title: Effects of mirabegron, a novel β3-adrenoceptor agonist, on primary bladder afferent activity and bladder microcontractions in rats compared with the effects of oxybutynin.
abstract: BACKGROUND
  Mirabegron is the first β3-adrenoceptor agonist that is clinically effective for overactive bladder.
  
  
  OBJECTIVE
  The effects of mirabegron on primary bladder mechanosensitive single-unit afferent activities (SAAs) and bladder microcontractions were evaluated and compared with the effects of oxybutynin.
  
  
  METHODS
  Female Sprague-Dawley rats were anesthetized. The SAAs generated from left L6 dorsal roots were identified by electrical stimulation of the left pelvic nerve and bladder distension. Nerves with conduction velocities (CVs) >2.5 m/s were designated as Aδ-fibers, and nerves with CVs<2.5 m/s were designated as C-fibers.
  
  
  METHODS
  Two measurements were performed in separate animals. First, after measuring the baselines of SAA during constant filling cystometry, the procedure was repeated with each intravenous administration of mirabegron at three doses-0.1, 0.3, and 1.0mg/kg-cumulatively. Second, the bladder was filled with saline until the intravesical pressure reached 30 cm H(2)O and was kept under an isovolumetric condition; then the recording was performed for 5 min with vehicle and mirabegron or oxybutynin administrated intravenously.
  
  
  CONCLUSIONS
  A total of 74 single-unit afferent fibers were isolated from 55 rats (Aδ-fibers: n=34; C-fibers: n=40). SAAs of both Aδ-fibers and C-fibers in response to bladder filling significantly decreased after mirabegron administration in a dose-dependent manner, which was more remarkable for Aδ-fibers. During an isovolumetric condition of the bladder, the mean bladder pressure and the number of microcontractions decreased after mirabegron administration, whereas these parameters did not change with oxybutynin administration. SAAs of Aδ-fibers were significantly decreased by mirabegron administration at both 0.3 and 1mg/kg, whereas SAAs of C-fibers decreased only at 1mg/kg. In contrast, oxybutynin (1mg/kg) did not alter either type of SAA.
  
  
  CONCLUSIONS
  The present study demonstrates that mirabegron can inhibit mechanosensitive bladder afferent activity, especially of Aδ-fibers, which may be related to suppression of bladder microcontractions.
authors.affiliation: Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Aizawa
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Igawa
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D005260:Female; D008333:Mandelic Acids / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000502:physiology*
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D013844:Thiazoles; C005419:oxybutynin; C520025:mirabegron