KW-5092, a novel gastrokinetic agent, facilitates luminal serotonin release from the guinea-pig colon

The present study was designed to determine the influence of KW-5092 ((1-[2-[[[5-(piperidinomethyl)-2-furanyl]methyl]amino]ethyl]-2- imidazolidinylidene) propanedinitrile fumarate), a novel gastroprokinetic agent on intraluminal serotonin (5-hydroxytryptamine, 5-HT) release which reflects the release of 5-HT from enterochromaffin cells, using the luminally perfused isolated guinea-pig proximal colon in vitro. 5-HT was determined by high-performance liquid chromatography with electrochemical detection. KW-5092 (1-10 microM) concentration-dependently caused an increase in the luminal 5-HT outflow. In the presence of atropine (0.2 microM) or tetrodotoxin (0.3 microM), the stimulatory action of KW-5092 (10 microM) was inhibited by 94% and 74%, respectively. These results suggest that KW-5092 stimulates intraluminal 5-HT release from luminally perfused proximal colon of the guinea-pig via the stimulation of cholinergic neurons. Because 5-HT is recognized as an important messenger substance in the control of intestinal motility, this stimulatory effect could be considered as an indirect action of KW-5092 that may contribute to its prokinetic effects.