Therapeutic Effect of Low-Frequency Auricular Vagus Nerve Stimulation on Diabetic Gastric Motility Disorder by Activating the Nitric Oxide/Soluble Guanylate Cyclase/Cyclic Guanosine Monophosphate/Protein Kinase G1 Pathway to Restore the Smooth Muscle Cell, Interstitial Cell of Cajal, and Platelet-Derived Growth Factor Receptor α-Positive Cell Syncytium.

BACKGROUND/AIMS: Diabetes mellitus is a prevalent chronic condition globally. A frequent complication is gastric motility disorder, which substantially impacts patients' quality of life and overall well-being. The SMC-ICC-PDGFRα+ (SIP) syncytium plays an important role in coordinating gastrointestinal (GI) motility. Auricular vagus nerve stimulation (aVNS) has demonstrated promising therapeutic efficacy against diabetic motility disorders, yet the underlying mechanism is not well understood. This study aims to evaluate whether low-frequency aVNS attenuates gastric dysmotility in diabetic rats through regulation of the SIP syncytium and its signaling pathways. MATERIALS AND METHODS: Male Sprague-Dawley rats were employed to induce a diabetic gastric motility disorder (DGMD) model using streptozotocin (STZ). The DGMD rats underwent treatment with aVNS, a combination of aVNS and body electroacupuncture (aVNS-EA), and sham aVNS. Gastric motility was evaluated by the solid gastric emptying rate (SGER). Gastric antrum pathology was assessed via hematoxylin and eosin (H&E) staining, SIP syncytium function was evaluated by immunofluorescence, and serum nitric oxide (NO) levels were measured with a Griess kit. RESULTS: Low-frequency aVNS significantly enhanced SGER and upregulated the expression of interstitial cells of Cajal (ICCs) and platelet-derived growth factor receptor alpha-positive (PDGFRα+) cells in the antrum; the smooth muscle marker α-SMA was increased at the immunofluorescence and messenger RNA (mRNA) levels, but not significantly at the protein level. aVNS-EA exhibited similar effects, whereas sham aVNS showed no significant change. aVNS also upregulated neuronal nitric oxide synthase (nNOS), increased NO release, and activated the soluble guanylate cyclase-cyclic guanosine monophosphate-protein kinase G1 (sGC-cGMP-PKG1) pathway. Treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), the soluble guanylate cyclase (sGC) inhibitor, reversed the aVNS-induced improvements in SGER and SIP syncytium integrity. CONCLUSIONS: In contrast, aVNS-EA benefits were only partially inhibited by ODQ. These results suggest that low-frequency aVNS improves gastric motility and SIP syncytium function in diabetic rats by activating the NO/sGC/cyclic guanosine monophosphate (cGMP)/protein kinase G1 (PKG1) pathway and that the aVNS-EA yields additional beneficial effects.