Activation of a myenteric 5-hydroxytryptamine-like receptor by metoclopramide

Cholinergically mediated contractions were evoked by electrical field stimulation (EFS) of guinea-pig distal ileum longitudinal muscle-myenteric plexus strips. Metoclopramide, 0.1-100 microM, dose-dependently increased the contractions, probably by increasing acetylcholine (ACh) release; contractions evoked by exogenous ACh in the presence of tetrodotoxin were not increased by metoclopramide. 5-Hydroxytryptamine (5-HT) 0.3-30 nM similarly increased the height of the EFS-evoked contractions, although the maximum increase was less than for metoclopramide; higher concentrations of 5-HT (3 and 30 microM) had no effects or caused inhibition. The compound, ICS 205-930, 0.001-1 microM, had no effect on the EFS-evoked contractions and caused inhibition at higher concentrations. Preincubation of the tissues with 5-HT, 0.3-30 nM, did not affect the increase in EFS-evoked contractions caused by metoclopramide, 1 or 100 microM, whereas 5-HT, 3 and 30 microM, prevented the response caused by metoclopramide 1 microM, but not 100 microM. ICS 205-930, 0.1 microM, had no effect on the increase in EFS-evoked contractions caused by metoclopramide 1 or 100 microM. The drug, at least in low concentrations, may therefore increase cholinergically mediated contractions of guinea-pig ileum by stimulating 5-HT-like receptors within the myenteric plexus, which differ from those antagonized by ICS 205-930.