5‐HT₄ receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle

Abstract

1 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 e ects in longitudinal muscle strips of canine and human large intestine. 2 Electrical ®eld 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. 3 The selective 5-HT 4 receptor agonist prucalopride (0.3 mM) enhanced EFS-evoked contractions, that were antagonized in both preparations by the selective 5-HT 4 receptor antagonist GR 113808 (0.1 mM). The prucalopride-induced increase was present in canine ascending and descending colon, but absent in rectum. Regional di erences in response to prucalopride were not observed in human ascending and sigmoid colon and rectum. Incubation with atropine (1 mM) or tetrodotoxin (0.3 mM) inhibited EFS-induced contractions, which were then una ected by prucalopride (0.3 mM) in both tissues. 4 In the presence of methysergide (3 mM; both tissues) and granisetron (0.3 mM; only human tissues), 5-HT (0.3 mM) enhanced EFS-induced contractions, an e ect that was antagonized by GR 113808 (0.1 mM). In the presence of atropine or tetrodotoxin, EFS-induced contractions were inhibited, leaving 5-HT (0.3 mM) ine ective in both preparations. 5 This study demonstrates for the ®rst 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.

Abatement of Morphine-Induced Slowing in Gastrointestinal Transit by Dai-kenchu-to, a Traditional Japanese Herbal Medicine

“…These effects of DKT on isolated intestine provide a pharmacological basis for recovery from morphine-induced disorder of GI transit. It has been recently demonstrated that GI transit may be coordinated by relaxation of the circular muscle and constriction of the longitudinal muscle through several neuronal networks including serotonin receptors (8,9). This supports the previous work of Grider and Makhlouf who showed that morphine slows GI transit by inhibiting relaxation of the circular muscle and contraction of the longitudinal muscle (10).…”

Anti-Diarrheal Activity and Toxicity of Learng Pid Samud Recipe

“…The effects such as inhibition of ileum contractions, slowing motility and propulsion of intraluminal contents are generally known to take part in anti-transit effect (Shook et al, 1989). Gastrointestinal (GI) transit may be coordinated by relaxation of the circular muscle and constriction of the longitudinal muscle (Prins et al, 2000;Shibata et al, 1999). Nerve supply of GI tract has two types, enteric system (myenteric and submucosal plexus) and extrinsic nerves (parasympathetic and sympathetic nerves).…”

Prukalopride in the Treatment of Chronic Constipation

“…Прукалоприд стимулирует сокращения в продольных гладких мышцах толстой кишки путем стимулирования высвобождения ацетилхолина посредством активации рецепторов 5-НТ 4 на пресинаптических холинергических кишечных нейронах [33]. Прукалоприд также индуцирует релаксацию толстой кишки за счет продольных гладких мышц и прямой кишки человека через локальную актива-цию 5-HT 4 -рецепторов [34].…”