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 ;LM) and/or ondansetron (2 pLM) in the bathing medium. 5-HT (0.1-1.0 ILM) caused a facilitation of the perstaltic reflex; the response curve to 5-HT was not altered by the presence of methysergide (1 pLM) and ondansetron (2 pM). 4 In the presence of methysergide (1 pM) plus ondansetron (2 ltM), 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 concentrationrelated 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 IM.5 The administration of SDZ 205-557 (1 pM) 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.

1 The 5-HT receptor involved in the e ect of mucosal application of 5-HT to facilitate peristalsis was investigated in the isolated guinea pig ileum. 2 An application of 5-HT (3 ± 100 mM) to the mucosal surface (by inclusion of 5-HT in the KrebsHenseleit solution passing through the lumen of the ileum) caused a concentration related facilitation of peristalsis characterized by a reduction in the peristaltic threshold. 3 Peristalsis was not modi®ed by methiothepine (0.1 mM), ritanserin (0.1 mM), ondansetron (5 mM), granisetron (1 mM) or SB 204070 (0.1 mM) administered alone to the mucosal surface. 4 The concentration ± response curve to mucosally applied 5-HT was not altered by the mucosally applied 5-HT 1/2 receptor antagonist methiothepine (0.1 mM), the 5-HT 2 receptor antagonist ritanserin (0.1 mM) or the 5-HT 4 receptor antagonist SB 204070 (0.1 mM). However, the mucosally applied 5-HT 3 receptor antagonists ondansetron (5 mM) and granisetron (1 mM) shifted the response curves to mucosally applied 5-HT to the right in a parallel and surmountable manner. The pD 2 values in the absence and presence of ondansetron were 5.42+0.07 and 4.12+0.10, respectively, (n=6) and that of granisetron were 5.45+0.12 and 4.50+0.10 respectively, (n=5). 5 Serosally applied ondansetron (5 mM) or granisetron (1 mM) had no e ect on the concentration ± response curve to mucosally applied 5-HT. However, the serosally applied ondansetron and granisetron antagonised the facilitatory e ect of serosally applied 5-HT (10 mM) when administered in the presence of serosally applied SB 204070 (0.1 mM). 6 It is concluded that the facilitatory e ect of mucosally applied 5-HT to reduce the peristaltic threshold in the guinea pig ileum is mediated via a 5-HT 3 receptor located on the mucosal and not the serosal side of the ileum.

Gastrointestinal motility can be assessed in vitro by investigating the effects of drugs or gene knockouts on intestinal propulsion, and on neurone-mediated responses evoked by electrical field stimulation (EFS). The latter predominantly measure enteric motor activity and can detect prokinetic activity of exogenous agents. Some evidence suggests that naloxone has prokinetic activity when evaluated for an ability to modulate responses to EFS, but the effects are inconsistent across different species or intestinal regions. Models of intestinal peristalsis measure an integrated sensory-motor nerve function and possess more intact neuro-neuronal connections. In such preparations, the effects of naloxone also suggest a prokinetic property but again, this is inconsistent. By contrast, consistent prokinetic activity of naloxone is apparent in models where peristalsis is compromised by drug-induced suppression of motor nerve activity or by modulation of endogenous processes using receptor antagonists or inappropriate intraluminal distension. These data suggest that endogenous opioids play little or no role in normal intestinal physiology, but suppress intestinal motility when motor function is compromised. Consequently, drugs that antagonize opioid receptors may exert prokinetic activity in conditions where intestinal motility is reduced, such as constipation. Further work is required to elucidate the opiate receptor(s) involved.

1 The aim of the present study was to investigate a 5-HT4 receptor involvement in the mediation of a 5-HT-induced relaxation response in the rat isolated ileum in vitro. 2 Ileal segments were taken at regular intervals from the ileo-caecal junction to duodenum. 5-HT (1,Mm) induced a relaxation or contraction response in segments taken from the terminal ileum: the relaxation decreased and finally disappeared as contractions dominated in the proximal tissues. The 5-HT-induced relaxations were enhanced in the terminal segments and the contractions attenuated in both terminal and proximal segments, in the presence of methysergide (1 giM) and atropine (0.1 uM). 8 The relaxation response to 5-HT in the rat terminal ileum was not antagonized by ritanserin (1 gM), ondansetron (1 uM) or Nw-nitro-L-arginine methyl ester (100 gM) and with only a twofold dextral shift of the concentration-response curve by tetrodotoxin (1 gM).9 It is concluded that the relaxant response to 5-HT in the terminal region of the ileum is mediated directly at the smooth muscle; a ranked indole agonist potency and selective antagonism by 5-HT4 receptor antagonists tropisetron, SDZ 205-557 and GR 113808 indicate a 5-HT4 receptor involvement in the relaxation response.

No abstract