Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.

<h4>Background</h4>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...

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Autores principales:	Angelo Livolsi, Nathalie Niederhoffer, Nassim Dali-Youcef, Walid Mokni, Catherine Olexa-Zorn, Jean-Pierre Gies, Luc Marcellin, Josiane Feldman, Pascal Bousquet
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/084581552bef4df3a78e99b73f778db8
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spelling	oai:doaj.org-article:084581552bef4df3a78e99b73f778db82021-11-18T07:01:21ZConstitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.1932-620310.1371/journal.pone.0015618https://doaj.org/article/084581552bef4df3a78e99b73f778db82010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21203511/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Angelo LivolsiNathalie NiederhofferNassim Dali-YoucefWalid MokniCatherine Olexa-ZornJean-Pierre GiesLuc MarcellinJosiane FeldmanPascal BousquetPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 12, p e15618 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Angelo Livolsi Nathalie Niederhoffer Nassim Dali-Youcef Walid Mokni Catherine Olexa-Zorn Jean-Pierre Gies Luc Marcellin Josiane Feldman Pascal Bousquet Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format	article
author	Angelo Livolsi Nathalie Niederhoffer Nassim Dali-Youcef Walid Mokni Catherine Olexa-Zorn Jean-Pierre Gies Luc Marcellin Josiane Feldman Pascal Bousquet
author_facet	Angelo Livolsi Nathalie Niederhoffer Nassim Dali-Youcef Walid Mokni Catherine Olexa-Zorn Jean-Pierre Gies Luc Marcellin Josiane Feldman Pascal Bousquet
author_sort	Angelo Livolsi
title	Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.
title_short	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_sort	constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/084581552bef4df3a78e99b73f778db8
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Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.

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