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NEUROREGULATION AND MOTILITY

Effect of mibefradil on sodium and calcium currents

Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, Minnesota

Submitted 19 January 2005 ; accepted in final form 21 March 2005

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 ₁3.3b + ₂, the human intestinal L-type Ca²⁺ channel subunits _1C + ₂, or Na_V1.5. Mibefradil significantly reduced expressed T-type Ca²⁺ current at concentrations 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.

ion channel; gastrointestinal tract; patch clamp

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