Evidence for two types of 5-hydroxytryptamine receptor on secretomotor neurons of the guinea-pig ileum.

Flat sheet preparations of the mucosa plus submucosa from the guinea-pig ileum were placed in Ussing chambers so that short circuit current (Isc), an index of electrolyte movement across the mucosa, could be measured. In these preparations, 5-hydroxytryptamine (5-HT) increases Isc indirectly by stimulating both cholinergic and non-cholinergic secretomotor neurons. The 5-HT3 receptor antagonist, ICS 205-930 (10(-13)-10(-5 M), substantially depressed the secretory response due to 5-HT (10(-6) M), but not that produced by direct activation of muscarinic receptors on the mucosal epithelium with carbachol (10(-6) M), or by stimulation of secretomotor neurons with substance P (10(-8) M) or 1,1-dimethyl-4-phenylpiperazinium (10(-5)M). The residual response to 5-HT, after the addition of a maximally effective concentration of ICS 205-930 (10(-6) M), was further reduced by hyoscine (10(-7) M). When that part of the 5-HT response attributable to the release of acetylcholine was blocked by hyoscine (10(-7) M), ICS 205-930 did not further modify the response to 5-HT. The hyoscine-resistant component was, however, substantially depressed by tetrodotoxin (3.5 x 10(-7) M). The response remaining after ICS 205-930 and hyoscine was not affected by methysergide (2 x 10(-5) M) or cyproheptadine (10(-7) M). We conclude that there are ICS 205-930 sensitive 5-HT receptors on cholinergic secretomotor neurons, and ICS 205-930, methysergide, and cyproheptadine insensitive 5-HT receptors on non-cholinergic secretomotor neurons.