Abstract
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.
Highlights
Cardiac rhythm displays a complex dynamics in physiological state which is due to non-linear interaction between cardiac pacemaker cells and the autonomic nervous system [1]
We initially assessed the effect of two doses of LPS on heart rate dynamics in conscious rats using a telemetric device
We looked at the effect of pre-treatment with either an α synthesis in alpha7-nicotinic acetylcholine receptor (α7nACHR) antagonist (MLA) or agonist (PHA) on heart rate dynamics and body temperature in naïve and endotoxemic conscious rats
Summary
Cardiac rhythm displays a complex dynamics in physiological state which is due to non-linear interaction between cardiac pacemaker cells and the autonomic nervous system [1]. A variety of methods have been developed to assess cardiac cycle dynamics in health and disease [2] These methods have provided evidence to show that heart rate dynamics is altered during systemic inflammation (e.g. in patients with sepsis) [2]. Heart rate variability (HRV) analysis has been used for non-invasive monitoring of patients with sepsis [3] These reports have shown that decreased HRV and increased cardiac cycle regularity has diagnostic and prognostic value in patients with systemic inflammatory response syndrome [3,4,5]. Incubation of mouse isolated atria with recombinant IL-6 was associated with a significant reduction in chronotropic response to carbacholine (a cholinergic agonist) in vitro [10] These reports indicate that activation of inflammatory pathways in cardiac pacemaker cells
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