Blackshaw L Ashley
Nerve Gut Research Laboratory, Department of Gastroenterology, Hepatology and General Medicine, Hanson Institute, Royal Adelaide Hospital, Australia.
Eur Rev Med Pharmacol Sci. 2008 Aug;12 Suppl 1:33-9.
Gastro-oesophageal reflux disease (GORD) is caused by disordered control of the gastro-oesophageal reflux barrier, comprised internally of the lower oesophageal sphincter (LOS) and externally the crural diaphragm (CD). Both relax briefly to allow bolus passage during oesophageal peristalsis. Brief relaxation also occurs prior to gastro-oesophageal reflux, known as transient LOS relaxation (TLOSR), normally allowing venting of gas. TLOSRs also account for up to 90% of acid reflux episodes. The development of GORD therefore depends upon the rate of TLOSR and the physical and chemical nature of refluxate. We established an animal model of reflux in ferrets, in which similar patterns of TLOSR are seen to humans. TLOSRs are mediated via a vago-vagal pathway initiated by tension receptors in the gastric musculature. They have central terminals in the brainstem which provide input to a central program generator. The program has 3 simultaneous outputs: 1. brief activation of vagal motor neurones to the LOS, which activate inhibitory enteric motorneurones, leading to smooth muscle relaxation: 2. suppression of oesophageal peristalsis: 3. suppression of motor output to the CD. We have investigated several aspects of the TLOSR pathway in ferrets, and determined that the optimal site for therapeutic pharmacological intervention is at gastric vagal tension receptor endings. Their responses to distension are potently inhibited by gamma-aminobutyric acid type B (GABAB) receptor agonists and metabotropic glutamate type 5 receptor (mGluR5) antagonists. These effects translate to inhibition of TLOSR and reflux in animal models and humans. Clinical studies indicate both types of drug may have potential in the treatment of GORD.
胃食管反流病（GORD）是由胃食管反流屏障控制紊乱引起的，该屏障内部由食管下括约肌（LOS）组成，外部由膈脚（CD）组成。在食管蠕动期间，两者都会短暂松弛以允许食团通过。在胃食管反流之前也会发生短暂松弛，称为短暂性LOS松弛（TLOSR），通常允许气体排出。TLOSR也占酸反流发作的90%。因此，GORD的发生取决于TLOSR的速率以及反流物的物理和化学性质。我们建立了雪貂反流动物模型，其中观察到与人类相似的TLOSR模式。TLOSR通过由胃肌肉组织中的张力感受器启动的迷走-迷走神经通路介导。它们在脑干中有中枢终末，为中枢程序发生器提供输入。该程序有3个同时输出：1. 迷走运动神经元对LOS的短暂激活，激活抑制性肠运动神经元，导致平滑肌松弛；2. 食管蠕动的抑制；3. 对CD运动输出的抑制。我们研究了雪貂TLOSR通路的几个方面，并确定治疗性药物干预的最佳部位是胃迷走张力感受器末梢。它们对扩张的反应被γ-氨基丁酸B型（GABAB）受体激动剂和代谢型谷氨酸5型受体（mGluR5）拮抗剂有效抑制。这些作用转化为动物模型和人类中TLOSR和反流的抑制。临床研究表明这两种药物在GORD治疗中可能都有潜力。
