Changes in 5-HT-mediated pathways in radiation-induced attenuation and recovery of ion transport in rat colon

Whole body exposure to high doses of ionizing radiation is associated with small intestinal and colonic dysfunction, the etiology of which remains unk nown. In this study, we investigated the role of both neural and nonneural 5-hydroxytryptamine (5-HT)-mediated pathways in radiation-induced attenuati on and recovery of colonic secretory function. Rats were exposed to whole b ody 10-Gy gamma irradiation, and distal colonic tissues were studied in Uss ing chambers 1, 3, and 7 days after exposure. Tissue responses to exogenous ly added 5-HT (nonneural pathway) and electrical field stimulation (EFS; ne ural pathway) were performed, and 5-HT receptor subtypes implicated in both responses were determined using three different 5-HT receptor antagonists: methysergide (5-HT2/1C), granisetron (5-HT3), and SDZ-205,557 (5-HT4). Max imal responses to exogenously added 5-HT were decreased at 1 and 3 days and returned to control values at 7 days. Responses to exogenous 5-HT were ins ensitive to both 5-HT2/1C and 5-HT3 antagonists and to TTX but were totally inhibited by SDZ-205,557 in both control and irradiated tissues. Responses to EFS were decreased 1 and 3 days after exposure and returned to control values at 7 days. In control tissues and 1 and 3 days after exposure, EFS r esponses were insensitive to both 5-HT2/1C and 5-HT4 antagonists but reduce d by granisetron in control (51%) and at 1 (64%) and 3 days (58%) after exp osure. Granisetron was more effective at 7 days (73% inhibition), which was concomitant with the appearance of a 5-HT4 antagonist-sensitive pathway (4 0% inhibition). In conclusion, neural and nonneural 5-HT-mediated pathways involve 5-HT3 and 5-HT4 receptors, respectively, in control as well as in i rradiated tissues 1 and 3 days after exposure. Conversely, the recovery of colonic transport is associated with additional 5-HT3-mediated pathways, pr obably in combination with 5-HT4 receptors.