瞬时受体香草酸亚型1（TRPV1）拮抗剂对大鼠食管迷走神经传入纤维酸诱导兴奋的不同作用。
Differential effects of transient receptor vanilloid one (TRPV1) antagonists in acid-induced excitation of esophageal vagal afferent fibers of rats.
作者信息
Peles S, Medda B K, Zhang Zhihong, Banerjee B, Lehmann A, Shaker R, Sengupta J N
机构信息
Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
出版信息
Neuroscience. 2009 Jun 30;161(2):515-25. doi: 10.1016/j.neuroscience.2009.03.040. Epub 2009 Mar 24.
Gastro-esophageal acid reflux can stimulate esophageal vagal sensory afferents by activating proton-sensitive ion channel transient receptor vanilloid one (TRPV1). The objective of this study was to investigate the response characteristics of vagal afferent fibers of rats to acid (0.1 N HCl) and capsaicin (CAP) following esophagitis and differential effects of two classes of TRPV1 antagonists on responses of vagal afferent fibers. The chronic reflux was induced by ligating the fundus of the stomach and partial constriction of pylorus. Extracellular single fiber recordings were made from the cervical vagal afferent fibers from naive control and fundus-ligated (FL) esophagitis rats. Innervations of fibers were identified to esophageal distension (ED) and subsequently tested to CAP and acid before and after injection of TRPV1 antagonist JYL1421 or AMG9810 (10 micromol/kg i.v.). Seventy-five vagal afferent fibers from 70 rats were identified to ED. Intra-esophageal CAP (0.1 ml of 1 mg/ml) excited 39.5% (17/43, 5/22 from naive and 12/21 from FL rats) fibers. In contrast, i.v. injection of CAP (0.03-0.3 micromol/kg) dose-dependently excited 72% (42/58) fibers. Responses to CAP were significantly greater for fibers from FL rats (n=32) than naive rats (n=25). TRPV1 antagonists JYL1421 and AMG9810 (10 micromol/kg) significantly blocked response to CAP. Intra-esophageal acid infusion stimulated 5/17 (29.4%) fibers from naive rats and 12/28 (42%) from FL rats. Effect of acid was significantly blocked by AMG9810, but not by JYL1421. Results indicate that following esophagitis the number of fibers responsive to CAP and acid is greater than noninflamed esophagus, which may contribute to esophageal hypersensitivity. Acid-induced excitation of vagal sensory afferents can be differentially attenuated by different classes of TRPV1 antagonists. Therefore, TRPV1 antagonists play a key role in attenuation of hypersensitivity following reflux-induced esophagitis. The use of TRPV1 antagonists could be an alternative to the traditional symptoms-based treatment of chronic acid reflux and esophageal hypersensitivity.
胃食管酸反流可通过激活质子敏感离子通道瞬时受体电位香草酸亚型1（TRPV1）来刺激食管迷走神经感觉传入纤维。本研究的目的是调查食管炎后大鼠迷走神经传入纤维对酸（0.1 N盐酸）和辣椒素（CAP）的反应特性，以及两类TRPV1拮抗剂对迷走神经传入纤维反应的不同影响。通过结扎胃底和部分幽门狭窄诱导慢性反流。对未处理的对照大鼠和胃底结扎（FL）食管炎大鼠的颈迷走神经传入纤维进行细胞外单纤维记录。将纤维的神经支配确定为食管扩张（ED），随后在注射TRPV1拮抗剂JYL1421或AMG9810（10 μmol/kg静脉注射）前后对CAP和酸进行测试。从70只大鼠中鉴定出75条对ED有反应的迷走神经传入纤维。食管内注射CAP（0.1 ml的1 mg/ml）可兴奋39.5%（17/43，未处理大鼠中5/22，FL大鼠中12/21）的纤维。相比之下，静脉注射CAP（0.03 - 0.3 μmol/kg）剂量依赖性地兴奋72%（42/58）的纤维。FL大鼠（n = 32）的纤维对CAP的反应明显大于未处理大鼠（n = 25）。TRPV1拮抗剂JYL1421和AMG9810（10 μmol/kg）显著阻断了对CAP的反应。食管内注入酸刺激了未处理大鼠的5/17（29.4%）纤维和FL大鼠的12/28（42%）纤维。AMG9810可显著阻断酸的作用，但JYL1421不能。结果表明，食管炎后对CAP和酸有反应的纤维数量多于未发炎的食管，这可能导致食管超敏反应。不同类别的TRPV1拮抗剂可对酸诱导的迷走神经感觉传入纤维兴奋产生不同程度的减弱作用。因此，TRPV1拮抗剂在减轻反流性食管炎后的超敏反应中起关键作用。使用TRPV1拮抗剂可能是慢性酸反流和食管超敏反应传统症状性治疗的一种替代方法。
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