Gender and estradiol as major factors in the expression and dimerization of nNOSα in rats with experimental diabetic gastroparesis.

Background: The molecular mechanisms of cellular changes responsible for diabetic gastroparesis, primarily seen in middle-aged women, still remain incompletely defined. We hypothesized that a decrease in the expression, dimerization, and post-translational modification of neuronal nitric oxide synthase alpha (nNOSα) is estrogen mediated and responsible for the gender-specific prevalence of this malady.

Methods: We induced diabetes by injecting male and female rats with streptozotocin. Male diabetic rats without gastroparesis were then injected with estrogen for 3 weeks and evaluated for gastroparesis development. Gastric tissues were analyzed for the elucidation of biochemical events associated with diabetes and gastroparetic dysfunction.

Results: Although male diabetic, gastroparetic (either streptozotocin- or estrogen-induced) rats exhibited similarity in disease pathology to that of females, the molecular mechanisms of development were different. Our results indicate that slow gastric emptying in both male diabetic, gastroparetic rat groups was not associated with the level of expression of nNOSα in gastric tissues. However, nNOSα dimerization, which reflects nNOSα activation, did decline slightly in the antrum of diabetic males with estrogen-induced gastroparesis, suggesting a possible estrogen role. Females with diabetic gastroparesis, in contrast, demonstrated significantly impaired levels and dimerization of nNOSα in the antrum and pylorus. Although the precise mechanism remains unknown, nNOSα dimerization impairment in female antrum is apparently associated with reduced phosphorylation of Ser(1416) in the activation loop of nNOSα.

Conclusion: Taken together, these results demonstrate that gender and estrogens may be leading factors, through molecular changes involved in nitric oxide synthesis down-regulation, within the antrum and pylorus of female diabetic, gastroparetic rats.