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Oxytocin Mediates the Estrogen-Dependent Contractile Activity of Endothelin-1 in Human and Rabbit Epididymis

Andrology Unit (A.M., L.V., R.M., C.C., G.F., Ma.M.) and Endocrinology Unit (P.F.), Department of Clinical Physiopathology; Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction (S.F.), Departments of Pharmacology and Clinical Physiopathology; Department of Anatomy, Histology and Forensic Medicine (G.B.V., Mi.M.); and Departments of Urology (N.M.) and Pharmacology (F.L.), University of Florence, Florence 50139, Italy

Address all correspondence and requests for reprints to: Mario Maggi, M.D., Andrology Unit, Department of Clinical Physiopathology, University of Florence, Viale G. Pieraccini, 6, 50139 Florence Italy. E-mail: m.maggi{at}dfc.unifi.it.

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, Orn⁸)-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 mo-tility necessary for sperm transport.

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