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 and prostaglandins during circumferential distension of the intestinal wall, in a dose dependent manner.The inhibited acetylcholine release, but not prostaglandin release, was reversed by naloxone. This suggests that loperamide inhibits acetylcholine release by interacting with opiate receptor sites in the myenteric plexus. The inhibition of prostaglandin release may be due to inhibition of prostaglandin synthesis in the intestine because loperamide prevented the biosynthesis of prostaglandin from arachidonic acid. Although a high concentration of loperamide (10-6 g/ml) inhibited the contraction of the intestine to acetylcholine, this compound inhibited the contraction to nicotine and serotonin at a concentration which had no effect on the contraction to acetylcholine.Thus loperamide apparently inhibits the peristaltic movement principally by reducing the release of acetylcholine and prostaglandin, at least during circumferential distension of the intestinal wall in vitro. The finding that loperamide inhibited the biosynthesis of prostaglandin may lead to elucidation of the mechanism of its antidiarrheal activity.Loperamide has been demonstrated to be a specific and safe antidiarrheal agent. It has a wide margin of safety and exhibits antidiarrheal effect without opiate-like central nervous effects (1, 2, 3). Pelemans and Vantrappen (4) reported that the efficacy of the drug could be demonstrated in patients with `functional' diarrhea due to an irritable colon as well as in patients with diarrhea as the result of organic lesions. A diarrhea induced by prostaglandin E1 was also prevented by loperamide (5). The pharmacology of loperamide differs significantly from that of other agents in that it acts locally to control diarrhea. The mechanism of action has not, however, been fully elucidated.Many authors have shown that loperamide inhibits peristaltic activity in vitro (6, 7) and in vivo (8, 9). Van Nueten et al. (6) suggested that the drug interacts with both choli nergic and non-cholinergic mechanisms involved in peristaltic activity. Inhibition of the peristaltic reflex by the drug can be reversed partially by prostaglandin E (10) which is con sidered to modulate the activity of the cholinergic nervous system in the myenteric plexus (11, 12). Recently, release of acetylcholine (ACh) (13, 14) and prostaglandins (15) has been demonstrated during the distension of the intestinal wall and the importance of these
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