Effects of Loperamide on Acetylcholine and Prostaglandin Release from Isolated Guinea Pig Ileum

Abstract

Loperamide, an effective antidiarrheal agent, was investigated in attempts to determine the site of action which underlies the antiperistaltic and other antidiarrheal actions. In in vitro studies, this compound applied in a dose over 10-8 g/ml, inhibited the release of both acetylcholine [ACh] and prostaglandins [PG] during circumferential distension of the intestinal wall, in a dose-dependent manner. The inhibited ACh release, but not PG release, was reversed by naloxone. This suggests that loperamide inhibits ACh release by interacting with opiate receptor sites in the myenteric plexus. The inhibition of PG release may be due to inhibition of PG synthesis in the intestine because loperamide prevented the biosynthesis of PG from arachidonic acid. Although a high concentration of loperamide (10-6 g/ml) inhibited the contraction of the intestine to ACh, this compound inhibited the contraction to nicotine and serotonin at a concentration which had no effect on the contraction to ACh. Thus, loperamide apparently inhibits the peristaltic movement principally by reducing the release of ACh and PG, at least during circumferential distension of the intestinal wall in vitro. The finding that loperamide inhibited PG biosynthesis may lead to elucidation of the mechanism of its antidiarrheal activity.