Abstract
BackgroundGastroparesis, a condition of abnormal gastric emptying, is most commonly observed in diabetic women. To date, the role of ovarian hormones and/or gastric hormone receptors on regulating nitrergic-mediated gastric motility remains inconclusive.AimThe purpose of this study is to investigate whether sex hormones/their receptors can attenuate altered Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), neuronal Nitric Oxide Synthase (nNOS) expression and nitrergic relaxation in gastric neuromuscular tissues exposed to in-vitro hyperglycemia (HG).MethodsGastric neuromuscular sections from adult female C57BL/6 J mice were incubated in normoglycemic (NG, 5 mM) or hyperglycemic (30 mM or 50 mM) conditions in the presence or absence of selective estrogen receptor (ER) agonists (ERα /PPT or ERβ: DPN); or non-selective sex hormone receptor antagonists (ER/ICI 182,780, or progesterone receptor (PR)/ RU486) for 48 h. mRNA, protein expression and nitrergic relaxation of circular gastric neuromuscular strips were assessed.ResultsOur findings in HG, compared to NG, demonstrate a significant reduction in ER, Nrf2, and nNOS expression in gastric specimens. In addition, in-vitro treatment with sex hormones and/or their agonists significantly (*p < 0.05) restored Nrf2/nNOSα expression and total nitrite production. Conversely, ER, but not PR, antagonist significantly reduced Nrf2/nNOSα expression and nitrergic relaxation.ConclusionsOur data suggest that ER’s can regulate nitrergic function by improving Nrf2/nNOS expression in experimental hyperglycemia.
Highlights
Gastroparesis, a condition of abnormal gastric emptying, is most commonly observed in diabetic women
The same studies further suggest that neuronal Nitric Oxide Synthase (nNOS) neurons are reduced in the longterm diabetes. Since hormones and their receptor agonists were able to restore nNOS protein expression, we suggest that our experimental HG model is related to the early stages, but not long-term diabetic conditions in which we would expect a loss of nNOS neurons. Taken together, these findings imply that direct regulation of multiple cellular molecules by estrogens may contribute to the modulation of gastric functions that have been recognized during hyperglycemic conditions
We demonstrate the relevance of sex hormones and gastric estrogen receptors in mediating nitrergic relaxation and Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/nNOS expression- both critical to gastrointestinal motility
Summary
Gastroparesis, a condition of abnormal gastric emptying, is most commonly observed in diabetic women. Gastroparesis patients often experience symptoms including severe nausea, vomiting, and abdominal pain [2, 3]. Emerging evidence strongly indicate that women and female rodents are likely to experience more severe disease manifestations of gastroparesis compared to males [3, 4]. Our laboratory has extensively reported nNOS expression and NO-mediated gut relaxation to be the predominant mechanism severely compromised in female rodent models of diabetic gastroparesis [5, 7, 8]. Despite extensive research, drug therapy that can improve gastric emptying and decrease symptoms, without too many side effects are limited. Since the underlying mechanisms of gastric dysmotility are poorly understood, it is imperative to work with experimental hyperglycemic conditions to establish translational relevance
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call