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PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia
Repetitive hypoxia is a key feature of obstructive sleep apnoea (OSA), a condition characterized by intermittent airways obstruction. Patients with OSA present with persistent increases in sympathetic activity and commonly develop hypertension. The objectives of this study were to determine if the p...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712064/ https://www.ncbi.nlm.nih.gov/pubmed/31496933 http://dx.doi.org/10.3389/fnins.2019.00881 |
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author | Farnham, Melissa M. J. Tallapragada, Vikram J. O’Connor, Edward T. Nedoboy, Polina E. Dempsey, Bowen Mohammed, Suja Fong, Angelina Y. Lung, Mandy S. Y. Derakhshan, Fatemeh Wilson, Richard J. A. Pilowsky, Paul M. |
author_facet | Farnham, Melissa M. J. Tallapragada, Vikram J. O’Connor, Edward T. Nedoboy, Polina E. Dempsey, Bowen Mohammed, Suja Fong, Angelina Y. Lung, Mandy S. Y. Derakhshan, Fatemeh Wilson, Richard J. A. Pilowsky, Paul M. |
author_sort | Farnham, Melissa M. J. |
collection | PubMed |
description | Repetitive hypoxia is a key feature of obstructive sleep apnoea (OSA), a condition characterized by intermittent airways obstruction. Patients with OSA present with persistent increases in sympathetic activity and commonly develop hypertension. The objectives of this study were to determine if the persistent increases in sympathetic nerve activity, known to be induced by acute intermittent hypoxia (AIH), are mediated through activation of the pituitary adenylate cyclase activating polypeptide (PACAP) signaling system. Here, we show that the excitatory neuropeptide PACAP, acting in the spinal cord, is important for generating the sympathetic response seen following AIH. Using PACAP receptor knockout mice, and pharmacological agents in Sprague Dawley rats, we measured blood pressure, heart rate, pH, PaCO(2), and splanchnic sympathetic nerve activity, under anaesthesia, to demonstrate that the sympathetic response to AIH is mediated via the PAC1 receptor, in a cAMP-dependent manner. We also report that both intermittent microinjection of glutamate into the rostroventrolateral medulla (RVLM) and intermittent infusion of a sub-threshold dose of PACAP into the subarachnoid space can mimic the sympathetic response to AIH. All the sympathetic responses are independent of blood pressure, pH or PaCO(2) changes. Our results show that in AIH, PACAP signaling in the spinal cord helps drive persistent increases in sympathetic nerve activity. This mechanism may be a precursor to the development of hypertension in conditions of chronic intermittent hypoxia, such as OSA. |
format | Online Article Text |
id | pubmed-6712064 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-67120642019-09-06 PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia Farnham, Melissa M. J. Tallapragada, Vikram J. O’Connor, Edward T. Nedoboy, Polina E. Dempsey, Bowen Mohammed, Suja Fong, Angelina Y. Lung, Mandy S. Y. Derakhshan, Fatemeh Wilson, Richard J. A. Pilowsky, Paul M. Front Neurosci Neuroscience Repetitive hypoxia is a key feature of obstructive sleep apnoea (OSA), a condition characterized by intermittent airways obstruction. Patients with OSA present with persistent increases in sympathetic activity and commonly develop hypertension. The objectives of this study were to determine if the persistent increases in sympathetic nerve activity, known to be induced by acute intermittent hypoxia (AIH), are mediated through activation of the pituitary adenylate cyclase activating polypeptide (PACAP) signaling system. Here, we show that the excitatory neuropeptide PACAP, acting in the spinal cord, is important for generating the sympathetic response seen following AIH. Using PACAP receptor knockout mice, and pharmacological agents in Sprague Dawley rats, we measured blood pressure, heart rate, pH, PaCO(2), and splanchnic sympathetic nerve activity, under anaesthesia, to demonstrate that the sympathetic response to AIH is mediated via the PAC1 receptor, in a cAMP-dependent manner. We also report that both intermittent microinjection of glutamate into the rostroventrolateral medulla (RVLM) and intermittent infusion of a sub-threshold dose of PACAP into the subarachnoid space can mimic the sympathetic response to AIH. All the sympathetic responses are independent of blood pressure, pH or PaCO(2) changes. Our results show that in AIH, PACAP signaling in the spinal cord helps drive persistent increases in sympathetic nerve activity. This mechanism may be a precursor to the development of hypertension in conditions of chronic intermittent hypoxia, such as OSA. Frontiers Media S.A. 2019-08-21 /pmc/articles/PMC6712064/ /pubmed/31496933 http://dx.doi.org/10.3389/fnins.2019.00881 Text en Copyright © 2019 Farnham, Tallapragada, O’Connor, Nedoboy, Dempsey, Mohammed, Fong, Lung, Derakhshan, Wilson and Pilowsky. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Farnham, Melissa M. J. Tallapragada, Vikram J. O’Connor, Edward T. Nedoboy, Polina E. Dempsey, Bowen Mohammed, Suja Fong, Angelina Y. Lung, Mandy S. Y. Derakhshan, Fatemeh Wilson, Richard J. A. Pilowsky, Paul M. PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia |
title | PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia |
title_full | PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia |
title_fullStr | PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia |
title_full_unstemmed | PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia |
title_short | PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia |
title_sort | pacap-pac1 receptor activation is necessary for the sympathetic response to acute intermittent hypoxia |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712064/ https://www.ncbi.nlm.nih.gov/pubmed/31496933 http://dx.doi.org/10.3389/fnins.2019.00881 |
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