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Effects of Endothelin Receptor Type-A and Type-B Antagonists on Prostaglandin F_2alpha-Induced Luteolysis of the Sheep Corpus Luteum¹

Department of Biology,³ Eberly College of Arts and Sciences and Division of Animal and Nutritional Sciences,⁴ Davis College of Agriculture, Forestry and Consumer Sciences, West Virginia University, Morgantown, West Virginia 26506

ABSTRACT

Three experiments were designed to examine the mechanisms that govern prostaglandin (PGF_2alpha)-induced regression of the sheep corpus luteum. Evidence is presented supporting the involvement of endothelin 1 (EDN1) in PGF_2alpha-induced luteolysis. Experiment 1 measured effects of PGF_2alpha when actions of EDN1 were blocked by sustained administration of a type-A endothelin (EDNRA) or type-B endothelin (EDNRB) antagonist in vivo. Experiment 2 examined antisteroidogenic actions of PGF_2alpha and EDN1 in the presence of an EDNRA or EDNRB antagonist in Day-8 luteal minces. In experiment 3, luteal cellular expression of EDNRA and EDNRB was determined immunohistochemically. Relative gene expression of EDNRA and EDNRB receptors was examined by real-time RT-PCR in Day-8 sheep corpora lutea. EDNRA, but not EDNRB, participated in antisteroidogenic actions of EDN1. During the first 12 h after PGF_2alpha-induced luteolysis, EDNRA antagonist did not prevent a decline in serum progesterone concentrations. Early actions of PGF_2alpha are either direct or mediated by something other than EDN1. However, beyond 12 h after PGF_2alpha, serum progesterone concentrations increased in EDNRA antagonist-treated animals until they were the same as saline-treated controls, whereas an EDNRB antagonist had no effect in vivo or in vitro. The EDNRA antagonist negated the antisteroidogenic actions of EDN1 but only partially abolished the actions of PGF_2alpha in vitro. In contrast, the EDNRB antagonist was ineffective in abolishing antisteroidogenic actions of EDN1 and PGF_2alpha. Whereas real-time RT-PCR demonstrated high expression of EDNRA and low expression of EDNRB, immunohistochemically, only EDNRA was located in small steroidogenic, endothelial, and smooth muscle cells. In summary, studies in ovine corpora lutea provided strong evidence that: 1) EDNRA, but not EDNRB, mediates antisteroidogenic actions of EDN1, 2) actions of PGF_2alpha are both independent of and dependent upon mediation by EDN1, and 3) small steroidogenic cells are targets for antisteroidogenic effects of EDN1. Furthermore, the results from experiment 1 suggest that the intermediary role of EDN1 may be more important in later stages of luteal regression.

corpus luteum, corpus luteum function, ovary, progesterone, steroid hormones

¹Supported in part by research grant IS-3553-04 from BARD, the United States-Israel Binational Agriculture Research and Development Fund to Rina Meidan, E.K.I, and J.A.F.; and by Hatch Project 427 (NE1007) of the West Virginia University Agricultural and Forestry Experiment Station. This work is published with the approval of the director of the WVU Agricultural and Forestry Experiment Station as Scientific Paper No. 3001 from the Division of Animal and Nutritional Sciences.

Correspondence: ²Jorge A. Flores, 53 Campus Drive, Suite 3190, P.O. Box 6057, Life Sciences Building, Department of Biology, West Virginia University, Morgantown, WV 26506. FAX: 304 293 6363; e-mail: jflores{at}wvu.edu