title: Effects on bladder function of combining elocalcitol and tolterodine in rats with outflow obstruction.
abstract: It has previously been shown that elocalcitol might protect bladder contractile function in experimental models and that elocalcitol has beneficial effects in patients with LUTS. In humans, elocalcitol was demonstrated with a very good safety profile but only exhibited limited efficacy on LUTS in patients with BPH and overactive bladder (OAB). Recent reports show that therapies with antimuscarinics, when combined with other drugs in clinical use, might perform better than a monotherapy in managing LUTS. It is not known how a combination of elocalcitol and an antimuscarinic performs on bladder dysfunction. The present study suggests that concomitant use of secosteroids and antimuscarinics has additive beneficial effects on obstruction-related functional changes in an experimental model. If confirmed also in a clinical setting, this could allow for individual dose adjustments to improve efficacy in obstruction-related LUTS, and possibly reduce unwanted adverse activities by antimuscarinic therapy.
  
  
  OBJECTIVE
  To evaluate the effects of tolterodine on urodynamics in elocalcitol- or vehicle-treated rats with partial urethral obstruction (PUO).
  
  
  METHODS
  After ethical approval, 20 female Sprague-Dawley rats were subjected to PUO and treated (gavage) for 14 days (once daily) with elocalcitol (75 µg/kg) or vehicle. Cystometries were performed on day 15 in awake rats before and after i.v. administration of tolterodine (1, 10 and 100 µg/kg).
  
  
  RESULTS
  No differences in bladder weights or body/bladder weight ratios were noted between groups. Tolterodine dose-dependently increased micturition intervals and volumes and bladder capacity in both elocalcitol- (n = 11) and vehicle-treated rats (n = 9). In elocalcitol-treated rats, flow pressure (FP) was dose-dependently reduced (12-20%) by tolterodine, whereas no effect on FP was noted in vehicle-treated animals (P < 0.05). Flow compliance (FC) was increased by tolterodine by 21-54% in vehicle-treated rats, and by 47-131% (P < 0.05 vs vehicle) in elocalcitol-treated animals. Maximal tension vs bladder weight was improved in elocalcitol-treated rats in comparison to vehicle (P < 0.05). The area under the curve (AUC) was reduced by tolterodine with 11-16% in vehicle-treated rats and 26-30% in elocalcitol -treated rats (P < 0.05).
  
  
  CONCLUSIONS
  Elocalcitol-treatment improved the effects of tolterodine on bladder compliance at the start of flow. The effects of tolterodine on AUC suggest that elocalcitol exerts additional beneficial actions on PUO-induced functional changes during the filling phase of micturition. The reduction of FP and increase in FC by elocalcitol and tolterodine could have translational value and, if valid in humans, support combined therapy in benign prostatic obstruction (BPO)-related lower urinary tract symptoms (LUTS).
authors.affiliation: Department of Pharmacology, Turku University, Turku, Finland.
authors.forename: Tomi
authors.initials: T
authors.lastname: Streng
authors.forename: Karl-Erik
authors.initials: KE
authors.lastname: Andersson
authors.forename: Petter
authors.initials: P
authors.lastname: Hedlund
authors.forename: Christian
authors.initials: C
authors.lastname: Gratzke
authors.forename: Enrico
authors.initials: E
authors.lastname: Baroni
authors.forename: Daniele
authors.initials: D
authors.lastname: D'Ambrosio
authors.forename: Fabio
authors.initials: F
authors.lastname: Benigni
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003408:Cresols / Q000008:administration & dosage / Q000494:pharmacology*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D007262:Infusions, Intravenous; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010665:Phenylpropanolamine / Q000008:administration & dosage / Q000494:pharmacology*; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects*; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy* / Q000503:physiopathology; D014563:Urodynamics / Q000187:drug effects; D014815:Vitamins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C487049:BXL628; D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D014815:Vitamins; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D002117:Calcitriol