The effect of mosapride citrate on proximal and distal colonic motor function in the guinea-pig in vitro.

摘要

Mosapride citrate (mosapride), a substituted benzamide, is a selective 5-HT(4) receptor agonist, and is known to have prokinetic properties on the stomach. However, it is unclear whether mosapride also has a prokinetic effect on the colon. We previously found that mosapride significantly shortened colonic transit time in the guinea-pig, an animal with a distribution of colonic 5-HT(4) receptors similar to that of a human. So, we aimed to separately evaluate the effect of mosapride on proximal and distal colonic motor function in the guinea-pig. Proximal (approximately 8 cm from the ileocolic junction) and distal colon (approximately 8 cm from the anus) were removed. Both ends of the colon were connected to a chamber containing a Krebs-Henseleit solution. To measure colonic transit time, artificial faeces were inserted into the oral side of the lumen and moved towards the anal side by intraluminal perfusion via a peristaltic pump. A total of 6 cm of transit was observed and time was measured in 2 cm increments. A tissue bath study, using electrical stimulation, was performed to estimate the contractile activity of the circular musculature of the colon. Immunohistochemical staining for 5-HT(4) receptors was performed in the myenteric plexus and circular muscle in both proximal and distal colon, and the stained area was measured using a microscope and computer software. Mosapride enhanced contraction at 10(-9) to 10(-7) mol L(-1), coinciding with rapid transit both in proximal and distal colon. This pattern was more prominent in proximal colon. At the high dose (10(-6) mol L(-1)) mosapride had little or no effect on colonic contraction. This stimulatory effect was attenuated by GR113808, atropine and tetrodotoxin. In the myenteric plexus, the density of 5-HT(4) receptors was significantly greater in the proximal colon than in the distal colon, but in circular muscle the density was greater in the distal colon. Thus, mosapride accelerates transit through increased contraction in the proximal colon more thandistal colon. The different distribution of neuronal and muscular 5-HT(4) receptors may support these findings. Therefore, mosapride may be a useful alternative to tegaserod and cisapride for constipation.