Stimulation of gastroduodenal motor activity: Dopaminergic and cholinergic modulation

The effects of domperidone, cisapride, metoclopramide and bethanechol were determined on antroduodenal coordination, in vitro in the gastroduodenal preparation of the guinea pig and in vivo in conscious Beagle dogs implanted with strain gauge force transducers. In vitro dopamine inhibited and the dopamine antagonist domperidone stimulated antroduodenal coordination. The effect of domperidone was blocked by atropine or tetrodotoxin, but not by hexamethonium. Propranolol, prazosin, and yohimbine did not enhance antroduodenal coordination. Only at one of the concentrations tested did bethanechol moderately enhance antroduodenal coordination. Cisapride stimulated antroduodenal coordination in a dose‐dependent manner. This effect could also be blocked by atropine or tetrodotoxin. Metoclopramide (at higher concentrations) also enhanced antroduodenal coordination. The order of potency (expressed in terms of EC50‐values) was domperidone (1.4 × 10 −7 M) = cisapride (1.9 × 10 −7 M) ≥ ≥ metoclopramide (2.2 × 10 −5 M). In vivo in conscious Beagle dogs, similar results were obtained. Bethanechol did not enhance antroduodenal coordination. In this case, the order of potency (expressed in terms of the percentage increase in antroduodenal coordination at 0.31 mg/kg, i.v.) was cisapride (208%) ≥ domperidone (152%) = metoclopramide (138%). Thus, domperidone, cisapride and, to a lesser extent, metoclopramide, but not bethanechol, can effectively improve antroduodenal coordination. The stimulatory effects of domperidone are mediated via specific dopamine receptors (i.e., different from α 1 ‐, α 2 ‐ or ß‐adrenergic receptors), located on postganglionic nerves in the myenteric plexus. The stimulatory effects of cisapride are mediated via cholinergic nerves in the myenteric plexus and the moderate effects of metoclopramide may be mediated via both mechanisms.