Investigation of the role of apelin in afferent vagal dysfunction-induced experimental functional dyspepsia

Objective: The aim of this study is to investigate the role of the endogenous peripheral apelin in experimental functional dyspepsia (FD) model-induced afferent vagal dysfunction. Method: For the experimental FD model, newborn Sprague Dawley pups underwent maternal separation (3 h/day) from postnatal day-1 to day-21. In adulthood, rats were loaded with restraint stress for 7 consecutive days (90 min/day). Body weight and food intake were monitored before the behavioral tests. Elevated plus maze and open field tests were used to assess the FD-induced anxiety-like behaviors. Solid gastric emptying (GE), esophago-gastric relaxation (EGR) and gastric accommodation reflex (GAR) were measured following overnight fasting. To evaluate EGR and GAR, esophageal and gastric distention were performed through a balloon catheter, respectively. The distention-induced changes in gastric tone were monitored through a pair of strain gauge transducers serosally implanted in the fundus and corpus. The alterations in expression of the apelin receptor (APJ), transient receptor potential vanilloid-1 (TRPV1), and TRP ankyrin-1 (TRPA1) were evaluated by immunohistochemistry. Results: Compared with the control rats, FD significantly decreased body weight and food intake, while produced anxiety-like behaviors. FD significantly also decreased GE, while remarkably diminishing the GAR and EGR response both in fundus and corpus. The FD-induced changes in GAR and EGR were significantly attenuated by preadministration of apelin receptor antagonist F13A (70 nmol-ml-kg-1, i.v). Our double immunofluorescence labeling studies demonstrated that APJ is present in afferent neuronal pericaria expressing TRPV1 and TRPA1. In esophageal- and gastric-projecting vagal afferent neurons, expressions of APJ and TRPV1 were upregulated in FD, whereas no change was detected in TRPA1. Moreover, expression of APJ was increased in gastric vagal afferent nerve endings in the myenteric neurons of the FD rats. Conclusion: Our findings demonstrate the therapeutic potential of apelin receptor antagonists in clinical treatment of FD.