title: Action of imipramine on activated ATP-sensitive K(+) channels in interstitial cells of Cajal from murine small intestine.
abstract: Tricyclic antidepressants have been widely used for the treatment of depression and as a therapeutic agent for the altered gastrointestinal (GI) motility of irritable bowel syndrome (IBS). The aim of this study was to clarify whether antidepressants directly modulate pacemaker currents in cultured interstitial cells of Cajal (ICC). We used the whole-cell patch-clamp techniques at 30 degrees C in cultured ICC from the mouse small intestine. Treatment of pinacidil, an ATP-sensitive K(+) channel opener, in the ICC using the current clamping mode, produced hyperpolarization of the membrane potential and decreased the amplitude of the pacemaker potentials. With the voltage clamp mode, we observed a decrease in the frequency and amplitude of pacemaker currents and increases in the resting outward currents. These effects of pinacidil on pacemaker potentials and currents were completely suppressed by glibenclamide, an ATP-sensitive K(+) channel blocker. Also, with the current clamp mode, imipramine blocked the affect of pinacidil on the pacemaker potentials. Observations of the voltage clamp mode with imipramine, desipramine and amitryptyline suppressed the action of pinacidil in the ICC. Next, we examined whether protein kinase C (PKC) and the G protein are involved in the action of imipramine on pinacidil induced pacemaker current inhibition. We used chelerythrine, a potent PKC inhibitor and GDPbetaS, a nonhydrolyzable guanosine 5-diphosphate (GDP) analogue that permanently inactivates GTP-binding proteins. We found that pretreatment with chelerythrine and intracellular application of GDPbetaS had no influence on the blocking action of imipramine on inhibited pacemaker currents by pinacidil. We conclude that imipramine inhibited the activated ATP-sensitive K(+) channels in ICC. This action does not appear to be mediated through the G protein and protein kinase C. Furthermore, this study may suggest another possible mechanism for tricyclic antidepressants related modulation of GI motility.
authors.affiliation: Department of Physiology, College of Medicine, Chosun University, 375 Seosuk-dong, Gwangju, Korea.
authors.forename: Seok
authors.initials: S
authors.lastname: Choi
authors.forename: Chan Guk
authors.initials: CG
authors.lastname: Park
authors.forename: Man Yoo
authors.initials: MY
authors.lastname: Kim
authors.forename: Geon Han
authors.initials: GH
authors.lastname: Lim
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Cheol Ho
authors.initials: CH
authors.lastname: Yeum
authors.forename: Pyung Jin
authors.initials: PJ
authors.lastname: Yoon
authors.forename: Insuk
authors.initials: I
authors.lastname: So
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Kim
authors.forename: Jae Yeoul
authors.initials: JY
authors.lastname: Jun
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology*; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D054086:KATP Channels; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018408:Patch-Clamp Techniques; D020110:Pinacidil / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; D020110:Pinacidil; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D007099:Imipramine