Effect of mibefradil on sodium and calcium currents

Peter R. Strege, Cheryl E. Bernard, Yijun Ou, Simon J. Gibbons, Gianrico Farrugia

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Interstitial cells of Cajal (ICC) generate the electrical slow wave. The ionic conductances that contribute to the slow wave appear to vary among species. In humans, a tetrodotoxin-resistant Na+ current (Na v1.5) encoded by SCN5A contributes to the rising phase of the slow wave, whereas T-type Ca2+ currents have been reported from cultured mouse intestine ICC and also from canine colonic ICC. Mibefradil has a higher affinity for T-type over L-type Ca2+ channels, and the drug has been used in the gastrointestinal tract to identify T-type currents. However, the selectivity of mibefradil for T-type Ca2+ channels over ICC and smooth muscle Na+ channels has not been clearly demonstrated. The aim of this study was to determine the effect of mibefradil on T-type and L-type Ca2+ and Na+ currents. Whole cell currents were recorded from HEK-293 cells coexpressing green fluorescent protein with either the rat brain T-type Ca2+ channel α13.3b + β2, the human intestinal L-type Ca2+ channel subunits α1C + β2, or Nav1.5. Mibefradil significantly reduced expressed T-type Ca2+ current at concentrations a ≥0.1 μM (IC50 = 0.29 μM), L-type Ca2+ current at > 1 μM (IC50 = 2.7 μM), and Na+ current at ≥ 0.3 μM (IC50 = 0.98 μM). In conclusion, mibefradil inhibits the human intestinal tetrodotoxin-resistant Na+ channel at submicromolar concentrations. Caution must be used in the interpretation of the effects of mibefradil when several ion channel classes are coexpressed.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume289
Issue number2 52-2
DOIs
StatePublished - Aug 2005

Fingerprint

Mibefradil
Interstitial Cells of Cajal
Sodium
Calcium
Inhibitory Concentration 50
Tetrodotoxin
HEK293 Cells
Green Fluorescent Proteins
Ion Channels
Intestines
Smooth Muscle
Gastrointestinal Tract
Canidae
Brain
Pharmaceutical Preparations

Keywords

  • Gastrointestinal tract
  • Ion channel
  • Patch clamp

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Effect of mibefradil on sodium and calcium currents. / Strege, Peter R.; Bernard, Cheryl E.; Ou, Yijun; Gibbons, Simon J.; Farrugia, Gianrico.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 289, No. 2 52-2, 08.2005.

Research output: Contribution to journalArticle

Strege, Peter R. ; Bernard, Cheryl E. ; Ou, Yijun ; Gibbons, Simon J. ; Farrugia, Gianrico. / Effect of mibefradil on sodium and calcium currents. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2005 ; Vol. 289, No. 2 52-2.
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AB - Interstitial cells of Cajal (ICC) generate the electrical slow wave. The ionic conductances that contribute to the slow wave appear to vary among species. In humans, a tetrodotoxin-resistant Na+ current (Na v1.5) encoded by SCN5A contributes to the rising phase of the slow wave, whereas T-type Ca2+ currents have been reported from cultured mouse intestine ICC and also from canine colonic ICC. Mibefradil has a higher affinity for T-type over L-type Ca2+ channels, and the drug has been used in the gastrointestinal tract to identify T-type currents. However, the selectivity of mibefradil for T-type Ca2+ channels over ICC and smooth muscle Na+ channels has not been clearly demonstrated. The aim of this study was to determine the effect of mibefradil on T-type and L-type Ca2+ and Na+ currents. Whole cell currents were recorded from HEK-293 cells coexpressing green fluorescent protein with either the rat brain T-type Ca2+ channel α13.3b + β2, the human intestinal L-type Ca2+ channel subunits α1C + β2, or Nav1.5. Mibefradil significantly reduced expressed T-type Ca2+ current at concentrations a ≥0.1 μM (IC50 = 0.29 μM), L-type Ca2+ current at > 1 μM (IC50 = 2.7 μM), and Na+ current at ≥ 0.3 μM (IC50 = 0.98 μM). In conclusion, mibefradil inhibits the human intestinal tetrodotoxin-resistant Na+ channel at submicromolar concentrations. Caution must be used in the interpretation of the effects of mibefradil when several ion channel classes are coexpressed.

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