title: In vivo blockade of α1-adrenergic receptors mitigates stress-disturbed cAMP and cGMP signaling in Leydig cells.
abstract: The molecular mechanism of stress-associated reproductive dysfunction is complex and largely unknown. This study was designed to systematically analyze molecular effects of systemic in vivo blockade of α1-adrenergic receptors (α1-ADRs) on stress-induced disturbance of cAMP/cGMP signaling in testosterone-producing Leydig cells using the following parameters (i) level of circulating stress hormones, LH and testosterone; (ii) level of main molecular markers of Leydig cell functionality (testosterone, Insl3, cAMP); (iii) expression of cAMP signaling (cAMP 'producers'/'effectors'/'removers') and (iv) expression of NO-cGMP signaling (NO-cGMP 'producers'/'effectors'/'removers'). The results showed that oral administration of α1-ADR blocker before stress increased cGMP and diminished stress-reduced cAMP production in Leydig cells. In the same cells, stress-induced effects on cAMP/cGMP signaling pathways elements were changed. Sustained in vivo α1-ADR blockade completely abolished stress-increased transcription of most abundantly expressed phosphodiesterase that remove cAMP (Pde4b) and potentiated stress-increased expression of PRKA, the main stimulator of Leydig cell steroidogenesis. In the same Leydig cells, stress-decreased NOS3 expression was abolished, while stress-increased GUCY1 (cGMP 'producer') and PRKG1 (cGMP 'effector') were potentiated. It is possible that all molecules mentioned could contribute, at least in part, in recovery of Leydig cell testosterone production. Presented data provide new role of α1-ADRs in stress-triggered disturbance of cAMP/cGMP signaling, and new molecular insights into the relationship between stress and mammalian reproduction. Regardless of whether the effects of α1-blocker + stress are direct or indirect, the results are important in terms of human reproductive health and the wide use of α1-ADR antagonists, alone or in combination, to treat post-traumatic stress disorders, hypertension, benign prostatic hyperplasia symptoms and potential drugs for prostate cancer prevention/treatment.
authors.affiliation: Reproductive Endocrinology and Signaling Group, Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Dositeja Obradovica Square 2, Novi Sad 21000, Serbia.
authors.forename: Natasa J
authors.initials: NJ
authors.lastname: Stojkov
authors.forename: Aleksandar Z
authors.initials: AZ
authors.lastname: Baburski
authors.forename: Maja M
authors.initials: MM
authors.lastname: Bjelic
authors.forename: Srdjan J
authors.initials: SJ
authors.lastname: Sokanovic
authors.forename: Aleksandar I
authors.initials: AI
authors.lastname: Mihajlovic
authors.forename: Dragana M
authors.initials: DM
authors.lastname: Drljaca
authors.forename: Marija M
authors.initials: MM
authors.lastname: Janjic
authors.forename: Tatjana S
authors.initials: TS
authors.lastname: Kostic
authors.forename: Silvana A
authors.initials: SA
authors.lastname: Andric
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D003345:Corticosterone / Q000097:blood; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D006152:Cyclic GMP / Q000096:biosynthesis / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000096:biosynthesis; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics; D017292:Doxazosin / Q000494:pharmacology; D004837:Epinephrine / Q000097:blood; D006162:Guanylate Cyclase / Q000096:biosynthesis; D007328:Insulin / Q000096:biosynthesis; D007985:Leydig Cells / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D011506:Proteins; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013312:Stress, Physiological / Q000187:drug effects*; D013739:Testosterone / Q000096:biosynthesis / Q000097:blood
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D007328:Insulin; C084797:Leydig insulin-like protein; D011506:Proteins; D018340:Receptors, Adrenergic, alpha-1; D018160:Receptors, Cytoplasmic and Nuclear; D013739:Testosterone; D007986:Luteinizing Hormone; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569721:Prkg1 protein, rat; D055372:AMP-Activated Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C546993:PDE4B protein, rat; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D017292:Doxazosin; D003345:Corticosterone; D004837:Epinephrine
keywords: Leydig cells; cAMP/cGMP signaling; doxazosin; stress; testosterone