Peristaltic contractions of the distal esophageal body and lower esophageal sphincter tone were evaluated in patients affected by gastroesophageal reflux disease after either acute intravenous (8.0 mg) administration or two oral doses (5.0 mg and 10.0 mg) of cisapride and in healthy controls after a 10.0-mg oral dose of cisapride. Intravenous cisapride administration enhanced the amplitude and duration of primary peristalsis and the lower esophageal sphincter tone, which reached normal control values. Likewise, the 10.0-mg oral dose effectively enhanced the lower esophageal sphincter resting pressure in both controls and in reflux patients, whereas the amplitude and duration of primary peristalsis was improved only in controls. The 5.0-mg oral dose of cisapride proved ineffective on distal esophageal motor activity in reflux patients. To evaluate whether atropine is capable of modifying the effects of cisapride on distal esophageal motor activity, cisapride was administered intravenously before and during intravenous atropine administration. Effects of cisapride on peristaltic contractions were completely blocked by atropine, irrespective of whether atropine was administered before or after cisapride. The lower esophageal sphincter pressure response to cisapride varied according to the sequence of drug administration, showing no effect when cisapride followed atropine administration and, when this sequence was reversed, no significant atropine-induced inhibition on cisapride-stimulated lower esophageal sphincter pressure. It is suggested that cisapride enhances distal esophageal motor activity by means of a muscarinic receptor mechanism at the level of the distal esophageal body and, at least in part, via a muscarinic-independent mechanism at the level of the lower esophageal sphincter.