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

Abstract

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 Ca(2+)-activated K(+) (BK(ca)) and L-type Ca(2+) 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 Ca(2+) 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 Ca(2+) channel opener, increased L-type Ca(2+) currents. This augmentation was also attenuated by TM. These results suggest that TM attenuates intestinal motility through inhibition of L-type Ca(2+) currents, and depolarizes membrane potentials by reducing BK(ca) currents. Thus, TM may be a multiple-ion channel regulator in the gastrointestinal tract.

Trimebutine as a modulator of gastrointestinal motility

“…Trimebutine might be a plausible modulator of GI motility, since it has been used for treatment of both hypermotility and hypomotility disorders including IBS, gastritis, and dyspepsia (Nagasaki et al, 1993a). In addition, as shown in this study, the effect of trimebutine is influenced by not only the state of the gut, but also its concentration (Tan et al, 2011). Further studies are needed to elucidate the mechanism underlying the concentration-dependent dual actions of this drug more clearly.…”

“…In this issue, Tan et al (2011) examined the effects of trimebutine on spontaneous contractions recorded by an isometric force transducer and on resting and action potentials detected by an intracellular microelectrode technique in smooth muscle strips from…”

Çocukluk Çağında Fonksiyonel Kabızlık Tedavisi: Senna, Trimebutin ve Laktülozun Karşılaştırılması

“…The other drug, trimebutine is effective in IBS with constipation or diarrhea. Trimebutine acts on GIS with dual effect and improves both hyper and hypomotility (20). There is only one adult study in the literature, evaluating the effect of trimebutine on chronic idiopathic constipation, and showed increased defecation frequency without significance (14).…”

Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells

“…TM possesses a moderate opiate receptor affinity that acts on the peripheral delta, mu, and kappa receptors [ 20 , 21 , 22 ]. TM is also thought to act directly on smooth muscles by inhibiting Ca 2+ influx and release from intracellular storage sites by blocking voltage dependent Ca 2+ currents [ 23 , 24 ]. Furthermore, TM decreases the amplitude of outward K + currents by inhibitory actions on both Ca 2+ -independent and-dependent types of K + channel [ 23 , 25 ].…”

“…TM is also thought to act directly on smooth muscles by inhibiting Ca 2+ influx and release from intracellular storage sites by blocking voltage dependent Ca 2+ currents [ 23 , 24 ]. Furthermore, TM decreases the amplitude of outward K + currents by inhibitory actions on both Ca 2+ -independent and-dependent types of K + channel [ 23 , 25 ]. The sodium channel-blocking activity of TM, which is probably responsible for the inhibitory effect on glutamate release, indicates a potential therapeutic effect of these compounds in pain [ 26 ].…”