title: Stimulatory action of endothelin-1 on rat Leydig cells: involvement of endothelin-A subtype receptor and phospholipase A2-arachidonate metabolism system.
abstract: In a previous report we have observed that endothelin-1 (ET-1) is able to stimulate testosterone (T) production by rat Leydig cells revealing an interaction with human chorionic gonadotropin (hCG). The present study was designed to further characterize the stimulatory action of ET on testicular steroidogenesis, to evaluate which subtype of ET receptors is involved in this activity and to examine the role of phospholipase A2 (PLA2)-arachidonate metabolism system in ET-1 transduction mechanism. To this purpose we investigated: i) the interaction of ET-1 with another secretagogue of T, like luteinizing hormone releasing hormone (LHRH); ii) the interference of ET(A) and ET(B) receptor antagonists (BQ-123 and BQ-788, respectively) and of inhibitors of PLA2 (quinacrine) and arachidonate lipoxygenase pathway (nordihydroguaiaretic acid:NDGA) on ET-1-induced T and PGE2 secretion from purified rat Leydig cells. Data obtained indicate that ET-1 amplified T and PGE2 response to LHRH and this secretagogue in turn potentiated testicular steroidogenesis stimulated by endothelin. The ET(A) antagonist, BQ-123, inhibited in a dose-related fashion ET-1-induced T production whereas ET(B) antagonist, BQ-788, failed to affect T response to the peptide. Furthermore, ET(A) antagonist inhibited the stimulatory effect of ET-1 on hCG- or LHRH-induced T secretion and it was able to exert a dose-dependent inhibition of ET-1-stimulated PGE2 output. Moreover, a PLA2 inhibitor quinacrine inhibited the stimulatory action of ET-1 on T production and suppressed basal and ET-1-induced PGE2 release whilst a lipoxygenase blocker NDGA did not modify T response to the peptide. Taken together these findings i) indicate additivity of effects between ET-1 and LHRH in stimulating T and PGE2 production; ii) confirm that ET(A) subtype receptors mediate the stimulatory action of ET-1 on rat Leydig cells; iii) strongly suggest that PLA2-arachidonate metabolism system is involved in endothelin transduction mechanism.
authors.affiliation: Department of Medical Pathophysiology, University of Rome La Sapienza, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Romanelli
authors.forename: S
authors.initials: S
authors.lastname: Fillo
authors.forename: A
authors.initials: A
authors.lastname: Isidori
authors.forename: D
authors.initials: D
authors.lastname: Conte
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010880:Piperidines / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010716:Phosphatidylinositols; D010880:Piperidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D016718:Arachidonic Acid; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; C086539:BQ 788; D009637:Masoprocol; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium