Erythromycin, a motilin agonist, enhances gastrointestinal motility but also stimulates endogenous pancreatic polypeptide (PP) secretion. We investigated whether the effect of erythromycin on PP release is dependent on (1) prokinetic activity of erythromycin generated from the antrum and (2) the long vagus nerve since erythromycin acts via cholinergic neurons. Erythromycin induced PP secretion was determined in 14 patients with antrectomy (6 patients with Billroth I type anastomosis, 8 patients with Billroth II type anastomosis), in 6 patients with truncal vagotomy and pyloroplasty but without gastric resection and in 8 healthy controls. Plasma PP levels in response to erythromycin (3 mg/kg i.v.) were determined at regular intervals for 180 min. Erythromycin induced a significant increase in plasma PP in the control subjects from 22 +/- 4 pmol/l (basal) to 49 +/- 4 pmol/l at 10 min. In the patients with truncal vagotomy plasma PP secretion after erythromycin was significantly (P < 0.05) increased (peak increment vs. basal: 98 +/- 10 pmol/l vs. 27 +/- 2 pmol/l) and prolonged compared to controls. In the patients with antrectomy no significant increases in plasma PP over basal were observed after erythromycin infusion. It is concluded that erythromycin stimulates PP secretion in healthy controls. The PP response to erythromycin is exaggerated after truncal vagotomy but absent after antrectomy indicating that the antrum is essential for erythromycin induced PP secretion.