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Back to 2014 Annual Meeting Posters Lubiprostone (Amitiza) Activates Cellular Prostanoid Signaling to Enhance Intestinal Motility in Human Colon Jinping Gao*1, Zhongxian Hu1, Yuxin Zhang1, Yingxiu Cheng1, Pengchao Zheng1, Xiyu Wang2, Guodu Wang2 1Surgery, The second people, Jingmen, China; 2Physiology and Cell Biology, Medical Center, The Ohio State University, Columbus, OH Background and Aims: Lubiprostone as a prostaglandin E derivative can activate chloride channels in bowel epithelia to stimulate intestinal secretion. It is widely applied for the treatment of adult chronic idiopathic constipation and irritable bowel syndrome with constipation in adult women. Clinic therapies of lubiprostone showed it can induce some side effects, such as nausea, diarrhea, abdominal pain and bloating and dyspnea. The study aims to investigate mechanism of the side effects in human colonic motility. Methods: Immunoflorescence staining with EP receptor antibodies was performed in the cryostat-sections of human colon. Colonic motility and pharmacological examinations were analyzed with organ bath system and human colonic longitudinal and circular axe muscle strips (LAMSs and CAMSs that obtained from colonic and rectum surgical operations of the patients. Results: Immunostaining showed that 325 of 598 submucosal and 471 of 633 myenteric neurons and their nerve fibers are immunoreactive for Anti-Hu and EP4 receptor. EP4 receptor immunopostive neurons co-expressed choline acetyransferase (ChAT) and substance P in myenteric plexus. Bath application of lubiprostone increased the amplitude of spontaneous contractile activity and lift baseline tension in dose-dependent manner in 17of 24 LAMSs from 5 male and 7 female patients. This action was suppressed by pre-treatment with 10µM SC19220, an EP1 antagonist. Electrical field stimulation (EFS) evoked contracting amplitudes of LAMSs were enhanced by lubiprostone in dose-dependent manner in 21of 24 LAMSs. The EFS-evoked responses were suppressed by preincubation with 10µM L161980, an EP4 antagonist, but not by the SC19220. These EFS-evoked responses also were inhibited by pre-application of 2 µM cAMPS-Rp, a cAMP antagonist, and abolished by 1µM tetrodotoxin (TTX). Pretreatment with atropine (10µM), the neurokinin 1 antagonist, CP96345 (10µM), or the neurokinin 2 antagonist, GR159897 (20µM), suppressed enhancement effect of lubiprostone on EFS-evoked contractions. PGE2 (30nM-1µM) mimicked the actions of lubiprostone in the LAMSs. Application of lubiprostone did not alter the spontaneous or EFS-evoked contractile activity of 28 colonic CAMSs from 8 male and 6 female patients. Conclusion: Lubiprostone can activate cellular prostanoid-cAMP signaling to enhance myogenic motility via EP1 receptor and neurogenic contracting responses via EP4 receptor in the human colon. The result suggested that side effects of lubiprostone may originate from its activating actions in EP receptors of enteric neurons and smooth muscles. Selective EP1 and EP4 antagonists may prevent the side effects of lubiprostone in clinic treatments. Back to 2014 Annual Meeting Posters |
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