We have demonstrated that erythromycin improves gastric emptying in dogs following truncal vagotomy and Roux-en-Y antrectomy (VRYA). To explore its mechanism of action we studied gastric emptying and myoelectric activity in a canine Roux model and administered atropine simultaneously with erythromycin. Tachyphylaxis was evaluated following short-term administration. Four dogs with delayed gastric emptying following VRYA were studied. Radionuclide solid gastric emptying was measured, with simultaneous myoelectric recordings obtained from the duodenum and Roux limb. Study groups were: (1) saline control (VRYA dogs); (2) erythromycin 1 mg/kg iv over 1 hr; (3) erythromycin 3 mg/kg po tid for 1 week, with repeat studies using erythromycin 1 mg/kg iv over 1 hr; and (4) atropine 0.5 mg/kg iv bolus, followed by a 1-hr infusion of atropine 0.05 mg/kg and erythromycin 1 mg/kg. Control Roux animals had severe gastric retention (73 +/- 5% at 2 hr, compared to 27 +/- 6% following iv erythromycin (P less than 0.01). Clustered spike bursts were observed in the Roux limb following erythromycin. Atropine abolished the gastrokinetic response and suppressed the myoelectric response to erythromycin (81 +/- 3% retention at 2 hr, P less than 0.01 compared to erythromycin alone). The response to erythromycin was unchanged after 1 week of tid administration (40 +/- 14% retention at 2 hr postprandial, P = NS). Erythromycin improves gastric emptying in VRYA dogs via a cholinergic pathway and does not exhibit tachyphylaxis following short-term administration.