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Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity

BACKGROUND: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study w...

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Autores principales: Livolsi, Angelo, Niederhoffer, Nathalie, Dali-Youcef, Nassim, Mokni, Walid, Olexa-Zorn, Catherine, Gies, Jean-Pierre, Marcellin, Luc, Feldman, Josiane, Bousquet, Pascal
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008725/
https://www.ncbi.nlm.nih.gov/pubmed/21203511
http://dx.doi.org/10.1371/journal.pone.0015618
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author Livolsi, Angelo
Niederhoffer, Nathalie
Dali-Youcef, Nassim
Mokni, Walid
Olexa-Zorn, Catherine
Gies, Jean-Pierre
Marcellin, Luc
Feldman, Josiane
Bousquet, Pascal
author_facet Livolsi, Angelo
Niederhoffer, Nathalie
Dali-Youcef, Nassim
Mokni, Walid
Olexa-Zorn, Catherine
Gies, Jean-Pierre
Marcellin, Luc
Feldman, Josiane
Bousquet, Pascal
author_sort Livolsi, Angelo
collection PubMed
description BACKGROUND: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity. Rabbits with marked vagal pauses following injection of phenylephrine were selected and crossed to obtain a vagal hyperreactive strain. The density of cardiac muscarinic receptors and acetylcholinesterase (AchE) gene expression were assessed. Blood markers of the observed cardiac abnormalities were also sought. METHODOLOGY/PRINCIPAL FINDINGS: Cardiac muscarinic M(2) and M(3) receptors were overexpressed in hyperreactive rabbits compared to control animals (2.3-fold and 2.5-fold, respectively) and the severity of the phenylephrine-induced bradycardia was correlated with their densities. A similar overexpression of M(2) receptors was observed in peripheral mononuclear white blood cells, suggesting that cardiac M(2) receptor expression can be inferred with high confidence from measurements in blood cells. Sequencing of the coding fragment of the M(2) receptor gene revealed a single nucleotide mutation in 83% of hyperreactive animals, possibly contributing for the transcript overexpression. Significant increases in AchE expression and activity were also assessed (AchE mRNA amplification ratio of 3.6 versus normal rabbits). This phenomenon might represent a compensatory consequence of muscarinic receptors overexpression. Alterations in M(2) receptor and AchE expression occurred between the 5th and the 7th week of age, a critical period also characterized by a higher mortality rate of hyperreactive rabbits (52% in H rabbits versus 13% in normal rabbits) and preceeded the appearance of functional disorders. CONCLUSIONS/SIGNIFICANCE: The results suggest that cardiac muscarinic receptor overexpression plays a critical role in the development of vagal hyperreactivity, whereas AchE hyperactivity appears as a compensatory consequence of it. Since similar vagal disorders were observed recently by us in SIDS, muscarinic receptor overexpression could become a marker of risk of vasovagal syncopes and SIDS.
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spelling pubmed-30087252011-01-03 Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity Livolsi, Angelo Niederhoffer, Nathalie Dali-Youcef, Nassim Mokni, Walid Olexa-Zorn, Catherine Gies, Jean-Pierre Marcellin, Luc Feldman, Josiane Bousquet, Pascal PLoS One Research Article BACKGROUND: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity. Rabbits with marked vagal pauses following injection of phenylephrine were selected and crossed to obtain a vagal hyperreactive strain. The density of cardiac muscarinic receptors and acetylcholinesterase (AchE) gene expression were assessed. Blood markers of the observed cardiac abnormalities were also sought. METHODOLOGY/PRINCIPAL FINDINGS: Cardiac muscarinic M(2) and M(3) receptors were overexpressed in hyperreactive rabbits compared to control animals (2.3-fold and 2.5-fold, respectively) and the severity of the phenylephrine-induced bradycardia was correlated with their densities. A similar overexpression of M(2) receptors was observed in peripheral mononuclear white blood cells, suggesting that cardiac M(2) receptor expression can be inferred with high confidence from measurements in blood cells. Sequencing of the coding fragment of the M(2) receptor gene revealed a single nucleotide mutation in 83% of hyperreactive animals, possibly contributing for the transcript overexpression. Significant increases in AchE expression and activity were also assessed (AchE mRNA amplification ratio of 3.6 versus normal rabbits). This phenomenon might represent a compensatory consequence of muscarinic receptors overexpression. Alterations in M(2) receptor and AchE expression occurred between the 5th and the 7th week of age, a critical period also characterized by a higher mortality rate of hyperreactive rabbits (52% in H rabbits versus 13% in normal rabbits) and preceeded the appearance of functional disorders. CONCLUSIONS/SIGNIFICANCE: The results suggest that cardiac muscarinic receptor overexpression plays a critical role in the development of vagal hyperreactivity, whereas AchE hyperactivity appears as a compensatory consequence of it. Since similar vagal disorders were observed recently by us in SIDS, muscarinic receptor overexpression could become a marker of risk of vasovagal syncopes and SIDS. Public Library of Science 2010-12-22 /pmc/articles/PMC3008725/ /pubmed/21203511 http://dx.doi.org/10.1371/journal.pone.0015618 Text en Livolsi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Livolsi, Angelo
Niederhoffer, Nathalie
Dali-Youcef, Nassim
Mokni, Walid
Olexa-Zorn, Catherine
Gies, Jean-Pierre
Marcellin, Luc
Feldman, Josiane
Bousquet, Pascal
Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity
title Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity
title_full Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity
title_fullStr Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity
title_full_unstemmed Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity
title_short Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity
title_sort constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008725/
https://www.ncbi.nlm.nih.gov/pubmed/21203511
http://dx.doi.org/10.1371/journal.pone.0015618
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