title: Sympathetic Hyperactivity, Increased Tyrosine Hydroxylase and Exaggerated Corpus Cavernosum Relaxations Associated with Oxidative Stress Plays a Major Role in the Penis Dysfunction in Townes Sickle Cell Mouse.
abstract: BACKGROUND
  Sickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease.
  
  
  OBJECTIVE
  Thus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide-cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice.
  
  
  METHODS
  Concentration-response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and α1A-, α1B- and α1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured.
  
  
  RESULTS
  The neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine-induced contractions were greater in the sickle mice, whereas α1A-, α1B- and α1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40% in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected.
  
  
  CONCLUSIONS
  Our study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice.
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Fábio H
authors.identifier: http://orcid.org/0000-0003-3374-5570
authors.initials: FH
authors.lastname: Silva
authors.affiliation: Laboratory of Multidisciplinary Research, São Francisco University Medical School, Bragança Paulista, SP, Brazil.
authors.forename: Mário A
authors.initials: MA
authors.lastname: Claudino
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Fabiano B
authors.initials: FB
authors.lastname: Calmasini
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Eduardo C
authors.initials: EC
authors.lastname: Alexandre
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Franco-Penteado
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Burnett
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D015153:Blotting, Western; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress; D010413:Penis / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D011941:Receptors, Adrenergic; D014665:Vasodilator Agents; D009599:Nitroprusside; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D014446:Tyrosine 3-Monooxygenase; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D000109:Acetylcholine