Selective inhibitory effect of imidafenacin and 5-hydroxymethyl tolterodine on capsaicin sensitive C fibers of the primary bladder mechanosensitive afferent nerves in the rat

  • J Urol. 2015 Apr;193(4):1423-32. doi: 10.1016/j.juro.2014.09.005.
Naoki Aizawa  1 ,  Hiroki Ito  1 ,  Rino Sugiyama  1 ,  Tetsuya Fujimura  1 ,  Motofumi Suzuki  1 ,  Hiroshi Fukuhara  1 ,  Yukio Homma  1 ,  Yasuhiko Igawa  2
Affiliations
  • 1. Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
  • 2. Departments of Continence Medicine and Urology (TF, MS, HF, YH), University of Tokyo Graduate School of Medicine, Tokyo, Japan. Electronic address: [email protected].
PMID: 25219701 DOI: 10.1016/j.juro.2014.09.005
Abstract

Purpose: 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.

Materials and 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.

Keywords
5-hydroxymethyl tolterodine; afferent; capsaicin; imidafenacin; neurons; urinary bladder.
Products