Characterization of the muscarine receptors involved in the modulation of serotonin release from the vascularly perfused small intestine of guinea pig

Summary Isolated small intestinal segments of the guinea pig were arterially perfused and the release of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent measured by HPLC with electrochemical detection. Test substances were applied via the arterial perfusion medium. McN-A-343, pilocarpine and oxotremorine inhibited concentration-dependently the outflow of 5-HT and 5-HIAA. Pirenzepine (0.03–0.1 mol/l) which can discriminate between M₁ and M₂-receptor subtypes antagonized completely this inhibitory effect. In the presence of 1 mol/l tetrodotoxin (TTx), all three muscarine receptor agonists increased the outflow of 5-HT and 5-HIAA. Oxotremorine 1 mol/l was most effective and increased the outflow of 5-HT by 145%, that of 5-HIAA by 235%. McN-A-343 and pilocarpine, both at a concentration of 10 mol/l, increased the outflow of 5-HT by about 40%, that of 5-HIAA by 50% and 71%, respectively. The stimulatory effect of oxotremorine was competitively antagonized by pirenzepine; a pA₂ value of 7.70 was calculated. In conclusion, the cholinergic modulation of the release of 5-HT from the enterochromaffin cells consists of an indirect inhibitory (via the release of a neurotransmitter) and a direct stimulatory component. Muscarine receptors mediating the indirect effect may belong to the M₁-subtype whereas the direct stimulatory effect may be mediated by a mixed population of M₁ and M₂ receptors or by a subtype of M₁ receptors.Send offprint requests to H. Schwörer at the above address