In:
American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 309, No. 6 ( 2015-09-15), p. G506-G512
Abstract:
Human jejunum smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs) express the SCN5A-encoded voltage-gated, mechanosensitive sodium channel Na V 1.5. Na V 1.5 contributes to small bowel excitability, and Na V 1.5 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 Na V 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 V 1.5 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 Na V 1.5 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.
Type of Medium:
Online Resource
ISSN:
0193-1857
,
1522-1547
DOI:
10.1152/ajpgi.00051.2015
Language:
English
Publisher:
American Physiological Society
Publication Date:
2015
detail.hit.zdb_id:
1477329-6
SSG:
12
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