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Effects of Vasopressin V1b Receptor Deficiency on Adrenocorticotropin Release from Anterior Pituitary Cells in Response to Oxytocin Stimulation

Department of Pharmacology (K.N., Y.F., R.M., A.S., N.M., M.H., J.Y., A.T.), National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 157-8535, Japan; Department of Genomic Drug Discovery Science (G.T.), Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; and Otsuka Pharmaceutical Co., Ltd. (T.Y., S.N., T.M.), Kawauchi-cho Tokushima 771-0192, Japan

Address all correspondence and requests for reprints to: Akito Tanoue, M.D., Ph.D., Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. E-mail: atanoue{at}nch.go.jp.

Oxytocin (OT) is one of the secretagogues for stress-induced ACTH release. OT-induced ACTH release is reported to be mediated by the vasopressin V1b receptor in the rat pituitary gland, which contains both OT and V1b receptors. We examined OT-induced ACTH release using primary cultures of anterior pituitary cells from wild-type (V1bR^+/+) and V1b receptor knockout (V1bR^–/–) mice. OT stimulated similar levels of ACTH release from pituitary cells of V1bR^+/+ and V1bR^–/– mice. OT-induced ACTH release was significantly inhibited by the selective V1b receptor antagonist SSR149415 and the OT receptor antagonist CL-14-26 in V1bR^+/+ mice. In addition, cotreatment with SSR149415 at 10^–6 M and CL-14-26 at 10^–6 M inhibited OT-induced ACTH release to the control level inV1bR^+/+ mice. In V1bR^–/– mice, OT-induced ACTH release was significantly inhibited by CL-14-26 at 10^–8 M and completely inhibited at 10^–7M. These results indicate that OT induces the ACTH response via OT and V1b receptors inV1bR^+/+ mice but via only OT receptors in V1bR^–/– mice. The gene expression level of the OT receptor was significantly higher in the anterior pituitary gland of V1bR^–/– mice than in that of V1bR^+/+ mice, suggesting that the OT receptor is up-regulated to compensate for ACTH release under conditions of V1b receptor deficiency.