title: Mechanisms of action of botulinum neurotoxins, β3-adrenergic receptor agonists, and PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI-RS 2011.
abstract: BACKGROUND
  Botulinum neurotoxins type A (BoNT/A), β(3)-adrenergic receptor agonists, and phosphodiesterase type 5 (PDE5) inhibitors are promising agents that mitigate lower urinary tract symptoms by attenuating the sensory system. However, whether they act directly on afferent nerves or indirectly through the other cell types is unclear.
  
  
  METHODS
  Spinal cord transected female mice were used as a model for neurogenic bladder overactivity. In vivo methods utilized decerebrate mouse cystometry. In vitro approaches included optical mapping of Ca(2+) transient, single unit afferent nerve recordings and tension measurements from bladder sheets and wall cross-sections. Immunohistochemistry was used to measure the expression of β(3)-adrenergic receptors on dorsal root ganglion (DRG) neurons.
  
  
  RESULTS
  Our unique approaches revealed the direct effects of BoNT/A in inhibiting neuropeptide release and firing rates in afferents following bladder injections. β(3)-adrenergic receptor agonists are demonstrated to directly inhibit afferent nerve firing independent of the relaxing effects on bladder smooth muscle. Moreover, data suggest the expression of these receptors on DRG neurons that send projections to the bladder. The mechanism of action of PDE5 inhibitors on bladder overactivity is discussed.
  
  
  CONCLUSIONS
  The questions raised during the plenary session of the 2011 International Consultation on Incontinence-Research Society meeting regarding the benefits of BoNT/A, β(3)-adrenergic receptor agonist and PDE5 inhibitor treatments of overactive bladder are addressed.
  
  
  CONCLUSIONS
  Our findings suggest that the abovementioned agents, in low enough concentrations, can directly inhibit afferent excitability without decreasing detrusor contractility. Accordingly, they have considerable potential for treating the sensory component of lower urinary tract dysfunctions.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. ajk5@pitt.edu
authors.forename: Anthony
authors.initials: A
authors.lastname: Kanai
authors.forename: Irina
authors.initials: I
authors.lastname: Zabbarova
authors.forename: Michael
authors.initials: M
authors.lastname: Oefelein
authors.forename: Piotr
authors.initials: P
authors.lastname: Radziszewski
authors.forename: Youko
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Karl-Erik
authors.initials: KE
authors.lastname: Andersson
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D003655:Decerebrate State; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000150:complications / Q000503:physiopathology; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D058986:Phosphodiesterase 5 Inhibitors; D019274:Botulinum Toxins, Type A; C545476:incobotulinumtoxinA