title: JTS-653 blocks afferent nerve firing and attenuates bladder overactivity without affecting normal voiding function.
abstract: OBJECTIVE
  We evaluated the role of TRPV1 in bladder overactivity based on afferent nerve firing and urodynamic parameters using the selective TRPV1 antagonist JTS-653.
  
  
  METHODS
  We evaluated the effects of JTS-653 on the increased pelvic nerve discharge and intravesical pressure induced by intravesical infusion of 100 μM capsaicin in anesthetized rats. The effects of JTS-653 on the urodynamic parameters of bladder overactivity induced by intravesical infusion of 30 nM resiniferatoxin or 0.2% acetic acid, or on normal bladder activity were evaluated by cystometry in conscious rats. The effects of JTS-653 on carbachol induced contraction were investigated using bladder muscle strips.
  
  
  RESULTS
  JTS-653 significantly suppressed the capsaicin induced increase in nerve discharge and intravesical pressure. Intravesical infusion of resiniferatoxin or acetic acid decreased the intercontraction interval and voided volume. JTS-653 significantly increased the intercontraction interval and voided volume in rats with resiniferatoxin or acetic acid induced bladder overactivity without affecting maximal voiding pressure. The antimuscarinic agent propiverine significantly decreased maximal voiding pressure but did not affect the intercontraction interval or voided volume in rats with acetic acid induced bladder overactivity. In normal rats JTS-653 showed no significant effects on the intercontraction interval, voided volume or maximal voiding pressure. JTS-653 did not affect carbachol induced contraction of the bladder muscle.
  
  
  CONCLUSIONS
  Our findings suggest that TRPV1 is involved in bladder overactivity via afferent nerve activation but it is not associated with normal voiding function. A TRPV1 antagonist would be a useful drug for bladder overactivity with a different pharmacological profile than antimuscarinic agents.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Inc., Osaka, Japan. yoshihiro.kitagawa@jt.com
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Wada
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Kanehisa
authors.forename: Atsuko
authors.initials: A
authors.lastname: Miyai
authors.forename: Kenji
authors.initials: K
authors.lastname: Usui
authors.forename: Mariko
authors.initials: M
authors.lastname: Maekawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakata
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuo
authors.forename: Mikio
authors.initials: M
authors.lastname: Hayashi
authors.forename: Mutsuyoshi
authors.initials: M
authors.lastname: Matsushita
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D009475:Neurons, Afferent / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation* / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000503:physiopathology*; D014554:Urination / Q000187:drug effects* / Q000502:physiology
chemical_list: C576953:3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3,4-dihydro-2H-benzo(b)(1,4)oxazine-8-carboxamide; D048588:Benzoxazines; D011725:Pyridines; D050916:TRPV Cation Channels