title: Oxytocin mediates the estrogen-dependent contractile activity of endothelin-1 in human and rabbit epididymis.
abstract: Epididymis is a sex steroid (androgen + estrogen)-sensitive duct provided with spontaneous motility, allowing sperm transport. We previously reported that the oxytocin (OT) receptor (OTR) mediates an estrogen-dependent increase in epididymal contractility. Because endothelin (ET)-1 also regulates epididymal motility, we tested its sex steroid dependence in a rabbit model. We demonstrated that estrogens up-regulate responsiveness to ET-1, which is reduced by blocking aromatase activity (letrozole, 2.5 mg/kg) or by triptorelin (2.9 mg/kg)-induced hypogonadism, whereas it is fully restored by estradiol valerate (3.3 mg/kg weekly) but not by testosterone enanthate (30 mg/kg weekly). However, changing sex steroid milieu did not affect either ET-1, its receptor gene, or protein expression. Two structurally distinct OTR-antagonists [(d(CH2)5(1), Tyr(Me)(2), Orn(8))-OT and atosiban] almost completely abolished ET-1 contractility, without competing for [125I]ET-1 binding, suggesting that OT/OTR partially mediates ET-1 action. Immunohistochemical studies in human and rabbit epididymis demonstrated that both OT and its synthesis-associated protein, neurophysin I, are expressed in the epithelial cells facing the muscular layer, suggesting local OT production. Quantitative RT-PCR demonstrated a high abundance of OT transcripts in human epididymis. OT transcript was also originally detected and partially sequenced in rabbit epididymis. To verify whether ET-1 regulates OT release, we used rabbit epididymal epithelial cell cultures. These cells expressed a high density of [125I]ET-1 binding sites and responded to ET-1 with a dose-dependent OT release. Hence, we propose that an ET-1-induced OT/OTR system activation underlies the estrogen-dependent hyperresponsiveness to ET-1. These local sources might promote the spontaneous motility necessary for sperm transport.
authors.affiliation: Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, University of Florence, 50139 Florence, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Filippi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Morelli
authors.forename: Linda
authors.initials: L
authors.lastname: Vignozzi
authors.forename: Gabriella Barbara
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Mirca
authors.initials: M
authors.lastname: Marini
authors.forename: Pietro
authors.initials: P
authors.lastname: Ferruzzi
authors.forename: Rosa
authors.initials: R
authors.lastname: Mancina
authors.forename: Clara
authors.initials: C
authors.lastname: Crescioli
authors.forename: Nicola
authors.initials: N
authors.lastname: Mondaini
authors.forename: Gianni
authors.initials: G
authors.lastname: Forti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ledda
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology*; D004822:Epididymis / Q000187:drug effects / Q000502:physiology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D007006:Hypogonadism / Q000139:chemically induced / Q000503:physiopathology; D000077289:Letrozole; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D014230:Triazoles / Q000494:pharmacology; D017329:Triptorelin Pamoate / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D009570:Nitriles; D014230:Triazoles; D017329:Triptorelin Pamoate; D004958:Estradiol; D010121:Oxytocin; D000077289:Letrozole