title: Selective inhibitory effect of imidafenacin and 5-hydroxymethyl tolterodine on capsaicin sensitive C fibers of the primary bladder mechanosensitive afferent nerves in the rat.
abstract: OBJECTIVE
  Imidafenacin and fesoterodine are used to treat overactive bladder. Imidafenacin, fesoterodine and its active metabolite 5-hydroxymethyl tolterodine are muscarinic receptor antagonists. It is believed that these agents act on afferent nerves in addition to smooth muscle. We investigated the effects of imidafenacin and 5-hydroxymethyl tolterodine on single unit afferent activity of mechanosensitive capsaicin sensitive and insensitive primary bladder afferent nerve fibers in rats.
  
  
  METHODS
  Female Sprague Dawley® rats were anesthetized. Single unit afferent activity was recorded from the L6 dorsal roots and classified by conduction velocity as that of Aδ or C fibers. After measuring control single afferent activity during constant filling cystometry the procedure was repeated with intravenous administration of imidafenacin (0.3 to 30 μg/kg) or 5-hydroxymethyl tolterodine (0.01 to 1 mg/kg) at cumulative doses with or without intravesical capsaicin or oxotremorine-M instillation.
  
  
  RESULTS
  A total of 139 single unit afferent fibers were isolated from 111 rats, including 19 Aδ and 120 C fibers. Neither imidafenacin nor 5-hydroxymethyl tolterodine significantly affected the overall single unit afferent activity of Aδ or C fibers. Based on capsaicin sensitivity C fibers were divided into capsaicin sensitive and insensitive groups. Each antimuscarinic inhibited the single unit afferent activity of capsaicin sensitive C fibers but not of capsaicin insensitive C fibers at the highest dose. Moreover, oxotremorine-M facilitated single unit afferent activity in a proportion of C fibers. The facilitated single unit afferent activity was significantly attenuated by the highest dose of imidafenacin.
  
  
  CONCLUSIONS
  These findings demonstrate that imidafenacin and 5-hydroxymethyl tolterodine can selectively inhibit capsaicin sensitive C fibers among mechanosensitive bladder afferents by antagonizing bladder muscarinic receptors.
authors.affiliation: Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Aizawa
authors.affiliation: Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Rino
authors.initials: R
authors.lastname: Sugiyama
authors.affiliation: Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Motofumi
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukuhara
authors.affiliation: Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.affiliation: Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan. Electronic address: yigawa-jua@umin.ac.jp.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Igawa
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology*; D003408:Cresols / Q000494:pharmacology*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects*; D009475:Neurons, Afferent / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation*
chemical_list: C109909:5-hydroxymethyl tolterodine; D001559:Benzhydryl Compounds; D003408:Cresols; D007093:Imidazoles; D018727:Muscarinic Antagonists; D002211:Capsaicin; C120953:imidafenacin
keywords: 5-hydroxymethyl tolterodine; afferent; capsaicin; imidafenacin; neurons; urinary bladder