Abstract
Women are more susceptible to functional bowel disorders than men and the severity of their symptoms such as diarrhea, constipation, abdominal pain and bloating changes over the menstrual cycle, suggesting a role for sex hormones in gastrointestinal function. Nitric oxide (NO) is a major inhibitory neurotransmitter in the gut and blockade of nitric oxide synthase (NOS; responsible for NO synthesis) increases colonic motility in male mice ex vivo. We assessed the effects of NOS inhibition on colonic motility in female mice using video imaging analysis of colonic motor complexes (CMCs). To understand interactions between NO and estrogen in the gut, we also quantified neuronal NOS and estrogen receptor alpha (ERα)-expressing myenteric neurons in estrus and proestrus female mice using immunofluorescence. Mice in estrus had fewer CMCs under control conditions (6 ± 1 per 15 min, n = 22) compared to proestrus (8 ± 1 per 15 min, n = 22, One-way ANOVA, p = 0.041). During proestrus, the NOS antagonist N-nitro-L-arginine (NOLA) increased CMC numbers compared to controls (189 ± 46%). In contrast, NOLA had no significant effect on CMC numbers during estrus. During estrus, we observed more NOS-expressing myenteric neurons (48 ± 2%) than during proestrus (39 ± 1%, n = 3, p = 0.035). Increased nuclear expression of ERα was observed in estrus which coincided with an altered motility response to NOLA in contrast with proestrus when ERα was largely cytoplasmic. In conclusion, we confirm a cyclic and sexually dimorphic effect of NOS activity in female mouse colon, which could be due to genomic effects of estrogens via ERα.
Highlights
Sexual dimorphism in gastrointestinal (GI) disorders is well documented and includes a higher prevalence of visceral pain disorders such as irritable bowel syndrome and gastroesophageal reflux disease as well as gallbladder and biliary tract diseases in women than in men of a similar age and health status (Palomba et al, 2011; Avramidou et al, 2018; Kim and Kim, 2018)
Estrogen dose-dependently inhibited the secretory responses induced by a well-established secretagogue cholera toxin in female rats, an effect seen in estrus but not in proestrus, but had no inhibitory effect on male rats (Alzamora et al, 2011a,b)
Chronic estrogen deficiency decreases Neuronal nitric oxide synthase (nNOS) activity leading to reduced nitrergic relaxation in the gastric antrum and contributes to reduced motility observed in gastroparesis (Ravella et al, 2013)
Summary
Sexual dimorphism in gastrointestinal (GI) disorders is well documented and includes a higher prevalence of visceral pain disorders such as irritable bowel syndrome and gastroesophageal reflux disease as well as gallbladder and biliary tract diseases in women than in men of a similar age and health status (Palomba et al, 2011; Avramidou et al, 2018; Kim and Kim, 2018). In the absence of the estrus cycle (i.e., in ovariectomized female rats), colonic transit is faster in keeping with a metestrus-diestrus phenotype typical of low estrogen levels (Ryan and Bhojwani, 1986). Chronic estrogen deficiency (in follicle stimulating hormone receptor knock-out female mice) decreases nNOS activity leading to reduced nitrergic relaxation in the gastric antrum and contributes to reduced motility observed in gastroparesis (Ravella et al, 2013). It remains unclear, whether changes in estrogen levels affect colonic activity via the inhibitory neurotransmitter, NO. In this study we investigated the role of NO in cyclic differences using ex vivo colonic motility and immunofluorescence assays during low (estrus) and high (proestrus) estrogen phases in female mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
