Lefebvre, Romain

Pauwelyn, Vicky

Van Deynse, Els

English

Ghent University Academic Bibliography

 Acta Gastro-enterologica Belgica - 27th Belgian Week of Gastroenterology, 25-28 February 2015, Brussels, Belgium http://www.bwge.be/archives/ Facilitation of cholinergic neurotransmission via 5-HT4 receptors in the murine gastrointestinal tract Vicky Pauwelyn, Els Van Deynse and Romain Lefebvre Department of Pharmacology - Heymans Institute,  Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium 1. INTRODUCTION Recent data in rats with mosapride and in mice with prucalopride, both selective 5-HT4 receptor agonists, showed that these agents activate the cholinergic anti-inflammatory pathway in the  rodent small intestine. This was suggested to be due to activation of 5-HT4 receptors on choliner-gic myenteric neurons dampening activation of resident macrophages. Till now however, even the presence of 5-HT4 receptors on cholinergic enteric neurons inducing smooth muscle contraction, a location established in the pig and human gastro-intestinal (GI) tract, was not firmly established in the murine GI tract. 2. AIM The aim of this study was therefore to investigate the influence of prucalopride on submaximal  cholinergic contractions in different regions of the murine GI tract. 3. METHODS Circular smooth muscle strips were prepared from the fundus, jejunum and colon (mucosa removed for jejunum and colon) and mounted between  2 stimulation electrodes in an organ bath with  oxygenated Krebs solution; isometric tension was registered. For each tissue, electrical field stimulation (EFS) was performed with different stimulation para-meters (voltage, frequency and interstimulus  interval) to select those parameters inducing  neurogenic cholinergic on-contractions as checked with tetrodotoxin (3 µM) and atropine (1 µM) respectively. EFS at these parameters induced reproducible contractions; the contraction ampli-tude was halved by decreasing the voltage (V50%) to study the influence of prucalopride (0.003 to  0.03 µM). The 5-HT4 receptor antagonist, GR113808 (0.3 µM), was studied versus 0.03 µM prucalopride. 4. RESULTS EFS-induced cholinergic on-contractions were obtained in the presence of guanethidine (4 µM) and L-NAME (300 µM) to exclude noradrenergic and nitrergic influences respectively. Additionally, for colon strips the P2Y1 receptor antagonist  MRS 2500 (1 µM) had to be added to avoid influ-ences of the relaxant neurotransmitter ATP. EFS with 10 s trains (500 µs pulse duration; maximal voltage; 4 [fundus] or 8 Hz [jejunum and colon]) at 5 (fundus and colon) or 10 min (jejunum) interval induced reproducible contractions. Upon reduc-tion of the stimulation voltage to V50%, reproduc-ible submaximal contractions were obtained; after adding prucalopride, contractions by EFS at V50% were followed for 50 min. Prucalopride concentration-dependently increas-ed contractions at V50%. The mean contraction force (%) 50 minutes after administration of pru-calopride (0.003, 0.01 and 0.03 µM) was 133, 181*, 204*** in the fundus; 122*, 124**, 138***  Acta Gastro-enterologica Belgica - 27th Belgian Week of Gastroenterology, 25-28 February 2015, Brussels, Belgium http://www.bwge.be/archives/ in the jejunum; 133, 136, 152** in the colon  (*P < 0.05; **P < 0.01; ***P < 0.001 versus con-trol; one-way ANOVA with Bonferroni correction; n = 6-9). The effect of 0.03 µM prucalopride was abolished by the selective 5-HT4 receptor antago-nist GR113808 (0.3 µM). 5. CONCLUSION These data suggest the presence of 5-HT4 recep-tors on cholinergic neurons innervating circular smooth muscle in murine fundus, jejunum and colon. The effective concentrations of pruca-lopride are lower than those needed at 5-HT4 receptors in the human and porcine GI tract. 

Facilitation of cholinergic neurotransmission via 5-HT4 receptors in the murine gastrointestinal tract

https://biblio.ugent.be/publication/6843766/file/6844900.pdf

Facilitation of cholinergic neurotransmission via 5-HT4 receptors in the murine gastrointestinal tract

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