THE EFFECT AND MECHANISM OF THE PROKINETIC ACTION OF CISAPRIDE ON GASTROINTESTINAL SMOOTH-MUSCLE

Cisapride is a new prokinetic agent which can facilitate or restore mo tility throughout the entire gastrointestinal tract. Although facilita tion of acetylcholine release has been suggested, the mechanism of act ion of cisapride is not clear. To investigate the effect and mechanism of action of cisapride, we used isolated muscle strips (with mucosa a nd submucosa removed) of guinea pig antrum, ileum and colon to study: (1) the dose response to cisapride, (2) the effect of antagonists (atr opine and tetrodotoxin) on the stimulatory effect of cisapride. Beside s these studies, we also used H-3-acetylcholine release method to inve stigate the acetylcholine release effect of cisapride. Cisapride elici ted a dose-related enhancement of baseline activity (motility index) o n the antrum and contraction on the ileum and colon at the dose of 4, 40 and 400 nM. At higher doses (4 muM) cisapride caused inhibition. Th is bell-shaped dose response curve suggested that cisapride might be a utoinhibitory or that the receptors of cisapride might consist of high affinity stimulatory and low affinity inhibitory sites. The stimulato ry responses elicited by cisapride (400 nM) were not significantly inh ibited by atropine and tetrodotoxin in the antrum, ileum and colon. Th is suggested that cisapride might act directly on the smooth muscle. C isapride (400 nM) evoked a rather small increase of H-3-acetylcholine release on the antrum, ileum and colon. Because the percentage of incr ease was small and we had demonstrated that the stimulatory effects of cisapride were not blocked by atropine and tetrodotoxin, the acetylch oline release effect of cisapride was considered unimportant.