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

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: Naoki Aizawa, Hiroki Ito, Rino Sugiyama, Tetsuya Fujimura, Motofumi Suzuki, Hiroshi Fukuhara, Yukio Homma, Yasuhiko Igawa
• Journal: The Journal of urology (J Urol) Vol. 193 Issue 4 Pg. 1423-32 (Apr 2015) ISSN: 1527-3792 [Electronic] United States
• PMID: 25219701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• 5-hydroxymethyl tolterodine
• Benzhydryl Compounds
• Cresols
• Imidazoles
• Muscarinic Antagonists
• Capsaicin
• imidafenacin

Topics

• Animals
• Benzhydryl Compounds (pharmacology)
• Capsaicin (pharmacology)
• Cresols (pharmacology)
• Female
• Imidazoles (pharmacology)
• Muscarinic Antagonists (pharmacology)
• Nerve Fibers, Unmyelinated (drug effects)
• Neurons, Afferent (drug effects)
• Rats
• Rats, Sprague-Dawley
• Urinary Bladder (drug effects, innervation)