Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Eur J Pharmacol. 2021 Nov 5;910:174491. doi: 10.1016/j.ejphar.2021.174491. Epub 2021 Sep 9.
The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 μM tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 μM carbenoxolone (a gap junction inhibitor), pretreatment with 100 μM CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl-free solution. However, pretreatment with 100 μM N-nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 μM VIP (6-28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation.
Cajal 间质细胞（ICCs）在协调胃肠道运动中发挥着重要作用。本研究旨在阐明 ICCs 是否以及如何参与烟碱型乙酰胆碱受体刺激引起的食管下括约肌（LES）松弛。应用 1,1-二甲基-4-苯基哌嗪（DMPP；烟碱型乙酰胆碱受体激动剂）可诱导猪 LES 环形平滑肌产生短暂松弛。DMPP 诱导的松弛不仅被 1 μM 河豚毒素消除，而且通过用 100 μM 卡波氯铵（缝隙连接抑制剂）预处理、用 100 μM CaCCinh-A01（作用为钙激活氯离子通道抑制剂的 anoctamin-1 阻断剂）预处理和用无氯溶液预处理来抑制 ICC 活性而消除。然而，用 100 μM N-硝基-L-精氨酸甲酯预处理对 DMPP 诱导的松弛影响不大。此外，DMPP 诱导的松弛被 1 mM 苏拉明（嘌呤 P2 受体拮抗剂）预处理抑制，但被 1 μM VIP（6-28）（血管活性肠肽（VIP）受体拮抗剂）预处理抑制。用三磷酸腺苷（ATP）刺激嘌呤 P2 受体可诱导松弛，该松弛被用 CaCCinh-A01 预处理抑制 ICC 活性所消除。总之，通过激活 anoctamin-1 使 ICC 膜超极化在 DMPP 诱导的松弛中起核心作用。ATP 可能是抑制性肠神经元的神经递质，刺激 ICC。ICC 作为烟碱型乙酰胆碱受体神经传递的接口，以诱导 LES 松弛。
