Effects of trimebutine maleate on colonic motility through Ca2+-activated K+ channels and L-type Ca2+ channels

摘要

The effects of trimebutine maleate (TM) on spontaneous contractions of colonic longitudinal muscle were investigated in guinea pigs. The contractile responses of smooth muscle strips were recorded by an isometric force transducer. Membrane and action potentials were detected by an intracellular microelectrode technique. The whole-cell patch clamp recording technique was used to record the changes in large conductance Ca2+-activated K+ (BK_ca) and L-type Ca2+ currents in colonic smooth muscle cells. At high concentrations (30, 100, and 300 μM), TM inhibited the amplitude of spontaneous contractions. At low concentrations (1 and 10 μM), TM attenuated the frequency and tone of smooth muscle strips, whereas TM had no influence on the amplitude of spontaneous contractions. TM depolarized the membrane potentials, but decreased the amplitude and frequency of action potentials at high concentrations. TM inhibited BK_ca and L-type Ca2+ currents in a dose-dependent manner. In the presence of the BK_ca channel opener, NS1619, TM also inhibited BK_ca currents. Bayk8644, a L-type Ca2+ channel opener, increased L-type Ca2+ currents. This augmentation was also attenuated by TM. These results suggest that TM attenuates intestinal motility through inhibition of L-type Ca2+ currents, and depolarizes membrane potentials by reducing BK_ca currents. Thus, TM may be a multiple-ion channel regulator in the gastrointestinal tract.