Estrogen relaxes gastric muscle cells via a nitric oxide‑ and cyclic guanosine monophosphate‑dependent mechanism: A sex‑associated differential effect

Abstract

Various gastrointestinal (GI) disorders have a higher prevalence in women than in men. In addition, estrogen has been demonstrated to have an inhibitory effect on the contractility of GI smooth muscle. Although increased plasma estrogen levels have been implicated in GI disorders, the role of gastric estrogen receptor (ER) in these sex-specific differences remains to be fully elucidated. The present study was designed to investigate the sex-associated differences in the expression of the two ER isoforms, ERα and ERβ, and the effect of estrogen on gastric muscle contraction via the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Experiments were performed on single gastric smooth muscle cells (GSMCs) isolated from male and female Sprague Dawley rats. The effect of acetylcholine (ACh), a muscarinic agonist, on the contraction of GSMCs was measured via scanning micrometry in the presence or absence of 1 µM 17β-estradiol (E2), an agonist to the majority of ERs, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), an ERα agonist, or diarylpropionitrile (DPN), an ERβ agonist. The protein expression levels of ER subtypes in GSMCs were measured using a specifically designed ELISA. GSMCs from female rats had a higher expression of ERα and ERβ protein compared with GSMCs from males. ACh induced less contraction in female that in male GSMCs. Pre-treatment of GSMCs with E2 reduced the contraction of GSMCs from both sexes, but to a greater extent in those from females. PPT and DPN inhibited ACh-induced contraction in GSMCs from females. Furthermore, E2 increased NO and cGMP levels in GSMCs from males and females; however, higher levels were measured in females. Of note, pre-incubation of female GSMCs with Nω-nitro-L-arginine, a NO synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylyl cyclase inhibitor, reduced the inhibitory effect of estrogen on GSMC contraction. In conclusion, estrogen relaxes GSMCs via an NO/cGMP-dependent mechanism, and the reduced contraction in GSMCs from females by estrogen may be associated with the sex-associated increased expression of ERα and ERβ, and greater production of NO and cGMP, compared with that in GSMCs from males.

Effect of progesterone on nitric oxide/cyclic guanosine monophosphate signaling and contraction in gastric smooth muscle cells

“…Similar to the effect of progesterone on GSMCs, our group recently reported on a reduction in the contraction of female GSMCs following treatment with the sex steroid hormone estrogen, and greater activation of the NO/cGMP pathway (41). These parallel findings strengthen the hypothesis that these sex steroid hormones affect stomach muscle cell contraction.…”

Role of Sex Hormones And Their Receptors On Gastric Nrf2 And Neuronal Nitric Oxide Synthase Function In An Experimental Hyperglycemia Model

“…After 90 min incubation, we observe differences in the e cacy of the selective ER agonists at various doses; though each ER agonists signi cantly enhanced nitrergic relaxation in gastric neuromuscular specimens exposed to in-vitro hyperglycemia. This is in line with Al-Shboul et al, reporting that estrogeninduced relaxation was greater in female gastric smooth muscle cells (GSMC) compared with that in male [44]. Our current studies further asserted that ERα agonist, PPT and the ERβ agonist, DPN induced relaxation to a greater extent than PPT, although this result was not statistically signi cant.…”

Role of sex hormones and their receptors on gastric Nrf2 and neuronal nitric oxide synthase function in an experimental hyperglycemia model

“…After 90 min incubation, we observe differences in the efficacy of the selective ER agonists at various doses; though each ER agonists significantly enhanced nitrergic relaxation in gastric neuromuscular specimens exposed to invitro hyperglycemia. This is in line with Al-Shboul et al, reporting that estrogen-induced relaxation was greater in female gastric smooth muscle cells (GSMC) compared with that in male [44]. Our current studies further asserted that ERα agonist, PPT and the ERβ agonist, DPN induced relaxation to a greater extent than PPT, although this result was not statistically significant.…”