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Previous reports have indicated that artificial stimulation of the vagus nerve reduces systemic inflammation in experimental models of sepsis. This phenomenon is a part of a broader cholinergic anti-inflammatory pathway which activates the vagus nerve to modulate inflammation through activation of alpha7 nicotinic acetylcholine receptors (α7nACHR). Heart rate variability represents the complex interplay between autonomic nervous system and cardiac pacemaker cells. Reduced heart rate variability and increased cardiac cycle regularity is a hallmark of clinical conditions that are associated with systemic inflammation (e.g. endotoxemia and sepsis). The present study was aimed to assess the role of α7nACHR in modulation of heart rate dynamics during systemic inflammation. Systemic inflammation was induced by injection of endotoxin (lipopolysaccharide) in rats. Electrocardiogram and body temperature were recorded in conscious animals using a telemetric system. Linear and non-linear indices of heart rate variability (e.g. sample entropy and fractal-like temporal structure) were assessed. RT-PCR and immunohistochemistry studies showed that α7nACHR is expressed in rat atrium and is mainly localized at the endothelial layer. Systemic administration of an α7nACHR antagonist (methyllycaconitine) did not show a significant effect on body temperature or heart rate dynamics in naïve rats. However, α7nACHR blockade could further reduce heart rate variability and elicit a febrile response in endotoxemic rats. Pre-treatment of endotoxemic animals with an α7nACHR agonist (PHA-543613) was unable to modulate heart rate dynamics in endotoxemic rats but could prevent the effect of endotoxin on body temperature within 24 h experiment. Neither methyllycaconitine nor PHA-543613 could affect cardiac beating variability of isolated perfused hearts taken from control or endotoxemic rats. Based on our observations we suggest a tonic role for nicotinic acetylcholine receptors in modulation of heart rate dynamics during systemic inflammation.

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We read with interest the recent review by Huston and Tracey [1], which described the neuronal circuit termed anti-inflammatory reflex in which the major component is descending branch of the vagus nerve. Based on this model, action potentials coming from the vagus nerve control lymphocytes to secrete acetylcholine that inhibits the production of pro-inflammatory cytokines through a7 nicotinic receptors [1,2]. In other words, pathogen-induced inflammation increases the activity of vagus nerve which controls the production of pro-inflammatory cytokines and prevents tissue damage.This model suggests that monitoring the vagus nerve activity may provide a useful tool as a measure of anti-inflammatory reflex in health and disease. As heart rate variability (HRV) in healthy subjects reflects cardiac vagal activity [3], the authors discussed that HRV can be used as a measure of anti-inflammatory reflex in a variety of acute or chronic illnesses [1].On the basis of this hypothesis, the existence of decreased heart rate and increased HRV during activation of anti-inflammatory reflex seems to be logical. To test this hypothesis, Fairchild et al. recently demonstrated that intraperitoneal injection of fungi or gram-positive bacteria induces rapid bradycardia corroborating the vagal activation and a transient increase in HRV followed by prolonged HRV depression [4]. However, intraperitoneal injection of gram-negative bacteria did not elicit a transient increase in HRV and in contrast showed a significant HRV reduction particularly in nonsurvivors [4]. Our report on conscious rats also showed that acute lipopolysaccharide (LPS) challenge is associated with HRV depression and tachycardia, which might be linked to partial uncoupling of cardiac pacemaker from cholinergic neural control [5]. Gholami et al. reported that a significant hyporesponsiveness of cardiac pacemaker to cholinergic stimulation occurs in endotoxemic rats [5]. Another recent study on mice also showed that interleukin-6 receptor is expressed in mouse atria, and incubation of isolated atria with recombinant interleukin-6 leads to impaired negative chronotropic responsiveness to cholinergic stimulation [6]. These reports indicate that partial isolation of cardiac pacemaker from cholinergic control occurs during systemic inflammation. Partial uncoupling of cardiac pacemaker from cholinergic neural control can explain HRV reduction during systemic inflammation and goes along with the fact that greater regularity (e.g. HRV reduction) in a complex system could indicate uncoupling of the system's components [7]. These reports may also suggest that analysing HRV may not necessarily provide information on vagal activity when an end-organ hyporesponsiveness to cholinergic stimulation exists.Recent report by Kl€ ockner et al. is also in line with a role for altered cardiac pacemaker dynamics in the pathogenesis of HRV reduction in sepsis [8]. They demonstrated that bacterial LPS interacts with pacemaker (HCN) channels in the atrium which may explain loss of HRV during s...

Sepsis, and other causes of acute systemic inflammation, can reduce heart rate variability (HRV) and increase cardiac cycle regularity in mammals. Thus, HRV monitoring has been used for early detection of sepsis in adults and neonates. Liver cirrhosis is associated with reduced basal HRV and the development of tolerance to the cardiac chronotropic effects of bacterial endotoxin. This may pose limitations on the use of heart rate monitoring in early detection of sepsis in this patient population. In a study to develop a physiomarker for the detection of sepsis in cirrhosis, we observed that endotoxin administration in adult cirrhotic rats leads to the development of transient heart rate decelerations, a phenomenon which has been reported in neonates with sepsis, and quantified using sample asymmetry analysis. In the present study, cirrhosis was induced by surgical ligation of the bile duct in rats. Cirrhotic rats were given intraperitoneal injections of either saline or endotoxin (1 mg kg). Changes in sample asymmetry and memory length of cardiac time-series were studied in conscious rats using implanted telemetric probes. Cirrhotic (but not control) rats exhibited increased sample asymmetry following endotoxin injection, which was consistent with the development of transient heart rate deceleration. Endotoxin administration in cirrhotic rats was associated with prolongation of memory length for observing decelerating perturbations in the cardiac rhythm. These findings may have application in the development of an HRV monitoring system for early detection of sepsis in cirrhosis.