title: Effect of mibefradil on sodium and calcium currents.
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(V)1.5) 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 alpha(1)3.3b + beta(2), the human intestinal L-type Ca2+ channel subunits alpha(1C) + beta(2), or Na(V)1.5. Mibefradil significantly reduced expressed T-type Ca2+ current at concentrations > or = 0.1 microM (IC(50) = 0.29 microM), L-type Ca2+ current at > 1 microM (IC(50) = 2.7 microM), and Na+ current at > or = 0.3 microM (IC(50) = 0.98 microM). 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.
authors.affiliation: Mayo Clinic College of Medicine, 8 Guggenheim Bldg., 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strege
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Bernard
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ou
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Gibbons
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007583:Jejunum / Q000502:physiology; D007668:Kidney / Q000166:cytology; D020748:Mibefradil / Q000494:pharmacology*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; C419385:L-type calcium channel alpha(1C); D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D015222:Sodium Channels; D020748:Mibefradil; D012964:Sodium; D002118:Calcium