5‐HT4 receptor mediated facilitation of the emptying phase of the peristaltic reflex in the guinea‐pig isolated ileum

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Abstract
1 The influence of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on the emptying phase (circular muscle contraction) of the peristaltic reflex was investigated in the guinea-pig isolated ileum. 2 The effect of drug application to the serosal surface was measured as the changes in threshold pressure required to trigger the peristaltic reflex and the interval between the peristaltic strokes. A facilitation or inhibition of peristalsis was defined as a reduction or increase in threshold pressure respectively. 3 Peristalsis was not modified by the inclusion of methysergide (1 μm) and/or ondansetron (2 μm) in the bathing medium. 5-HT (0.1–1.0 μm) caused a facilitation of the perstaltic reflex; the response curve to 5-HT was not altered by the presence of methysergide (1 μm) and ondansetron (2 μm). 4 In the presence of methysergide (1 μm) plus ondansetron (2 μm), 5-HT (7.36 ± 0.06), 5-methoxytryptamine (7.01 ± 0.17), 5-carboxamidotryptamine (5.43 ± 0.06), renzapride (6.09 ± 0.17), (S)-zacopride (5.99 ± 0.11), (R)-zacopride (5.61 ± 0.13) and metoclopramide (4.8 ± 0.65) caused a concentration-related facilitation of the peristaltic reflex, the pEC50 values (mean ± s.e.mean) being shown in parentheses. 2-Methyl-5-HT was ineffective up to 10 μm. 5 The administration of SDZ 205–557 (1 μm) alone failed to modify the peristaltic reflex, but caused a parallel dextral shift in the concentration-effect curve to 5-HT (apparent pKB 7.38 ± 0.30). It failed to modify the effect of acetylcholine to enhance the peristaltic reflex. 6 It is concluded that the rank order of potency of the 5-HT agonists from the indole and substituted benzamide series to facilitate the emptying phase of the peristaltic reflex in the guinea-pig ileum closely correlates with their published actions as 5-HT4 agonists in other systems. An agonist action on the 5-HT4 receptor is also supported by the potency of the 5-HT3/5-HT4 antagonist SDZ 205–557 (but not the 5-HT3 antagonist ondansetron) to inhibit the effects of 5-HT.