title: Sustained in vivo blockade of α₁-adrenergic receptors prevented some of stress-triggered effects on steroidogenic machinery in Leydig cells.
abstract: This study was designed to systematically analyze and evaluate the effects of in vivo blockade of α₁-adrenergic receptors (α₁-ADRs) on the stress-induced disturbance of steroidogenic machinery in Leydig cells. Parameters followed 1) steroidogenic enzymes/proteins, transcription factors, and cAMP/testosterone production; 2) the main hallmarks of stress (epinephrine, glucocorticoids); and 3) transcription profiles of ADRs and oxidases with high affinity to inactivate glucocorticoids. Results showed that sustained blockade of α₁-ADRs prevented stress-induced 1) decrease of the transcripts/proteins for main steroidogenic CYPs (CYP11A1, CYP17A1); 2) decrease of Scarb1 and Hsd3b1 transcripts; 3) decrease of transcript for Nur77, one of the main activator of the steroidogenic expression; and 4) increase of Dax1 and Arr19, the main steroidogenic repressors in Leydig cells. In the same cells, the expression of steroidogenic stimulatory factor Creb1, StAR, and androgen receptor increased. In this signaling scenario, stress-induced stimulation of Adra1a/Adra1b/Adrbk1 and Hsd11b2 (the unidirectional oxidase with high affinity to inactivate glucocorticoids) was not changed. Blockade additionally stimulated stress-increased transcription of the most abundantly expressed ADRs Adra1d/Adrb1/Adrb2 in Leydig cells. In the same cells, stress-decreased testosterone production, the main marker of Leydig cells functionality, was completely prevented, while reduction of cAMP, the main regulator of androgenesis, was partially prevented. Accordingly, the presented data provide a new molecular/transcriptional base for "fight/adaptation" of steroidogenic cells and new molecular insights into the role of α₁-ADRs in stress-impaired Leydig cell steroidogenesis. The results are important in term of wide use of α₁-ADR selective antagonists, alone/in combination, to treat high blood pressure, nightmares associated with posttraumatic stress disorder, and disrupted sexual health.
authors.affiliation: Reproductive Endocrinology and Signaling Group, Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
authors.forename: Natasa J
authors.initials: NJ
authors.lastname: Stojkov
authors.forename: Marija M
authors.initials: MM
authors.lastname: Janjic
authors.forename: Aleksandar Z
authors.initials: AZ
authors.lastname: Baburski
authors.forename: Aleksandar I
authors.initials: AI
authors.lastname: Mihajlovic
authors.forename: Dragana M
authors.initials: DM
authors.lastname: Drljaca
authors.forename: Srdjan J
authors.initials: SJ
authors.lastname: Sokanovic
authors.forename: Maja M
authors.initials: MM
authors.lastname: Bjelic
authors.forename: Tatjana S
authors.initials: TS
authors.lastname: Kostic
authors.forename: Silvana A
authors.initials: SA
authors.lastname: Andric
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D017292:Doxazosin / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006728:Hormones / Q000378:metabolism; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D012149:Restraint, Physical; D013256:Steroids / Q000096:biosynthesis*; D013315:Stress, Psychological / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000728:Androgens; D018076:DNA, Complementary; D006728:Hormones; D018340:Receptors, Adrenergic, alpha-1; D013256:Steroids; D014157:Transcription Factors; D012313:RNA; D007986:Luteinizing Hormone; D000242:Cyclic AMP; D017292:Doxazosin
keywords: doxazosin; steroidogenic machinery; stress; testosterone; α1-adrenergic receptors