Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity

Livolsi, Angélo; Niederhoffer, Nathalie; Dali‐Youcef, Nassim; Mokni, Walid; Olexa-Zorn, Catherine; Gies, Jean-Pierre; Marcellin, Luc; Feldman, Josiane; Bousquet, Pascal

doi:10.1371/journal.pone.0015618

Cited by 4 publications

(13 citation statements)

References 32 publications

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“…The detailed mechanisms by which the responsiveness of the cholinergic antiinflammatory pathway is regulated remain unclear. Recent evidence suggests that vagal reactivity and cholinesterase activity depend on the constitutive expression of acetylcholine receptors at the peripheral organs …”

Section: Discussionmentioning

confidence: 99%

The Cholinergic System and Inflammation: Common Pathways in Delirium Pathophysiology

Cerejeira

Nogueira

Luis.³

et al. 2012

J American Geriatrics Society

174

139

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OBJECTIVES:To investigate whether delirium is associated with an unbalanced inflammatory response or a dysfunctional interaction between the cholinergic and immune systems. DESIGN: Cohort observational study. SETTING: General hospital orthopedic ward. PARTICIPANTS: One hundred one individuals aged 60 and older with no previous cognitive impairment undergoing elective arthroplasty. MEASUREMENTS: Incidence of postoperative delirium, plasma cholinesterase activity (acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)) and inflammatory mediators (C-reactive protein (CRP), interleukin (IL)-1 beta, tumor necrosis factor alpha, IL-6, IL-8, IL-10) before and after surgery. RESULTS: Thirty-seven participants developed postoperative delirium and had greater production of CRP and proinflammatory to anti-inflammatory ratio after surgery. In participants with delirium, but not in controls, preoperative levels of plasma cholinesterase activity correlated with DCRP (AChE: ρ = 0.428, P = .008 and BuChE: ρ = 0.423, P = .009), DIL-6 (AChE: ρ = 0.339, P = .04), and DP/A ratio (AChE: ρ = 0.346, P = .04). CONCLUSION: Delirium was associated not only with an unbalanced inflammatory response, but also with a dysfunctional interaction between the cholinergic and immune systems. Comprehensive understanding of the relationship between the cholinergic and immune systems is crucial to developing new insights into delirium pathophysiology and novel therapeutic interventions. J Am Geriatr Soc 2012.

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Section: Discussionmentioning

confidence: 99%

The Cholinergic System and Inflammation: Common Pathways in Delirium Pathophysiology

Cerejeira

Nogueira

Luis.³

et al. 2012

J American Geriatrics Society

174

139

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“…Compared with controls, SIDS cases showed an increase in both the density of cardiac muscarinic receptors and the erythrocyte acetylcholinesterase enzyme activity. A subsequent study demonstrated that the cardiac muscarinic receptor overexpression plays a critical role in the development of vagal hyperreactivity, whereas the acetylcholinesterase hyperactivity appears as a compensatory consequence of it [65]. …”

Section: Sudden Infant Death Syndromementioning

confidence: 99%

Cardiac Ion Channelopathies and the Sudden Infant Death Syndrome

Wilders

2012

ISRN Cardiology

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The sudden infant death syndrome (SIDS) causes the sudden death of an apparently healthy infant, which remains unexplained despite a thorough investigation, including the performance of a complete autopsy. The triple risk model for the pathogenesis of SIDS points to the coincidence of a vulnerable infant, a critical developmental period, and an exogenous stressor. Primary electrical diseases of the heart, which may cause lethal arrhythmias as a result of dysfunctioning cardiac ion channels (“cardiac ion channelopathies”) and are not detectable during a standard postmortem examination, may create the vulnerable infant and thus contribute to SIDS. Evidence comes from clinical correlations between the long QT syndrome and SIDS as well as genetic analyses in cohorts of SIDS victims (“molecular autopsy”), which have revealed a large number of mutations in ion channel-related genes linked to inheritable arrhythmogenic syndromes, in particular the long QT syndrome, the short QT syndrome, the Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Combining data from population-based cohort studies, it can be concluded that at least one out of five SIDS victims carries a mutation in a cardiac ion channel-related gene and that the majority of these mutations are of a known malignant phenotype.

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“…The measurement of acetylcholine in real time is neither easy nor reliable. Thus, we tested the hypothesis of muscarinic receptor overexpression, first in an experimental model of vagal hyperactivity [11] and an abnormally high muscarinic receptor density was observed in the myocardium of rabbits presenting VO [11,12]. We have observed a good correlation between the muscarinic receptor density and the ECG R-R intervals, i .…”

Section: Introductionmentioning

confidence: 99%

“…This observation concerned the M 2 and M 3 subtypes of muscarinic receptors expressed in the heart of rabbits. But it was for the M 2 receptors (M 2 R) that the correlation was the best [12]. For the rest of our exploratory work in this area, we focused on the M 2 subtype.…”

Section: Introductionmentioning

confidence: 99%

“…For our work in humans, we had one more reason to focus on this subtype; it is the subtype mainly expressed in the human myocardium [13]. M 2 R overexpression was most often accompanied by an unexpected increase of AchE expression or activity [12,14]. This AchE abnormality was interpreted as a possible compensatory response to M 2 R overexpression.…”

Section: Introductionmentioning

confidence: 99%

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Increased expression of blood muscarinic receptors in patients with reflex syncope

et al. 2019

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Aims Pathophysiology of reflex syncope is not fully understood but a vagal overactivity might be involved in this syncope. Previously, overexpression of muscarinic M 2 receptors and acetylcholinesterase was found in particular in the heart and in lymphocytes of rabbits with vagal overactivity as well as in hearts of Sudden Infant Death Syndromes. The aim of this present study was to look at M 2 receptor expression in blood of patients with reflex syncope. The second objective was to measure acetylcholinesterase expression in these patients. Methods and results 136 subjects were enrolled. This monocenter study pooled 45 adults exhibiting recurrent reflex syncope compared with 32 healthy adult volunteers (18–50 years) and 38 children exhibiting reflex syncope requiring hospitalization compared with 21 controls (1–17 years). One blood sample was taken from each subject and blood mRNA expression of M2 receptors was assessed by qRT-PCR. Taking into account the non-symmetric distributions of values in both groups, statistical interferences were assessed using bayesian techniques. A M 2 receptor overexpression was observed in adult and pediatric patients compared to controls. The medians [q1;q3] were 0.9 [0.3;1.9] in patients versus 0.2 [0.1;1.0] in controls; the probability that M 2 receptor expression was higher in patients than in controls (Pr[patients>controls]) was estimated at 0.99. Acetylcholinesterase expression was also increased 0.7 [0.4;1.6] in patients versus 0.4 [0.2;1.1] in controls; the probability that acetylcholinesterase expression was higher in patients than in controls (Pr[patients>controls]) was estimated at 0.97. Both in adults and children, the expression ratio of M 2 receptors over acetylcholinesterase was greater in the patient group compared with the control group. Conclusion M 2 receptor overexpression has been detected in the blood of both, adults and children, exhibiting reflex syncope. As in our experimental model, i . e . rabbits with vagal overactivity, acetylcholinesterase overexpression was associated with M 2 receptor overexpression. For the first time, biological abnormalities are identified in vagal syncope in which only clinical signs are, so far, taken into account for differential diagnosis and therapeutic management. Further work will be needed to validate potential biomarkers of risk or severity associated with the cholinergic system.

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Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity

Cited by 4 publications

References 32 publications

The Cholinergic System and Inflammation: Common Pathways in Delirium Pathophysiology

The Cholinergic System and Inflammation: Common Pathways in Delirium Pathophysiology

Cardiac Ion Channelopathies and the Sudden Infant Death Syndrome

Increased expression of blood muscarinic receptors in patients with reflex syncope

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