Lower esophageal sphincter is achalasic in nNOS-/- and hypotensive in W/WV mutant mice
Lower esophageal sphincter is achalasic in nNOS-/- and hypotensive in W/WV mutant mice
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DOI：
10.1053/gast.2001.25541
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发表时间：
2001-07-01
期刊：
影响因子：
29.4
通讯作者：
Goyal, RK
中科院分区：
文献类型：
--
作者：
Sivarao, DV;Mashimo, HL;Goyal, RK
背景与目的：有研究认为，氮能神经以Cajal肌间质细胞(ICC IM)为中介，介导下食道括约肌(LES)松弛。氮能通路的功能障碍已被证明会导致失弛缓症患者的LES高血压和松弛功能受损。我们确定具有神经元型一氧化氮合酶基因中断(nNOS(-/-))的小鼠和缺乏ICC-IM的W/W-v小鼠是否存在贲门失弛缓症样LES功能障碍。方法：使用定制的微型导管组件在麻醉小鼠身上进行腔内测压。在野生型、N omega-硝基-L-精氨酸甲酯盐酸盐(L-NAME)处理组、nNOS(-/-)组和W/W-v小鼠中，量化基础LES压以及吞咽和迷走神经诱发的LES松弛。结果：野生型小鼠LES维持基础压(24+/-3 mm Hg；N=8)，正常放松至吞咽(87%+/-3%；N=8)和迷走神经刺激(91%+/-4%mm Hg；N=6)。前处理。静脉注射L(100 mg/kg)可减弱LES对上述两种刺激的松弛作用(P<；0.05)。NNOS(-/-)中的LES显著高血压(36+/-5 mm HS；N=10；P<；0.05)，并伴有明显的松弛障碍(P<；0.05)。与之相反，W/W-v小鼠LES血压显著降低(11+/-2 mm Hg；N=6；P<；0.05)，松弛功能正常，可被L-NAME阻断。结论：nNOS(-/-)小鼠存在LES高血压，松弛功能受损，类似于贲门失弛缓症。相比之下，W/W-v小鼠有低血压的LES，但松弛未受损害，这表明ICC-IM在氮能神经传递中没有发挥作用。
Background & Aims: It has been proposed that nitrergic nerves mediate lower esophageal sphincter (LES) relaxation with intramuscular interstitial cells of Cajal (ICC IM) as an intermediary. Dysfunction of the nitrergic pathway has been shown to cause LES hypertension and impaired relaxation in achalasia. We determined whether mice with neuronal nitric oxide synthase gene disruption (nNOS(-/-)) and W/W-v mice lacking ICC-IM have achalasia-like LES dysfunction. Methods: Intraluminal manometry using a customized micro-sized catheter assembly was performed in anesthetized mice. Basal LES pressure and swallow- and vagal-evoked LES relaxations were quantified in wild-type, N omega -nitro-L-arginine methyl ester HCl salt (L-NAME)-treated, nNOS(-/-), and W/W-v mice. Results: Wild-type mouse LES maintained a basal pressure (24 +/- 3 mm Hg; N = 8) and relaxed normally to swallow (87% +/- 3%; N = 8) and vagal stimulation (91% +/- 4% mm Hg; N = 6). Pretreatment. with L-NAME (100 mg/kg, intravenously) attenuated LES relaxation to both stimuli (P < 0.05). The LES in nNOS(-/-) was significantly hypertensive (36 +/- 5 mm HS; N = 10; P < 0.05) with a markedly impaired relaxation (P < 0.05). In contrast, W/W-v mouse LES was significantly hypotensive (11 +/- 2 mm Hg; N = 6; P < 0.05) with normal relaxation that was blocked by L-NAME, Conclusions: nNOS(-/-) mice have LES hypertension with impaired relaxation resembling achalasia. In contrast, W/W-v mice have hypotensive LES with unimpaired relaxation, suggesting that ICC-IM do not play a role in nitrergic neurotransmission.