Opossum lower esophageal sphincter smooth muscle contains inhibitory dopaminergic receptors. Since metoclopramide is a dopaminergic antagonist in many experimental situations, the present study was designed to investigate whether this mechanism could explain the lower esophageal sphincter (LES) stimulating action of metoclopramide in man. The interactions of (1) oral L-dopa, a dopamine precursor, and metoclopramide; and (2) L-dopa and the cholinergic agent, bethanechol, on lower esophageal sphincter pressure (LESP) in normal subjects were examined. Oral L-dopa significantly inhibited LESP response to either oral metoclopramide 20 mg (P less than 0.05), or intravenous metoclopramide 20 mg (P less than 0.05). In contrast, L-dopa did not inhibit the LESP response to subcutaneous bethanechol (0.07 mg/kg). Mean basal LESP measured 50 min after ingestion of 1000 mg L-dopa, 19.3 +/- 3.1 mm Hg, was significantly less than basal LESP after L-dopa placebo, 29.3 +/- 4 mm Hg (P less than 0.01). It is concluded that (1) L-dopa inhibited the metoclopramide-induced rise in LESP but not peak stimulation of LESP by bethanechol; (2) there is evidence for the possibility of LES dopaminergic inhibitory receptors in man; and (3) these data are consistent with the hypothesis that metoclopramide acts on the LES by blocking a dopaminergic pressure-lowering mechanism.