title: Urinary Bladder Dysfunction in Transgenic Sickle Cell Disease Mice.
abstract: BACKGROUND
  Urological complications associated with sickle cell disease (SCD), include nocturia, enuresis, urinary infections and urinary incontinence. However, scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms in SCD is lacking.
  
  
  OBJECTIVE
  Thus, the aim of this study was to evaluate urinary function, in vivo and ex vivo, in the Berkeley SCD murine model (SS).
  
  
  METHODS
  Urine output was measured in metabolic cage for both wild type and SS mice (25-30 g). Bladder strips and urethra rings were dissected free and mounted in organ baths. In isolated detrusor smooth muscle (DSM), relaxant response to mirabegron and isoproterenol (1nM-10μM) and contractile response to (carbachol (CCh; 1 nM-100μM), KCl (1 mM-300mM), CaCl2 (1μM-100mM), α,β-methylene ATP (1, 3 and 10 μM) and electrical field stimulation (EFS; 1-32 Hz) were measured. Phenylephrine (Phe; 10nM-100μM) was used to evaluate the contraction mechanism in the urethra rings. Cystometry and histomorphometry were also performed in the urinary bladder.
  
  
  RESULTS
  SS mice present a reduced urine output and incapacity to produce typical bladder contractions and bladder emptying (ex vivo), compared to control animals. In DSM, relaxation in response to a selective β3-adrenergic agonist (mirabegron) and to a non-selective β-adrenergic (isoproterenol) agonist were lower in SS mice. Additionally, carbachol, α, β-methylene ATP, KCl, extracellular Ca2+ and electrical-field stimulation promoted smaller bladder contractions in SS group. Urethra contraction induced by phenylephrine was markedly reduced in SS mice. Histological analyses of SS mice bladder revealed severe structural abnormalities, such as reductions in detrusor thickness and bladder volume, and cell infiltration.
  
  
  CONCLUSIONS
  Taken together, our data demonstrate, for the first time, that SS mice display features of urinary bladder dysfunction, leading to impairment in urinary continence, which may have an important role in the pathogenesis of the enuresis and infections observed the SCD patients.
authors.affiliation: Department of Pharmacology, State University of Campinas, Campinas, SP, Brazil; Laboratory of Multidisciplinary Research, São Francisco University Medical School, Bragança Paulista, SP, Brazil.
authors.forename: Mário Angelo
authors.initials: MA
authors.lastname: Claudino
authors.affiliation: Department of Pharmacology, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Luiz Osório Silveira
authors.initials: LO
authors.lastname: Leiria
authors.affiliation: Hematology and Hemotherapy Center, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Fábio Henrique
authors.initials: FH
authors.lastname: da Silva
authors.affiliation: Department of Pharmacology, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Eduardo Costa
authors.initials: EC
authors.lastname: Alexandre
authors.affiliation: Department of Pharmacology, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Andre
authors.initials: A
authors.lastname: Renno
authors.affiliation: Department of Pharmacology, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Fabiola Zakia
authors.initials: FZ
authors.lastname: Mónica
authors.affiliation: Department of Pharmacology, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: de Nucci
authors.affiliation: Department of Clinical Pathology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Kleber Yotsumoto
authors.initials: KY
authors.lastname: Fertrin
authors.affiliation: Department of Pharmacology, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.affiliation: Hematology and Hemotherapy Center, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Fernando Ferreira
authors.initials: FF
authors.lastname: Costa
authors.affiliation: Hematology and Hemotherapy Center, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Carla Fernanda
authors.initials: CF
authors.lastname: Franco-Penteado
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002122:Calcium Chloride; D002217:Carbachol / Q000494:pharmacology; D004195:Disease Models, Animal; D004231:Diuresis; D004558:Electric Stimulation; D006451:Hemoglobin, Sickle / Q000235:genetics; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014521:Urethra / Q000187:drug effects / Q000503:physiopathology; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
chemical_list: D000083:Acetanilides; D006451:Hemoglobin, Sickle; D013844:Thiazoles; D010656:Phenylephrine; D011189:Potassium Chloride; D001285:Atropine; D000255:Adenosine Triphosphate; D002217:Carbachol; D007545:Isoproterenol; D002122:Calcium Chloride; C520025:mirabegron; C002630:alpha,beta-methyleneadenosine 5'-triphosphate