title: Preclinical assessment of potential interactions between botulinum toxin and neuromodulation for bladder micturition reflex.
abstract: BACKGROUND
  While botulinum toxin A (BoNT-A) has become a more commonly used second-line treatment for patients with detrusor overactivity, it remains unknown whether the impacts of this therapy may persist to influence other therapies such as sacral neuromodulation. In this preclinical study we have evaluated urodynamic functions to intradetrusor injection of BoNT-A and the bladder inhibitory effects of spinal nerve stimulation (SNS) following BoNT-A treatment.
  
  
  METHODS
  Female rats were anesthetized with 3 % isoflurane. BoNT-A (2 units, 0.2 ml) or saline were injected into the detrusor. Rats then were housed for 2 days to 1 month before neuromodulation study. Monopolar electrodes were placed under each of the L6 spinal nerve bilaterally under urethane anesthesia. A bladder cannula was inserted via the urethra for saline infusion and intravesical pressure recording.
  
  
  RESULTS
  Intradetrusor injection of BoNT-A for 1-2 weeks or 1 month significantly increased bladder capacity compared with saline injection (p < 0.05, two-way ANOVA). Following BoNT-A, SNS attenuated the frequency of bladder contractions, either eliminating bladder contractions or reducing the contraction frequency during electrical stimulation. Inhibition of the contraction frequency by SNS following BoNT-A treated rats was not different from that measured following saline injection.
  
  
  CONCLUSIONS
  BoNT-A increased the bladder capacity, but compensating for additional saline infusion to the enlarged urinary bladder in BoNT-A pretreated rats, the bladder contractions induced by bladder filling were attenuated by SNS. BoNT-A did not alter the ability of SNS to inhibit bladder contraction following intradetrusor injection of BoNT-A for 2 days, 1-2 weeks or 1 month. These results support further pre-clinical and clinical studies to evaluate potential interactions or combination therapy with neuromodulation and intradetrusor BoNT-A therapeutic approaches.
authors.affiliation: Medtronic plc, Neuromodulation Research, 7000 Central Avenue, Minneapolis, MN, 55432, USA. xin.su@medtronic.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Su
authors.affiliation: Physiological Research Laboratories, 7000 Central Avenue, Minneapolis, MN, 55432, USA. anickles2003@yahoo.com.
authors.forename: Angela
authors.initials: A
authors.lastname: Nickles
authors.affiliation: Medtronic plc, Neuromodulation Research, 7000 Central Avenue, Minneapolis, MN, 55432, USA. dwight.e.nelson@medtronic.com.
authors.forename: Dwight E
authors.initials: DE
authors.lastname: Nelson
mesh_terms: D000283:Administration, Intravesical; D000704:Analysis of Variance; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004599:Electric Stimulation Therapy / Q000379:methods*; D005260:Female; D015552:Injections, Intralesional; D009465:Neuromuscular Agents / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000008:administration & dosage; D013127:Spinal Nerves; D053201:Urinary Bladder, Overactive / Q000175:diagnosis / Q000188:drug therapy*; D014554:Urination / Q000187:drug effects*; D014563:Urodynamics
chemical_list: D009465:Neuromuscular Agents; D012965:Sodium Chloride; D019274:Botulinum Toxins, Type A