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The American Journal of Pathology
TRPV1 dysfunction impairs gastric nitrergic neuromuscular relaxation in high fat diet induced diabetic gastroparesis mice
Siyuan Xu, Shaochan Liang, Ying Pei, Rui Wang, Yao Zhang, Yifei Xu, Bin Huang, Haiwen Li, Juanjuan Li, Bo Tan, Hongying Cao, Shaoju Guo
Diabetes melitus, neuromuscular junction
Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying of solid food without mechanical obstruction. Nitrergic neuron–mediated fundus relaxation and intragastric peristalsis are pivotal for gastric emptying and are impaired in patients with 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 an HFD, mice exhibited obesity, hyperglycemia, insulin resistance, and delayed gastric emptying. Cholinergic- and nitrergic-mediated neuromuscular contractions and relaxation were impaired. The antral tone of the DGP mice was also attenuated. Interestingly, activating or suppressing TRPV1 facilitates or inhibits gastric fundus relaxation in normal mice. These effects were neutralized by using a nitric oxide synthase (NOS) inhibitor. Activation or suppression of TRPV1 also increases or reduces NO release. TRPV1 is 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 an 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.