Arch Pharm Res Vol 34, No 6, 861-864, 2011 DOI 10.1007/s12272-011-0600-7
THIS MONTH IN APR
Trimebutine as a Modulator of Gastrointestinal Motility Hyun-Tai Lee1 and Byung Joo Kim2 1
Department of Life Science & Biotechnology, College of Natural Sciences, Dong-eui University, Busan 614714, Korea and 2Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Korea Trimebutine has been used for treatment of both hypermotility and hypomotility disorders of the gastrointestinal (GI) tract, such as irritable bowel syndrome. In this issue, Tan et al. (2011) examined the concentration-dependent dual effects of trimebutine on colonic motility in guinea pig. The authors suggested that trimebutine attenuated colonic motility mainly through the inhibition of L-type Ca2+ channels at higher concentrations, whereas, at lower concentrations, it depolarized membrane potentials by reducing BKca currents, resulting in the enhancement of the muscle contractions. Trimebutine might be a plausible modulator of GI motility, which gives an insight in developing new prokinetic agents. Further studies to elucidate the effects of trimebutine on the interstitial cells of Cajal, the pacemaker in GI muscles would promote the therapeutic benefits as a GI modulator.
Gastrointestinal (GI) dysmotility is an important mechanism in various GI disorders including irritable bowel syndrome (IBS). IBS is one of the most common multifactorial GI disorders managed by general practitioners, but current therapeutic options for this disorder are limited (Pasricha, 2007; Spiller et al., 2007). IBS is characterized by pain and discomfort in the abdomen related to abnormal bowel habits (Longstreth et al., 2006). The prevalence of IBS can vary depending on the diagnostic criteria used, but it appears to affect about 12% (up to 20%) of the population worldwide (Mearin et al., 2001; Long et al., 2010). Due to its high prevalence, chronic nature, and incapacitating symptoms, quality of life is reduced in patients with IBS, and the costs for this disease are substantial to society (Simren et al., 2004). Therefore, from an economic and humanitarian point of view, more effective therapeutic options are necessary for the treatment of IBS. Trimebutine has been commonly used for the treatment of IBS to relieve abdominal pain and alter bowel habits, although its clinical efficacy and mechanism of Correspondence to: Hyun-Tai Lee, Department of Life Science & Biotechnology, College of Natural Sciences, Dong-eui University, Busan 614-714, Korea Tel: 82-51-890-1534, Fax: 82-51-890-1532 E-mail:
[email protected]
action remain still unclear (Delvaux and Wingate, 1997; Fioramonti and Bueno, 2002). This drug is known to have a unique spasmolytic activity, which might be related to its local anesthetic, antimuscarinic, and weak mu opioid agonist effects (Roman et al., 1999). In isolated intestines from guinea pigs and rabbits, trimebutine showed “dual actions” that stimulated or inhibited spontaneous contractions depending on the prior contractile activity in the preparation (Takenaga et al., 1986). It has been reported that the effects of trimebutine on GI tracts were mediated by a Ca2+ antagonist-like action with inhibiting the influx of extracellular Ca2+ in the smooth muscle cells: trimebutine inhibited the Ca2+ influx through voltage dependent L-type Ca2+ channels and the Ca2+ release from intracellular Ca2+ stores (Nagasaki et al., 1991, 1993a). Furthermore, trimebutine had also an inhibitory effect on the K+ current evoked upon membrane depolarization of the GI smooth muscles at the resting conditions to induce contractions: the drug inhibited outward K+ currents through delayed rectifier K+ channels and Ca2+ dependent K+ channels (Nagasaki et al., 1993b; Morisawa et al., 2000). 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
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Fig. 1. Ionic currents through the L-type Ca2+ channel and BKca channel on the plasma membrane (A), and the concentration-dependent dual actions of trimebutine on GI smooth muscle cells (B).
guinea pig colon. They also measured the changes in large conductance Ca2+-activated K+ (BKca) and L-type Ca2+ currents in the colonic smooth muscle cells to evaluate the action of trimebutine on those cells, using a whole-cell patch clamp recording technique. Trimebutine significantly reduced the amplitude of spontaneous contractions in the smooth muscle strips at higher concentrations (30-300 µM), but there was no significant change (or apparently slight increase) in amplitude at lower concentrations (1-10 µM). Trime-
butine reduced the frequency of both spontaneous muscle contractions and action potentials in a dosedependent manner. Trimebutine depolarized the resting membrane potentials at lower concentrations (1-30 µM), and decreased the amplitude of action potentials at higher concentrations (30-300 µM). Both BKca and L-type Ca2+ currents in colonic smooth muscle cells were reduced by trimebutine in a dosedependent manner. The augmentations induced by each ion channel opener (i.e., NS1619 as a BKca channel
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opener and Bayk8644 as an L-type Ca2+ channel opener) were also attenuated by trimebutine. From the results, the authors summarized and concluded that trimebutine attenuated intestinal motility mainly through inhibition of L-type Ca2+ channels at higher concentrations. At lower concentrations of trimebutine, however, depolarization of membrane potentials by reducing outward BKca currents could be a dominant signal to enhance the contractions of colonic smooth muscles (Fig. 1). For curing GI motility dysfunctions, a primary concern has been the development of more efficient prokinetic agents that “enhance” GI motility, in the field of gastroenterology and the related pharmaceutical industry. As mentioned above in the IBS case, however, “modulation” (rather than “enhancement”) of GI motility might be an advanced strategy, which maintains the homeostasis within the gut. In this paper, the authors finally suggested that trimebutine may be a multiple-ion channel regulator in the gut. The duality of the action of trimebutine is very interesting and deserves consideration for developing new drugs to improve GI dysmotility, even though the findings from this study were not quite novel in themselves. 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. The effects of trimebutine seem to be more complicated because it is likely to act on interstitial cells of Cajal (ICCs), a well-known key player in the initiation and regulation of GI motility, as well as smooth muscles and enteric nerves. ICCs generate pacemaker signals (i.e., slow waves) to maintain the basal tone of the GI smooth muscles, mediate or transduce inputs from the enteric nervous system to the GI smooth muscles, and act as mechanosensors in the gut (Won et al., 2005; Farrugia, 2007). Considering the central role of ICCs in GI motility, it is not surprising that many human GI motility disorders are associated with loss of these cells in dysfunctional regions of the GI tract (Sanders, 2006). Research into the biology of ICCs provides exciting new opportunities to understand the etiology of diseases that have long eluded comprehension. Some transient receptor potential (TRP) channels, such as TRPC4 and TRPM7, or Ca2+activated Cl− channels have been suggested that they
might be responsible for pacemaking activity in ICCs (Kim et al., 2006; Hwang et al., 2009; Zhu et al., 2009). However, the effects of trimebutine on ICCs and the related ion channels have not been reported. In the future, therefore, more sophisticated studies are needed to clarify the role of trimebutine in the whole GI tract containing smooth muscles, enteric nervous system, and ICCs.
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