title: Long-term treatment with the beta-3 adrenoceptor agonist, mirabegron ameliorates detrusor overactivity and restores cyclic adenosine monophosphate (cAMP) levels in obese mice.
abstract: OBJECTIVE
  To evaluate the effects of the beta-3 adrenoceptor agonist, mirabegron in a mouse model of detrusor overactivity induced by obesity.
  
  
  METHODS
  C57BL/6 male mice were fed with standard chow or high-fat diet for 12 weeks. Lean and obese mice were treated orally with mirabegron (10 mg/kg/day) from the last 2 weeks of diet. Cystometric evaluations, functional assays, protein expression for phosphodiesterase type 4 (PDE4), and cyclic adenosine monophosphate (cAMP) measurement were carried out.
  
  
  RESULTS
  In obese mice the body weight, epididymal fat mass, fasting glucose, and low-density lipoprotein (LDL) levels were higher (P < 0.001) than in the lean mice. A reduction of 34% and 54% and an increase of 35% in the epididimal fat, LDL, and HDL levels (P < 0.05), respectively, were observed in the obese group treated with mirabegron, whereas no changes were seen in the lipid profile from lean mice. Obese group showed irregular micturition pattern, characterized by significant increases in frequency and non-void contractions. Carbachol, potassium chloride, and electrical-field stimulation induced detrusor smooth muscle (DSM) contractions, which were greater in bladders from obese mice than from lean mice. Two-week treatment with mirabegron restored all the contractile response alterations in the DSM. Basal intracellular levels of cAMP were reduced (68%), whereas PDE4 protein expression was increased (54%) in bladder from obese mice. Mirabegron restored the cAMP levels in obese bladder, without changing the PDE4 expression.
  
  
  CONCLUSIONS
  Mirabegron was able to completely restore the urinary alterations seen in the bladder from obese mice.
authors: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors: Fabiano B
authors: FB
authors: Calmasini
authors: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors: Mariana G
authors: MG
authors: de Oliveira
authors: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors: Eduardo C
authors: EC
authors: Alexandre
authors: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors: Fábio H
authors: FH
authors: da Silva
authors: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors: Carmem P V
authors: CPV
authors: da Silva
authors: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors: Tuany Z
authors: TZ
authors: Candido
authors: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors: Edson
authors: E
authors: Antunes
authors: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors: Fabíola Z
authors: FZ
authors: Mónica
mesh_terms: D000083:Acetanilides / Q000494:pharmacology / Q000627:therapeutic use*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014554:Urination / Q000187:drug effects
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D013844:Thiazoles; D002217:Carbachol; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C095813:Pde4a protein, mouse; C520025:mirabegron
keywords: cAMP; detrusor; obesity; overactivity