title: Combined treatment with a β3-adrenergic receptor agonist and a muscarinic receptor antagonist inhibits detrusor overactivity induced by cold stress in spontaneously hypertensive rats.
abstract: This study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the β3-adrenergic receptor (AR) agonist mirabegron could inhibit detrusor overactivity induced by cold stress in spontaneously hypertensive rats (SHRs).
  
  
  
  Thirty-two female 10-week-old SHRs were fed an 8% NaCl-supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then intravenously administered vehicle, 0.1 mg/kg solifenacin alone, 0.1 mg/kg mirabegron alone, or the combination of 0.1 mg/kg mirabegron and 0.1 mg/kg solifenacin (n = 8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 4 ± 2°C) for 40 min. Finally, the rats were returned to RT. After the cystometric investigations, the β3-ARs and M3-MRs expressed within the urinary bladders were analyzed.
  
  
  
  Just after transfer from RT to LT, vehicle-, solifenacin-, and mirabegron-treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress-induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination-treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M3-MR and β3-AR mRNA. The tissue distribution of M3-MRs was similar to that of the β3-ARs.
  
  
  
  This study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress-induced detrusor overactivity in SHRs. Neurourol. Urodynam. 36:1026-1033, 2017. © 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Minagawa
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tetsuichi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokoyama
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakazawa
authors.affiliation: Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishizuka
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D003080:Cold Temperature; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D000069464:Solifenacin Succinate / Q000494:pharmacology*; D013312:Stress, Physiological; D013844:Thiazoles / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology; D064804:Urological Agents / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D018727:Muscarinic Antagonists; D013844:Thiazoles; D064804:Urological Agents; D000069464:Solifenacin Succinate; C520025:mirabegron
keywords: cold stress; lower urinary tract symptoms; muscarinic receptor antagonist; spontaneously hypertensive rat; β3-adrenergic receptor agonist