Prokinetic benzamides stimulate peristaltic activity in the isolated guinea pig ileum by activation of 5-HT4 receptors.

Substituted benzamides such as metoclopramide, cisapride, zacopride, renzapride or BRL 20627, stimulate intestinal motility in various species. As they are antagonists at 5-HT3 and agonists at 5-HT4 receptors and as both mechanisms could potentially contribute to their gastrointestinal prokinetic effect, the underlying mechanism is unclear. To clarify this, the effect of some substituted benzamides on gut motility was investigated in the isolated guinea pig ileum using the Trendelenburg technique, in which pressure-induced peristaltic contractions are measured. All benzamides stimulated the peristaltic reflex with the rank order of potency: renzapride greater than cisapride greater than BRL 20627 greater than (+/-)-zacopride greater than metoclopramide. ICS 205-930, granisetron and 2-methyl-5-HT did not change the peristaltic response. 5-HT and 5-methoxytryptamine potently mimicked the effect of the benzamides. The effect of 5-HT was not blocked by ICS 205-930 (10(-7) M). These results indicate that the Trendelenburg preparation is suitable for the investigation of intestinal prokinetic effects of the substituted benzamides. Furthermore, the results suggest that the intestinal effect of benzamides results from activation of 5-HT4 receptors rather than from blockade of 5-HT3 receptors.