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Influence of sildenafil on the purinergic components of nerve‐mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice
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 bladd...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555867/ https://www.ncbi.nlm.nih.gov/pubmed/30924527 http://dx.doi.org/10.1111/bph.14669 |
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author | Chakrabarty, Basu Ito, Hiroki Ximenes, Manuela Nishikawa, Nobuyuki Vahabi, Bahareh Kanai, Anthony J. Pickering, Anthony E. Drake, Marcus J. Fry, Christopher H. |
author_facet | Chakrabarty, Basu Ito, Hiroki Ximenes, Manuela Nishikawa, Nobuyuki Vahabi, Bahareh Kanai, Anthony J. Pickering, Anthony E. Drake, Marcus J. Fry, Christopher H. |
author_sort | Chakrabarty, Basu |
collection | PubMed |
description | 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 (12 weeks), aged (24 months), 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 (20 μM) inhibited nerve‐mediated contractions in young mice, with an increase in f (1/2) 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. |
format | Online Article Text |
id | pubmed-6555867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65558672019-06-10 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. Br J Pharmacol Research Papers 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 (12 weeks), aged (24 months), 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 (20 μM) inhibited nerve‐mediated contractions in young mice, with an increase in f (1/2) 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. John Wiley and Sons Inc. 2019-05-11 2019-07 /pmc/articles/PMC6555867/ /pubmed/30924527 http://dx.doi.org/10.1111/bph.14669 Text en © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Research Papers Chakrabarty, Basu Ito, Hiroki Ximenes, Manuela Nishikawa, Nobuyuki Vahabi, Bahareh Kanai, Anthony J. Pickering, Anthony E. Drake, Marcus J. Fry, Christopher H. Influence of sildenafil on the purinergic components of nerve‐mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice |
title | Influence of sildenafil on the purinergic components of nerve‐mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice |
title_full | Influence of sildenafil on the purinergic components of nerve‐mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice |
title_fullStr | Influence of sildenafil on the purinergic components of nerve‐mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice |
title_full_unstemmed | Influence of sildenafil on the purinergic components of nerve‐mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice |
title_short | Influence of sildenafil on the purinergic components of nerve‐mediated and urothelial ATP release from the bladder of normal and spinal cord injured mice |
title_sort | influence of sildenafil on the purinergic components of nerve‐mediated and urothelial atp release from the bladder of normal and spinal cord injured mice |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555867/ https://www.ncbi.nlm.nih.gov/pubmed/30924527 http://dx.doi.org/10.1111/bph.14669 |
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