Indirect action of 5-hydroxytryptamine on the isolated muscularis mucosae of the guinea-pig oesophagus.

1 The site of action of 5-hydroxytryptamine (5-HT) was examined on the isolated muscularis mucosae attached to the submucous plexus of the guinea-pig oesophagus. Isotonic responses of the longitudinal muscularis mucosae were recorded.2 5-HT produced a transient contraction of the muscularis mucosae at concentrations higher than 3 muM. The contraction was rapid in onset, reaching a peak in about 15 s or less, and was restored to the basal level after 20 to 30 s without washing out 5-HT. When the 5-HT-induced contraction faded to the basal tone, successive applications of 5-HT no longer produced any contracture.3 Nicotine (Nic), at concentrations higher than 10 muM, also produced a transient contraction which had a very similar pattern to that induced by 5-HT. Again, the successive application of Nic no longer produced any contracture following prior treatment with Nic itself. However, the 5-HT-induced contraction was not modified by the presence of Nic.4 Exogenously applied acetylcholine (ACh) produced a concentration-dependent contraction of the muscularis mucoase, the 50% effective concentration (EC(50)) was 69 +/- 5.6 nM. The contraction was sustained during incubation with ACh, and was not modified by prior treatment with 5-HT or Nic.5 The 5-HT (100 muM)-induced contraction was completely abolished by tetrodotoxin (0.2 muM) and atropine (0.2 muM). This means that the action is mediated by stimulating cholinergic nerves in the submucous plexus attached to muscularis mucosae. Moreover, the stimulating action of 5-HT does not involve nicotinic receptors, since the action was not blocked by hexamethonium (100 muM).6 Among several 5-MT antagonists examined, methysergide (1 muM), ketanserin (1 muM) and morphine (100 muM) failed to modify the 5-HT (100 muM)-induced contraction significantly. Cinanserin (0.1-3 muM), cyproheptadine (3-100 nM) and phenoxybenzamine (0.1-3 muM) inhibited the 5-HT-induced contraction, in a concentration-dependent manner, and each highest concentration abolished the response. However, none of these antagonists was specific for 5-HT, but the Nic (100 muM) or ACh (0.1 muM)-induced contractions were also inhibited by them.7 The present results indicate that 5-HT contracts the muscularis mucosae of the guinea-pig oesophagus indirectly by stimulating cholinergic nerves in the submucous plexus, and has no direct action on the muscularis mucosae. In addition, the type of 5-HT receptors responsible for the stimulant action may be different from those in other parts of the gastrointestinal tract, blood vessels or brain, because of the different effects of 5-HT antagonists.