Naoki Aizawa1, Hiroki Ito1, Rino Sugiyama1, Tetsuya Fujimura1, Motofumi Suzuki1, Hiroshi Fukuhara1, Yukio Homma1, Yasuhiko Igawa2. 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: yigawa-jua@umin.ac.jp.
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.
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.
Authors: Timothy D Ungerer; Kyoungeun A Kim; Stephanie L Daugherty; James R Roppolo; Changfeng Tai; William C de Groat Journal: Exp Neurol Date: 2016-07-14 Impact factor: 5.330
Authors: Hiroki Ito; Anthony E Pickering; Yasuhiko Igawa; Anthony J Kanai; Christopher H Fry; Marcus J Drake Journal: Front Physiol Date: 2017-02-06 Impact factor: 4.566