Department of Pharmacology - Heymans Institute, Ghent University, Ghent, Belgium.
Department of Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium.
Neurogastroenterol Motil. 2018 Feb;30(2). doi: 10.1111/nmo.13162. Epub 2017 Aug 10.
Gastroprokinetic properties of 5-HT receptor agonists, such as prucalopride, are attributed to activation of 5-HT 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 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT receptors in human large intestine.
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.
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-HT receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT 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-HT receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT receptor agonist in the large intestine.
5-HT 受体激动剂（如普芦卡必利）的胃肠动力特性归因于激活支配胃肠道平滑肌层平滑肌的胆碱能神经上的 5-HT 受体，增加乙酰胆碱释放和肌肉收缩。在猪胃和结肠中，已表明磷酸二酯酶（PDE）4 控制这些 5-HT 受体的信号通路。本研究旨在研究 PDE 对人大肠中这些 5-HT 受体的介导控制。
从人大肠中制备环形平滑肌条；孵育[³H]-胆碱后，电诱导的氚流出被确定为乙酰胆碱释放的测量。研究了 PDE 抑制对普芦卡必利对电诱导乙酰胆碱释放的促进作用的影响。
非选择性 PDE 抑制剂 IBMX 增强了普芦卡必利对电诱导乙酰胆碱释放的促进作用。选择性抑制剂长春西汀（PDE1）、EHNA（PDE2）和西洛司他（PDE3）没有影响，而 rolipram 和罗氟司特（PDE4）增强了普芦卡必利诱导的促进作用与 IBMX 相同的程度。
在人大肠环形平滑肌中，促进胆碱能神经传递到大肠环形平滑肌的 5-HT 受体的细胞内途径受 PDE4 控制。如果在电诱导的人大肠环形平滑肌条的胆碱能收缩的功能测定中证实 5-HT 受体激动作用与 PDE4 抑制之间的协同作用，那么选择性 5-HT 受体激动剂与选择性 PDE4 抑制剂的联合可能增强 5-HT 受体激动剂在大肠中的体内促动力作用。
