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Synergy between 5‐ HT 4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle
Author(s) -
Pauwelyn V.,
Ceelen W.,
Lefebvre R. A.
Publication year - 2018
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13162
Subject(s) - acetylcholine , ibmx , cholinergic , endocrinology , medicine , chemistry , receptor , rolipram , agonist , muscarinic acetylcholine receptor , pharmacology , phosphodiesterase , biology , biochemistry , forskolin , enzyme
Abstract Background Gastroprokinetic properties of 5‐ HT 4 receptor agonists, such as prucalopride, are attributed to activation of 5‐ HT 4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase ( PDE ) 4 has been shown to control the signaling pathway of these 5‐ HT 4 receptors. The aim of this study was to investigate the PDE ‐mediated control of these 5‐ HT 4 receptors in human large intestine. Methods Circular smooth muscle strips were prepared from human large intestine; after incubation with [³H]‐choline, electrically induced tritium outflow was determined as a measure for acetylcholine release. The influence of PDE inhibition on the facilitating effect of prucalopride on electrically induced acetylcholine release was studied. Key Results The non‐selective PDE inhibitor IBMX enhanced the facilitating effect of prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine ( PDE 1), EHNA ( PDE 2) and cilostamide ( PDE 3) did not influence, while rolipram and roflumilast ( PDE 4) enhanced the prucalopride‐induced facilitation to the same extent as IBMX . Conclusions & Inferences In human large intestinal circular muscle, the intracellular pathway of 5‐ HT 4 receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE 4. If the synergy between 5‐ HT 4 receptor agonism and PDE 4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions of human large intestinal circular smooth muscle strips, combination of a selective 5‐ HT 4 receptor agonist with a selective PDE 4 inhibitor might enhance the in vivo prokinetic effect of the 5‐ HT 4 receptor agonist in the large intestine.