Evidence for the involvement of 5-HT4 receptors in the 5-hydroxytryptamine-induced pattern of migrating myoelectric complex in sheep.

1. The effects induced by 5-hydroxytryptamine (5-HT) on gastrointestinal myoelectric activity in conscious sheep were recorded through electrodes chronically implanted and analysed by computer. The 5-HT receptors and the cholinergic neuronal pathways involved in these actions were investigated. 2. The intravenous (i.v.) administration of 5-HT (2, 4 and 8 micrograms kg-1 min-1, 5 min) induced an antral inhibition concomitant with a duodenal activity front that migrated to the jejunum, followed by a period of intestinal inactivity. This myoelectric pattern closely resembled that observed in the phases III and I of the migrating myoelectric complex (MMC) in sheep. The 0.5 microgram kg-1 min-1 dose evoked the same pattern in only two out of the six animals used. Likewise, the 1 microgram kg-1 min-1 dose similarly affected four of the six animals. In addition, a transient stimulation was observed in the antrum and jejunum when the two highest doses were used. 3. The 5-HT1 antagonist, methiothepin (0.1 mg kg-1), the 5-HT2 antagonists, ritanserin (0.1 mg kg-1) and ketanserin (0.3 mg kg-1), the 5-HT3 antagonists, granisetron (0.2 mg kg-1) and ondansetron (0.5 mg kg-1), as well as the 5-HT4 antagonist, GR113808 (0.2 mg kg-1), did not modify the spontaneous gastrointestinal myoelectric activity. However, the cholinoceptor antagonists, atropine (0.2 mg kg-1) and hexamethonium (2 mg kg-1), inhibited gastrointestinal activity. 4. When these antagonists were injected i.v. 10 min before 5-HT (2 or 4 micrograms kg-1 min-1, 5 min), only GR113808, atropine and hexamethonium were able to modify the 5-HT-induced actions, all of them being completely blocked by the three antagonists. 5. Our data show that 5-HT initiates a MMC-like pattern in the gastrointestinal area in sheep through 5-HT4 receptors. Furthermore, these actions are mediated by cholinergic neural pathways involving muscarinic and nicotinic receptors. However, our results do not indicate a role for either 5-HT1, 5-HT2 or 5-HT3 receptors in the 5-HT-induced effects.