molecular identity of Na(+) current in the human colon smooth muscle and to examine the effects of ranolazine on Na(+) 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 NaV1.5 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 NaV1.5 protein were identified in human colon circular muscle. Freshly dissociated human colon SMCs had Na(+) currents (-1.36 ± 0.36 pA/pF), shear stress increased Na(+) peaks by 17.8 ± 1.8% and accelerated the time to peak activation by 0.7 ± 0.3 ms. Ranolazine (50 μM) blocked peak Na(+) current by 43.2 ± 9.3% and inhibited shear sensitivity by 25.2 ± 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 NaV1.5 is found in human colonic circular smooth muscle. Ranolazine blocks both peak amplitude and mechanosensitivity of Na(+) 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.

Original languageEnglish (US)
Pages (from-to)G506-12
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number6
StatePublished - Sep 15 2015


  • Colon
  • Colon, Ascending
  • Constipation
  • HEK293 Cells
  • Humans
  • Muscle Contraction
  • Myocytes, Smooth Muscle
  • NAV1.5 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Physical Stimulation
  • Potassium Channel Blockers
  • Potassium Channels, Voltage-Gated
  • Ranolazine
  • Journal Article
  • Research Support, N.I.H., Extramural


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