Characterization of 5-hydroxytryptamine receptors mediating mucosal secretion in guinea-pig ileum.

1. The receptor subtypes through which 5-hydroxytryptamine (5-HT) increases electrolyte secretion across the mucosa of guinea-pig ileum were studied. 2. Flat sheep preparations of guinea-pig mucosa plus submucosa were placed in Ussing chambers and the short circuit current (ISC), an index of net electrogenic electrolyte transport across the mucosa, was measured under voltage clamp conditions. 3. Low concentrations of 5-HT (10-300 nM) evoked monophasic increases in ISC which were significantly reduced by hyoscine (100 nM), tetrodotoxin (TTX, 300 nM) and the 5-HT2 receptor antagonist, ketanserin (3-300 nM). 4. Higher concentrations of 5-HT (1-10 microM) produced biphasic responses which were reduced by hyoscine (100 nM), TTX (300 nM), ketanserin (3-300 nM) and also by the 5-HT3 receptor antagonists, granisetron (1 microM) and ICS 205-930 (100 nM). 5. 2-Methyl-5-HT (1-100 microM) and alpha-methyl-5-HT (30 nM-30 microM), agonists at 5-HT3 and 5-HT2 receptors respectively, also evoked ISC increases. These responses were reduced by hyoscine (100 nM) and abolished by TTX (300 nM) and the respective receptor antagonists, granisetron (1 microM) and ketanserin (30 nM). 6. The 5-HT4 receptor antagonist, SDZ 205-557 (300 nM) had no effect on the response to 5-HT. 7. The TTX-resistant response to 5-HT was not affected by 5-HT2,3 or 4 receptor antagonists. 8. These results indicate that 5-HT mediates secretion partly by an action on 5-HT3 receptors located on cholinergic and noncholinergic secretomotor neurones, partly by an action on higher affinity'5-HT2-like' receptors predominantly on noncholinergic neurones, and partly by a direct action on the epithelium.