Influence of sildenafil on the purinergic components of nerve-mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice

Chakrabarty, Basu; Ito, Hiroki; Ximenes, Manuela; Nishikawa, Nobuyuki; Vahabi, Bahareh; Kanai, Anthony J.; Pickering, Anthony E.; Drake, Marcus J.; Fry, Christopher H.

Abstract

© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. Background and purpose: PDE inhibitors such as sildenafil alleviate lower urinary tract symptoms; however, a complete understanding of their action on the bladder remains unclear. We are investigating the effects of sildenafil, on post and preganglionic nerve-mediated contractions of the mouse bladder, and neuronal and urothelial ATP release. Experimental approach: Bladders were used from young (12weeks), aged (24months), and spinal cord transected (SCT), mice, for in vitro contractility experiments. An arterially perfused in situ whole mouse model was used to record bladder pressure. Nerve-mediated contractions were generated by electrical field stimulation (EFS) of postganglionic nerve terminals or the pelvic nerve. ATP release during EFS in intact detrusor strips, and during stretch of isolated mucosa strips, was measured using a luciferin-luciferase assay. Key results: Sildenafil (20μM) inhibited nerve-mediated contractions in young mice, with an increase in f1/2 values in force–frequency relationships, demonstrating a greater effect at low frequencies. Sildenafil reduced the atropine-resistant, purinergic component of nerve-mediated contractions, and suppressed neuronal ATP release upon EFS in vitro. Sildenafil reduced the preganglionic pelvic nerve stimulated bladder pressure recordings in situ; comparable to in vitro experiments. Sildenafil reduced stretch-induced urothelial ATP release. Sildenafil also relaxed nerve-mediated contractions in aged and SCT mice. Conclusion and implications: Sildenafil has a greater effect on the low-frequency, purinergic-mediated contractions and suppresses neuronal ATP release. In addition, sildenafil reduces stretch-induced urothelial ATP release. These results demonstrate a novel action of sildenafil to selectively inhibit ATP release from nerve terminals innervating detrusor smooth muscle and the urothelium.

• Journal Article Type: Article
• Acceptance Date: Mar 12, 2019
• Online Publication Date: Mar 29, 2019
• Publication Date: Jul 1, 2019
• Deposit Date: Mar 13, 2019
• Publicly Available Date: Mar 30, 2020
• Journal: British Journal of Pharmacology
• Print ISSN: 0007-1188
• Electronic ISSN: 1476-5381
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 176
• Issue: 13
• Pages: 2227-2237
• DOI: https://doi.org/10.1111/bph.14669
• Public URL: https://uwe-repository.worktribe.com/output/849972
• Publisher URL: https://doi.org/10.1111/bph.14669
• Additional Information: Additional Information : This is the peer reviewed version of the following article: [Chakrabarty, B. , Ito, H. , Ximenes, M. , Nishikawa, N. , Vahabi, B. , Kanai, A. , Pickering, T. , Drake, M. J. and Fry, C. H. (2019) Influence of sildenafil on the purinergic components of nerve-mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice. British Journal of Pharmacology. ISSN 0007-1188], which has been published in final form at https://doi.org/10.1111/bph.14669. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving
• Contract Date: Mar 13, 2019