Regionally dependent neuromuscular functions of motilin and 5‐HT₄ receptors in human isolated esophageal body and gastric fundus

Abstract

Selective motilin and 5-HT₄ agonists have different, region-dependent abilities to modulate human esophageal and stomach neuromuscular activity, exemplified by weak inhibition (motilin) or excitation (5-HT₄) in esophageal body and excitation for both in stomach. In different patients with motility dysfunctions, motilin and 5-HT₄ agonists may reduce gastro-esophageal reflux in different ways.

The effect of levosulpiride on in vitro motor patterns in the human gastric fundus, antrum, and jejunum

“…Our results suggest that the prokinetic effect of levosulpiride is mainly caused by the increase in acetylcholine release from EMNs. This facilitatory effect has been demonstrated in the human gastric antrum, fundus and in other areas of the gastrointestinal tract such as the colon, and has been widely reported in other species such as rodents . Our results showing an increase in cholinergic EFS‐induced contractions are similar to those reported in the human antrum for the specific 5HT 4 agonist prucalopride with an E max of about 50% increase, although the potency for this specific agonist was higher .…”

5‐HT4 receptors facilitate cholinergic neurotransmission throughout the murine gastrointestinal tract

“…DMSO added cumulatively after reaching a stable effect with 0.03 μmol/L prucalopride showed no effect so that it is unlikely that DMSO suppresses the effect of prucalopride at 5‐HT 4 receptors. When the concentration‐dependency of the facilitating effect of prucalopride on cholinergic contractions was studied in rat forestomach, canine stomach, porcine stomach, human stomach and human colon, a similar degree of maximal facilitation was observed as in the murine GI tract but higher concentrations than 0.03 μmol/L prucalopride were required to obtain this maximal effect, even in tissues with a similar pEC 50 . This suggests a higher number and/or a more effective coupling of the 5‐HT 4 receptors enhancing myenteric cholinergic neurotransmission in the murine GI tract, at least fundus and colon, as no comparative data for prucalopride are available for the small intestine in the literature.…”

“…The concentration‐dependency of the facilitation by prucalopride was clearly illustrated for the three tissues when it was added cumulatively, also showing that the maximal effect of prucalopride was nearly reached from 0.03 μmol/L onwards. The pEC 50 values (from 8.37 in the fundus to 7.83 in the jejunum, roughly corresponding with an EC 50 of 0.004‐0.015 μmol/L), were similar to those reported for canine (pEC 50 7.9) and porcine stomach (pEC 50 8.25) but clearly lower than those reported for rat forestomach (EC 50 1.1 μmol/L), human colon (EC 50 2.3 μmol/L) and human gastric fundus (pEC 50 5.6) . The facilitating effect of 0.03 μmol/L prucalopride was concentration‐dependently depressed by GR 113808 and abolished by 0.3 μmol/L GR 113808.…”

Synergy between 5‐HT4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle

“…16,18 The facilitation of enteric cholinergic neurotransmission by prucalopride in the porcine and human GI tract is pronounced and sustained. 6,[19][20][21] Still, this effect was shown to be enhanced by the selective PDE4 inhibitor rolipram in porcine stomach and colon. 9,22 We recently confirmed this 23 with the selective PDE4 inhibitor roflumilast, marketed for chronic obstructive pulmonary disease, 24 and the highly selective 5-HT 4 receptor agonist velusetrag, 25 The aim of the present study was therefore to investigate whether the signal transduction pathway of 5-HT 4 receptors in myenteric cholinergic neurons innervating human large intestinal circular muscle is controlled by PDEs, and if so whether PDE4 is the isozyme involved.…”

“…The facilitation of enteric cholinergic neurotransmission by prucalopride in the porcine and human GI tract is pronounced and sustained . Still, this effect was shown to be enhanced by the selective PDE4 inhibitor rolipram in porcine stomach and colon .…”