4.7 Article

Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists

期刊

BRITISH JOURNAL OF PHARMACOLOGY
卷 167, 期 4, 页码 763-774

出版社

WILEY
DOI: 10.1111/j.1476-5381.2012.02009.x

关键词

motilin; GSK962040; human; stomach; neurogastroenterology

资金

  1. Blizard Institute Core Pathology Unit
  2. GlaxoSmithKline
  3. MRC
  4. BBSRC
  5. Pseudo-obstruction Research Trust
  6. MRC [G0900805] Funding Source: UKRI
  7. Medical Research Council [G0900805] Funding Source: researchfish

向作者/读者索取更多资源

BACKGROUND AND PURPOSE Delayed gastric emptying is poorly managed. Motilin agonists are potential treatments but inadequate understanding into how enteric nerve functions are stimulated compromises drug/dose selection. Resolution is hampered by extreme species dependency so methods were developed to study human gastrointestinal neuromuscular activities and the neurobiology of motilin. EXPERIMENTAL APPROACH Protocols to study neuromuscular activities were developed for different regions of human stomach and intestine (71 patients) using circular muscle preparations and electrical field stimulation (EFS) of intrinsic nerves. Other tissues were fixed for immunohistochemistry. KEY RESULTS EFS evoked contractions and/or relaxations via cholinergic and nitrergic neurons, with additional tachykinergic activity in colon; these were consistent after 154 min (longer if stored overnight). Motilin 1300 nM and the selective motilin agonist GSK962040 0.130 mu M acted pre-junctionally to strongly facilitate cholinergic contractions of the antrum (Emax approximate to 1000% for motilin), with smaller increases in fundus, duodenum and ileum; high concentrations increased baseline muscle tension in fundus and small intestine. There were minimal effects in the colon. In the antrum, cholinergic facilitation by motilin faded irregularly, even with peptidase inhibitors, whereas facilitation by GSK962040 was long lasting. Motilin receptor immunoreactivity was identified in muscle and myenteric plexus predominantly in the upper gut, co-expressed with choline acetyltransferase in neurons. CONCLUSIONS AND IMPLICATIONS Motilin and GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. Facilitation by motilin was short lived, consistent with participation in migrating motor complexes. Long-lasting facilitation by GSK962040 suggests different receptor interactions and potential for clinical evaluation. LINKED ARTICLE This article is commented on by Depoortere, pp. 760762 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02046.x

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据