The role of cholinergic nerves in the cyclic activation of interdigestive motility and secretion was studied in 23 healthy volunteers. Net fluid transport in a distal duodenal segment and the release of pancreaticobiliary secretions into the duodenal lumen, were measured with a triple lumen perfusion technique. Interdigestive motor activity was recorded with a low-compliance pneumohydraulic system, and the transmural potential difference (PD) was measured as an on-line marker of electrogenic anion secretion. Transport parameters were related to the migrating motor complex (MMC) in the control situation and after the administration of atropine (0.01 mg kg-1 body wt, i.v.). The early part of the MMC cycle was characterized by low motor activity, low release of bile and pancreatic juice into the duodenal lumen, a slightly lumen positive transmural PD, and a non-significant net fluid absorption ('absorptive mode'). Under control conditions, motor activity and pancreaticobiliary secretions subsequently increased and there was a shift in net fluid transport and transmural PD in the secretory direction ('secretory mode'). Furthermore, there was a significant correlation between contraction frequency, a more lumen negative PD, and the magnitude of net fluid secretion. After the administration of atropine, the secretory mode was abolished, but there was still a significant correlation between contraction frequency and transmural PD. In conclusion, cholinergic neurones seem to mediate the shift from the absorptive to the secretory mode in the human distal duodenum. The antisecretory effect of atropine may be the result of inhibition of motilin release, reduced activation of tension-sensitive intramural secretory pathways, or blockade of cholinergic neurones to the secreting epithelium.