5-HT4receptors facilitate cholinergic neurotransmission throughout the murine gastrointestinal tract.
BACKGROUND
In the gastrointestinal tract of several species, facilitating 5-HT4receptors were proposed on myenteric cholinergic neurons innervating smooth muscle by in vitro study of the effect of the selective 5-HT4receptor agonist prucalopride on submaximal cholinergic contractions. This was not yet established in the murine gastrointestinal tract.


METHODS
In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L-NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride.


RESULTS
Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 μmol/L onwards. The facilitation in the different series with 0.03 μmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 μmol/L prucalopride was concentration-dependently inhibited by GR 113808.


CONCLUSIONS
In the murine gastrointestinal tract, activation of 5-HT4receptors with prucalopride enhances cholinergic contractions, illustrating facilitation of myenteric cholinergic neurotransmission. The degree of enhancement with prucalopride is of similar magnitude as previously reported in other species, but the effective concentrations are lower than those needed in the gastrointestinal tract of other species.
Department of Pharmacology - Heymans Institute, Ghent University, Ghent, Belgium.
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http://orcid.org/0000-0002-6329-1103
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Pauwelyn
Department of Pharmacology - Heymans Institute, Ghent University, Ghent, Belgium.
R A
RA
Lefebvre
D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003838:Deoxyadenine Nucleotides / Q000008:administration & dosage; D004558:Electric Stimulation; D005748:Gastric Fundus / Q000187:drug effects / Q000502:physiology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000502:physiology*; D006145:Guanethidine / Q000008:administration & dosage; D018738:Hexamethonium / Q000008:administration & dosage; D007583:Jejunum / Q000187:drug effects / Q000502:physiology; D008297:Male; D008464:Mecamylamine / Q000008:administration & dosage; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage; D009435:Synaptic Transmission
C495475:2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate; D001572:Benzofurans; D003838:Deoxyadenine Nucleotides; D058828:Serotonin 5-HT4 Receptor Agonists; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; D018738:Hexamethonium; D008464:Mecamylamine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D006145:Guanethidine
5-HT4 receptor; cholinergic neurotransmission; gastrointestinal tract; mouse; prucalopride