Prins N H, Akkermans L M, Lefebvre R A, Schuurkes J A
Department of Gastrointestinal Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Br J Pharmacol. 2000 Nov;131(5):927-32. doi: 10.1038/sj.bjp.0703615.
5-HT(4) receptors mediate circular muscle relaxation in both human and canine large intestine, but this phenomenon alone can not explain the improvement in colonic motility induced by selective 5-HT(4) receptor agonists in vivo. We set out to characterize 5-HT(4) receptor-mediated effects in longitudinal muscle strips of canine and human large intestine. Electrical field stimulation (EFS) was applied providing submaximal isotonic contractions. L-NOARG (0.1 mM) was continuously present in the organ bath to preclude nitric oxide-induced relaxation to EFS. The selective 5-HT(4) receptor agonist prucalopride (0.3 microM) enhanced EFS-evoked contractions, that were antagonized in both preparations by the selective 5-HT(4) receptor antagonist GR 113808 (0.1 microM). The prucalopride-induced increase was present in canine ascending and descending colon, but absent in rectum. Regional differences in response to prucalopride were not observed in human ascending and sigmoid colon and rectum. Incubation with atropine (1 microM) or tetrodotoxin (0.3 microM) inhibited EFS-induced contractions, which were then unaffected by prucalopride (0.3 microM) in both tissues. In the presence of methysergide (3 microM; both tissues) and granisetron (0.3 microM; only human tissues), 5-HT (0.3 microM) enhanced EFS-induced contractions, an effect that was antagonized by GR 113808 (0.1 microM). In the presence of atropine or tetrodotoxin, EFS-induced contractions were inhibited, leaving 5-HT (0.3 microM) ineffective in both preparations. This study demonstrates for the first time that in human and canine large intestine, 5-HT(4) receptors are located on cholinergic neurones, presumably mediating facilitating release of acetylcholine, resulting in enhanced longitudinal muscle contractility. This study and previous circular muscle strip studies suggest that 5-HT(4) receptor agonism facilitates colonic propulsion via a coordinated combination of inhibition of circumferential resistance and enhancement of longitudinal muscle contractility.
5-羟色胺（5-HT）(4)受体介导人和犬类大肠的环形肌松弛，但仅这一现象无法解释选择性5-HT(4)受体激动剂在体内引起的结肠动力改善。我们着手研究5-HT(4)受体在人和犬类大肠纵行肌条中的介导作用。施加电场刺激（EFS）以产生次最大等张收缩。器官浴中持续存在L-硝基精氨酸（L-NOARG，0.1 mM）以防止一氧化氮诱导的对EFS的松弛作用。选择性5-HT(4)受体激动剂普芦卡必利（0.3 microM）增强了EFS诱发的收缩，在两种制剂中，该作用均被选择性5-HT(4)受体拮抗剂GR 113808（0.1 microM）拮抗。普芦卡必利诱导的增加在犬类升结肠和降结肠中存在，但在直肠中不存在。在人升结肠、乙状结肠和直肠中未观察到对普芦卡必利反应的区域差异。用阿托品（1 microM）或河豚毒素（0.3 microM）孵育可抑制EFS诱导的收缩，然后两种组织中的收缩均不受普芦卡必利（0.3 microM）影响。在存在麦角新碱（3 microM；两种组织）和格拉司琼（0.3 microM；仅人组织）的情况下，5-羟色胺（5-HT，0.3 microM）增强了EFS诱导的收缩，该作用被GR 113808（0.1 microM）拮抗。在存在阿托品或河豚毒素的情况下，EFS诱导的收缩受到抑制，使5-羟色胺（5-HT，0.3 microM）在两种制剂中均无效。本研究首次证明，在人和犬类大肠中，5-HT(4)受体位于胆碱能神经元上，可能介导促进乙酰胆碱释放，从而增强纵行肌收缩力。本研究和先前的环形肌条研究表明，5-HT(4)受体激动作用通过抑制周向阻力和增强纵行肌收缩力的协同组合促进结肠推进。
