5-HT(4) RECEPTOR-MEDIATED FACILITATION OF THE EMPTYING PHASE OF THE PERISTALTIC REFLEX IN THE GUINEA-PIG ISOLATED ILEUM

1 The influence of 5-hydroxytryptamine (5-HT) receptor agonists and an tagonists on the emptying phase (circular muscle contraction) of the p eristaltic 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 facilitati on 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 muM) and/or ondansetron (2 muM) in t he bathing medium. 5-HT (0.1 - 1.0 muM) caused a facilitation of the p erstaltic reflex; the response curve to 5-HT was not altered by the pr esence of methysergide (1 muM) and ondansetron (2 muM). 4 In the prese nce of methysergide (1 muM) plus ondansetron (2 muM), 5-HT (7.36 +/- 0 .06), 5-methoxy-tryptamine (7.01 +/- 0.17), 5-carboxamidotryptamine (5 .43 +/- 0.06), renzapride (6.09 +/- 0.17), (S)-zacopride (5.99 +/- 0.1 1), (R)-zacopride (5.61 +/- 0.13) and metoclopramide (4.8 +/- 0.65) ca used a concentration-related facilitation of the peristaltic reflex, t he pEC50 values (mean +/- s.e.mean) being shown in parentheses. 2-Meth yl-5-HT was ineffective up to 10 muM. 5 The administration of SDZ 205- 557 (1 muM) alone failed to modify the peristaltic reflex, but caused a parallel dextral shift in the concentration-effect curve to 5-HT (ap parent pK(B) 7.38 +/- 0.30). It failed to modify the effect of acetylc holine to enhance the peristaltic reflex. 6 It is concluded that the r ank order of potency of the 5-HT agonists from the indole and substitu ted benzamide series to facilitate the emptying phase of the peristalt ic reflex in the guinea-pig ileum closely correlates with their publis hed actions as 5-HT4 agonists in other systems. An agonist action on t he 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 i nhibit the effects of 5-HT.