Ablation of the Right Cardiac Vagus Nerve Reduces Acetylcholine Content without Changing the Inflammatory Response during Endotoxemia.

Konstanze Plaschke,Thorsten Brenner,Thuc Do,Jürgen Kopitz,Florian Uhle,Markus Weigand

doi:10.3390/ijms19020442

Abstract

Acetylcholine is the main transmitter of the parasympathetic vagus nerve. According to the cholinergic anti-inflammatory pathway (CAP) concept, acetylcholine has been shown to be important for signal transmission within the immune system and also for a variety of other functions throughout the organism. The spleen is thought to play an important role in regulating the CAP. In contrast, the existence of a “non-neuronal cardiac cholinergic system” that influences cardiac innervation during inflammation has been hypothesized, with recent publications introducing the heart instead of the spleen as a possible interface between the immune and nervous systems. To prove this hypothesis, we investigated whether selectively disrupting vagal stimulation of the right ventricle plays an important role in rat CAP regulation during endotoxemia. We performed a selective resection of the right cardiac branch of the Nervus vagus (VGX) with a corresponding sham resection in vehicle-injected and endotoxemic rats. Rats were injected with lipopolysaccharide (LPS, 1 mg/kg body weight, intravenously) and observed for 4 h. Intraoperative blood gas analysis was performed, and hemodynamic parameters were assessed using a left ventricular pressure-volume catheter. Rat hearts and blood were collected, and the expression and concentration of proinflammatory cytokines using quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were measured, respectively. Four hours after injection, LPS induced a marked deterioration in rat blood gas parameters such as pH value, potassium, base excess, glucose, and lactate. The mean arterial blood pressure and the end-diastolic volume had decreased significantly. Further, significant increases in blood cholinesterases and in proinflammatory (IL-1β, IL-6, TNF-α) cytokine concentration and gene expression were obtained. Right cardiac vagus nerve resection (VGX) led to a marked decrease in heart acetylcholine concentration and an increase in cardiac acetylcholinesterase activity. Without LPS, VGX changed rat hemodynamic parameters, including heart frequency, cardiac output, and end-diastolic volume. In contrast, VGX during endotoxemia did not significantly change the concentration and expression of proinflammatory cytokines in the heart. In conclusion we demonstrate that right cardiac vagal innervation regulates cardiac acetylcholine content but neither improves nor worsens systemic inflammation.

Highlights

Despite intensive research, sepsis and septic shock still represent the major causes of death in intensive care units (ICU) [1,2,3]
Autonomic dysfunction in septic cardiomyopathy [7] is reflected by decreased heart rate variability
Before administering LPS (T1, baseline), no significant differences between the groups were determined for the following parameters: pH value, pCO2, pO2, bicarbonate (HCO3−), base excess (BE), hematocrit (Hk), hemoglobin (Hb), potassium (K+), glucose (Glu), and lactate (Lac) concentrations

Summary

Introduction

Sepsis and septic shock still represent the major causes of death in intensive care units (ICU) [1,2,3]. According to the CAP concept, acetylcholine—the principal vagal neurotransmitter—was able to reduce in vitro proinflammatory cytokine levels in response to endotoxin in human macrophages and in vivo through direct electrical stimulation of the efferent vagal nerve in rats [9]. These experiments highlighted the link between the immune and vegetative nervous systems, and the concept of the cholinergic anti-inflammatory reflex was postulated [10]. In the present paper we sought to determine whether the heart’s parasympathetic innervation plays an important role in regulating (systemic) inflammation during endotoxemia

Methods

Results

Discussion

Conclusion