School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China.
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Am J Pathol. 2023 May;193(5):548-557. doi: 10.1016/j.ajpath.2023.01.005. Epub 2023 Feb 3.
Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying of solid food. Nitrergic neuron-mediated fundus relaxation and intragastric peristalsis are pivotal for gastric emptying and are impaired in DGP. Transient receptor potential vanilloid 1 (TRPV1) ion channels are expressed in gastrointestinal vagal afferent nerves and have a potential role in relevant gastrointestinal disorders. In this study, mice with high-fat diet (HFD)-induced type 2 diabetes mellitus (T2DM), associated with gastroparesis, were used to determine the role of TRPV1 in DGP. After feeding with HFD, mice exhibited obesity, hyperglycemia, insulin resistance, and delayed gastric emptying. Cholinergic- and nitrergic neuron-mediated neuromuscular contractions and relaxation were impaired. The antral tone of the DGP mice was attenuated. Interestingly, activating or suppressing TRPV1 facilitated or inhibited gastric fundus relaxation in normal mice. These effects were neutralized by using a nitric oxide synthase (NOS) inhibitor. Activation or suppression of TRPV1 also increased or reduced NO release. TRPV1 was specifically localized with neuronal NOS in the gastric fundus. These data suggest that TRPV1 activation facilitates gastric fundus relaxation by regulating neuronal NOS and promoting NO release. However, these effects and mechanisms disappeared in mice with DGP induced by HFD diet. TRPV1 expression was only marginally decreased in the fundus of DGP mice. TRPV1 dysfunction may be a potential mechanism underlying the dysfunction of DGP gastric nitrergic neuromuscular relaxation.
糖尿病性胃轻瘫（DGP）的特征是固体食物胃排空延迟。氮能神经元介导的胃底舒张和胃内蠕动对于胃排空至关重要，并且在 DGP 中受损。瞬时受体电位香草酸 1（TRPV1）离子通道在胃肠道迷走传入神经中表达，并在相关胃肠道疾病中具有潜在作用。在这项研究中，使用高脂肪饮食（HFD）诱导的 2 型糖尿病（T2DM）小鼠，伴发胃轻瘫，以确定 TRPV1 在 DGP 中的作用。在用 HFD 喂养后，小鼠表现出肥胖、高血糖、胰岛素抵抗和胃排空延迟。胆碱能和氮能神经元介导的神经肌肉收缩和舒张受损。DGP 小鼠的胃窦张力减弱。有趣的是，在正常小鼠中，激活或抑制 TRPV1 促进或抑制胃底舒张。这些作用被一氧化氮合酶（NOS）抑制剂中和。激活或抑制 TRPV1 也增加或减少 NO 释放。TRPV1 特异性定位于胃底的神经元 NOS。这些数据表明，TRPV1 激活通过调节神经元 NOS 促进 NO 释放，从而促进胃底舒张。然而，这些作用和机制在 HFD 饮食诱导的 DGP 小鼠中消失了。DGP 小鼠胃底的 TRPV1 表达仅略有下降。TRPV1 功能障碍可能是 DGP 胃氮能神经肌肉舒张功能障碍的潜在机制。
