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

Vicky Pauwelyn (UGent) , Wim Ceelen (UGent) and Romain Lefebvre (UGent)
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Abstract
Background: Gastroprokinetic properties of 5-HT4 receptor agonists, such as prucalopride, are attributed to activation of 5-HT4 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-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine. Methods: Circular smooth muscle strips were prepared from human large intestine; after incubation with [H-3]-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 (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the prucalopride-induced facilitation to the same extent as IBMX. Conclusions & Inferences: In human large intestinal circular muscle, the intracellular pathway of 5-HT4 receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT4 receptor agonism and PDE4 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-HT4 receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT4 receptor agonist in the large intestine.
Keywords
5-HT4 receptor, acetylcholine release, human large intestine, phosphodiesterase, prucalopride, OBSTRUCTIVE PULMONARY-DISEASE, PIG DESCENDING COLON, SMOOTH-MUSCLE, IN-VITRO, NUCLEOTIDE PHOSPHODIESTERASES, CHOLINERGIC NEUROTRANSMISSION, NEUROMUSCULAR FUNCTIONS, SELECTIVE INHIBITORS, CHRONIC CONSTIPATION, INOTROPIC RESPONSE

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Citation

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Chicago
Pauwelyn, Vicky, Wim Ceelen, and Romain Lefebvre. 2018. “Synergy Between 5-HT4 Receptor Stimulation and Phosphodiesterase 4 Inhibition in Facilitating Acetylcholine Release in Human Large Intestinal Circular Muscle.” Neurogastroenterology and Motility 30 (2).
APA
Pauwelyn, V., Ceelen, W., & Lefebvre, R. (2018). Synergy between 5-HT4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle. NEUROGASTROENTEROLOGY AND MOTILITY, 30(2).
Vancouver
1.
Pauwelyn V, Ceelen W, Lefebvre R. Synergy between 5-HT4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle. NEUROGASTROENTEROLOGY AND MOTILITY. 2018;30(2).
MLA
Pauwelyn, Vicky, Wim Ceelen, and Romain Lefebvre. “Synergy Between 5-HT4 Receptor Stimulation and Phosphodiesterase 4 Inhibition in Facilitating Acetylcholine Release in Human Large Intestinal Circular Muscle.” NEUROGASTROENTEROLOGY AND MOTILITY 30.2 (2018): n. pag. Print.
@article{8550941,
  abstract     = {Background: Gastroprokinetic properties of 5-HT4 receptor agonists, such as prucalopride, are attributed to activation of 5-HT4 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-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine. 
Methods: Circular smooth muscle strips were prepared from human large intestine; after incubation with [H-3]-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 (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the prucalopride-induced facilitation to the same extent as IBMX. 
Conclusions \& Inferences: In human large intestinal circular muscle, the intracellular pathway of 5-HT4 receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT4 receptor agonism and PDE4 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-HT4 receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT4 receptor agonist in the large intestine.},
  articleno    = {e13162},
  author       = {Pauwelyn, Vicky and Ceelen, Wim and Lefebvre, Romain},
  issn         = {1350-1925},
  journal      = {NEUROGASTROENTEROLOGY AND MOTILITY},
  keyword      = {5-HT4 receptor,acetylcholine release,human large intestine,phosphodiesterase,prucalopride,OBSTRUCTIVE PULMONARY-DISEASE,PIG DESCENDING COLON,SMOOTH-MUSCLE,IN-VITRO,NUCLEOTIDE PHOSPHODIESTERASES,CHOLINERGIC NEUROTRANSMISSION,NEUROMUSCULAR FUNCTIONS,SELECTIVE INHIBITORS,CHRONIC CONSTIPATION,INOTROPIC RESPONSE},
  language     = {eng},
  number       = {2},
  pages        = {10},
  title        = {Synergy between 5-HT4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle},
  url          = {http://dx.doi.org/10.1111/nmo.13162},
  volume       = {30},
  year         = {2018},
}

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