Effects of Endothelin Receptor Type-A and Type-B Antagonists on Prostaglandin F₂alpha-Induced Luteolysis of the Sheep Corpus Luteum

• Published in: Biology of reproduction 2008-04, Vol.78 (4), p.688-696
• Main Authors: Doerr, Matthew D, Goravanahally, Madhusudan P, Rhinehart, Justin D, Inskeep, E. Keith, Flores, Jorge A
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Corpus Luteum - chemistry; Corpus Luteum - drug effects; Dinoprost - pharmacology; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1 - pharmacology; Endothelin-1 - physiology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Hormone metabolism and regulation; Luteolysis - drug effects; Mammalian female genital system; Oligopeptides - pharmacology; Peptides, Cyclic - pharmacology; Piperidines - pharmacology; Progesterone - analysis; Progesterone - blood; Receptor, Endothelin A - analysis; Receptor, Endothelin A - genetics; Receptor, Endothelin B - analysis; Receptor, Endothelin B - genetics; RNA - analysis; Sheep - physiology; Vertebrates: reproduction
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.107.064105

Three experiments were designed to examine the mechanisms that govern prostaglandin (PGF₂alpha)-induced regression of the sheep corpus luteum. Evidence is presented supporting the involvement of endothelin 1 (EDN1) in PGF₂alpha-induced luteolysis. Experiment 1 measured effects of PGF₂alpha 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 PGF₂alpha 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 PGF₂alpha-induced luteolysis, EDNRA antagonist did not prevent a decline in serum progesterone concentrations. Early actions of PGF₂alpha are either direct or mediated by something other than EDN1. However, beyond 12 h after PGF₂alpha, 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 PGF₂alpha in vitro. In contrast, the EDNRB antagonist was ineffective in abolishing antisteroidogenic actions of EDN1 and PGF₂alpha. 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 PGF₂alpha 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.