Synergistic effect between 5-HT₄ receptor agonist and phosphodiesterase 4-inhibitor in releasing acetylcholine in pig gastric circular muscle in vitro

详细信息    查看全文

• 作者：Romain A. Lefebvre^a ; ^{romain.lefebvre@ugent.be" class="auth_mail" title="E-mail the corresponding author} ; Inge Van Colen^a ; Vicky Pauwelyn^a ; Joris H. De Maeyer^b
• 关键词：5-HT4 receptor ; Phosphodiesterase 4 ; Stomach ; Acetylcholine release ; Prucalopride ; Velusetrag
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：781
• 期：Complete
• 页码：76-82
• 全文大小：703 K

文摘

5-HT₄ receptor agonists have a gastroprokinetic effect by facilitating acetylcholine release from cholinergic nerves innervating gastrointestinal smooth muscle. The role of phosphodiesterase (PDE) 4 in the signal transduction pathway of the 5-HT₄ receptors located on the cholinergic neurons towards the circular muscle layer in pig stomach was investigated by analysis of acetylcholine release. Circular muscle strips were prepared from pig proximal stomach and tritium outflow, induced by electrical field stimulation, was studied as a marker for acetylcholine release after incubation with [³H]-choline. The PDE4-inhibitor roflumilast concentration-dependently (0.1–1 µM) enhanced the facilitating effect of a submaximally effective concentration of the 5-HT₄ receptor agonist prucalopride (0.01 µM) on electrically induced acetylcholine release. Roflumilast (0.3 µM) enhanced acetylcholine release per se but in the combined presence of roflumilast and prucalopride, acetylcholine release was enhanced more than the sum of the effect of the 2 compounds alone. The 5-HT₄ receptor agonist velusetrag concentration-dependently (0.01–0.1 µM) enhanced acetylcholine release; the effect of the minimally effective concentration (0.01 µM) was significantly enhanced by 1 µM of the PDE4-inhibitor rolipram, again to a level higher than the sum of the effect of the 2 compounds alone. The synergistic effect between 5-HT₄ receptor agonists and PDE4-inhibitors demonstrates that the intracellular pathway of the 5-HT₄ receptors located on cholinergic neurons towards pig gastric circular muscle is controlled by PDE4. Combining a 5-HT₄ receptor agonist with a PDE4-inhibitor might thus enhance its gastroprokinetic effect.