5-HT4 RECEPTORS ARE NOT INVOLVED IN THE CONTROL OF SMALL-INTESTINAL TRANSIT IN THE FASTED CONSCIOUS RAT

Cisapride and metoclopramide are used clinically in the treatment of g astro-oesophageal reflux disease and also in a variety of motility dis orders of the gastrointestinal tract. Their prokinetic effect is thoug ht to be due to the augmentation of acetylcholine release from the mye nteric plexus, an effect likely to be mediated through the stimulation of 5-HT4 receptors. The role of 5-HT4 receptors in the control of int estinal motility in man and animals is not clear, therefore we have in vestigated their role in the control of small intestinal transit in th e rat. Radioactive microspheres were administered into the proximal du odenum of fasted conscious rats through an indwelling cannula. The ext ent of small intestinal transit was examined by determining the distri bution of the microspheres within the intestine. Following i.p. inject ion small intestinal transit was inhibited (78%) by atropine (3 mg/kg) , suggesting the presence of a basal cholinergic influence. Furthermor e, in the presence of p-amino clonidine intestinal transit was stimula ted (126%) by bethanechol (3 mg/kg). The. 5-HT4 receptor agonists cisa pride (1.0 mg/kg) and zacopride (1.0 mg/kg) failed to increase small i ntestinal transit. The 5-HT4 receptor selective antagonist GR125487 (1 mg/kg) was also without effect. These data suggest that 5-HT4 recepto rs are not involved in the control of small intestinal transit in the fasted conscious rat.