R 50 595, a selective non-competitive antagonist of cisapride, BRL 24924 and 5-hydroxytryptamine on the guinea-pig ileum

5-Hydroxytryptamine and substituted benzamides such as cisapride and BRL 2492 enhance the twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus preparation of the guinea-pig. The effects of these benzamides and 5-HT could possibly be mediated via similar receptor-effector systems. The aim of our study was therefore to determine whether R 50 595, an analogue of cisapride devoid of intrinsic activity, could specifically interfere with the effects of cisapride and BRL 24924 and if so, whether it would also affect the responses to serotonin. R 50 595 had no effect on the twitch responses of the electrically stimulated preparation up to a concentration of 3 × 10 −7 M. Cisapride and BRL 24924 both enhanced the contractile response to electrical stimulation by a maximum of 37 ± 7% at 3 × 10 −7 M for cisapride and 36 ± 6% for BRL 24924, also at 3 × 10 −7 M. R 50 595 (10 −7-3 × 10 −7 M) antagonized the effects of cisapride and BRL 24924 in a non-competitive way. 5-HT enhanced the contractile responses by a maximum of 24 ± 3.2% at 3 × 10 −8 M. The effects of 5-HT were completely abolished at a concentration of 3 × 10 −7 M R 50 595. R 50 595 also antagonized the effects of 5-HT in a non-competitive way. At a concentration of 3 × 10 −7 M, R 50 595 had no effect on the enhancement of the twitch responses caused by ranitidine (maximal enhancement: 54 ± 5% at 10 −4 M), levamisole (maximal enhancement: 35 ± 3% at 3 × 10 −5 M) or Bay K 8644 (maximal enhancement: 42 ± 6% at 3 × 10 −7 M). Our data imply that R 50 595 is a selective non-competitive antagonist of the effects of substituded benzamides and 5-hydroxytryptamine. This suggests that the benzamides, cisapride and BRL 24924, exert their effect on the ileum via an agonistic action on a serotonin receptor.