Several receptor subtypes contribute to 5-hydroxytryptamine-induced secretion by rat ileum in-vitro

The receptors contributing to 5-hydroxytryptamine (5-HT)-induced secretion by rat ileum were investigated in-vitro using selective agonists and antagonists. 5-HT induced a dose-dependent increase in the short-circuit current (SCC) generated by both intact and stripped sheets of rat ileum. 1-Phenylbiguanide, a selective 5-HT3 agonist, and 5-methoxytryptamine, an agonist that lacks affinity for 5-HT3 receptors, also increased the SCC. In intact sheets 5-HT was more effective than either 1-phenylbiguanide or 5-methoxytryptamine, whereas in stripped sheets 5-HT and 5-methoxytryptamine were equipotent, with 1-phenylbiguanide having little effect. Tetrodotoxin abolished the response of intact sheets to 1-phenylbiguanide but only reduced the responses to 5-HT and 5-methoxytryptamine by 57% and 54%, respectively. This inhibition was reduced to 25% in stripped sheets. The 5-HT3 antagonist granisetron abolished the response to 1-phenylbiguanide, but did not alter the effects of 5-HT. Ketanserin, a 5-HT2 antagonist, had a small effect on the actions of 5-methoxytryptamine in intact, but not stripped, sheets and no effect on the response to 5-HT in either preparation. Tropisetron, a 5-HT3 and 5-HT4 antagonist, inhibited the response to 5-methoxytryptamine, but had less effect on the response to 5-HT. Desensitization to 1-phenylbiguanide inhibited the response to 5-HT in intact, but not stripped sheets, whereas desensitization to 5-methoxytryptamine abolished the 5-HT response in stripped sheets, but induced only 42% inhibition in intact sheets. Previous exposure to a combination of both 1-phenylbiguanide and 5-methoxytryptamine abolished the 5-HT-induced increase in SCC in both preparations. The findings suggest that 5-HT-induced ileal secretion involves more than one 5-HT receptor subtype and that both neural and non-neural mechanisms contribute to the response.