Endotoxin depresses heart rate variability in mice: cytokine and steroid effects

Abstract

Heart rate variability (HRV) falls in humans with sepsis, but the mechanism is not well understood. We utilized a mouse model of endotoxemia to test the hypothesis that cytokines play a role in abnormal HRV during sepsis. Adult male C57BL/6 mice underwent surgical implantation of probes to continuously monitor electrocardiogram and temperature or blood pressure via radiotelemetry. Administration of high-dose LPS (Escherichia coli LPS, 10 mg/kg, n = 10) caused a biphasic response characterized by an early decrease in temperature and heart rate at 1 h in some mice, followed by a prolonged period of depressed HRV in all mice. Further studies showed that LPS doses as low as 0.01 mg/kg evoked a significant decrease in HRV. With high-dose LPS, the initial drops in temperature and HR were temporally correlated with peak expression of TNFalpha 1 h post-LPS, whereas maximal depression in HRV coincided with peak levels of multiple other cytokines 3-9 h post-LPS. Neither hypotension nor hypothermia explained the HRV response. Pretreatment with dexamethasone prior to LPS significantly blunted expression of 7 of the 10 cytokines studied and shortened the duration of depressed HRV by about half. Interestingly, dexamethasone treatment alone caused a dramatic increase in both low- and high-frequency HRV. Administration of recombinant TNFalpha caused a biphasic response in HR and HRV similar to that caused by LPS. Understanding the role of cytokines in abnormal HRV during sepsis could lead to improved strategies for detecting life-threatening nosocomial infections in intensive care unit patients.

Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

“…In the early response to LPS challenge, heart rate and blood pressure slightly decrease, TNF␣ levels increase, and heart rate variability drops significantly in mice. 49 Because Tph1 Ϫ/Ϫ mice showed a similar response in these parameters as WT mice, they appear to be independent of non-neuronal serotonin (serotoninenhanced sympathetic tachycardia is primarily mediated by neuronal serotonin receptors). 50 Serotonin is a known platelet coactivator and enhances the procoagulant properties of activated platelets, which may also affect intravascular coagulopathy in sepsis.…”

Mouse models of sepsis elicit spontaneous action potential discharge and enhance intracellular Ca2+ signaling in postganglionic sympathetic neurons

“…In both cell types, enhanced high-K + -stimulated Ca 2+ transients are evident within 1 h of the induction of endotoxemia and persist for several hours. In this model, the plasma concentration of several cytokines, including tumor necrosis factor a, interleukin (IL)-6, IL-12p40, macrophage inflammatory protein (MIP)-1, Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) and granulocyte colony stimulating factor (G-CSF) are already elevated by this time (Fairchild et al, 2009). The effects of endotoxemia on sympathetic neuron function appear to last for longer than that of adrenal chromaffin cells, as sympathetic neurons isolated from 24-h endotoxemic mice continued to exhibit enhanced intracellular Ca 2+ signaling, whereas Ca 2+ dynamics in adrenal chromaffin cells had returned to control levels by this time point (Lukewich and Lomax, 2014).…”

“…This is in contrast to sepsis, where norepinephrine secretion appears to be enhanced through an increase in intracellular Ca 2+ dynamics rather than I Ca . The differential effects of gastrointestinal and systemic inflammation on sympathetic neuron function may result from differences in the nature and intensity of the inflammation that is produced during each of these conditions (Alex et al, 2009;Fairchild et al, 2009). Although it is unclear why both of these conditions produce opposite effects on sympathetic neuron function, these studies highlight the dynamic regulation of the SNS during pathological inflammation.…”

Experimental examination of anti-inflammatory effects of a 5-HT3 receptor antagonist, tropisetron, and concomitant effects on autonomic nervous function in a rat sepsis model

“…Recently, many investigators have attempted to utilize HRV analysis [16][17][18] for non-invasive, prompt, and objective assessment of autonomic nervous activity. HRV analysis in various animal models of [15,19,20] and patients with [21][22][23][24] sepsis has been documented in several published articles. While tropisetron induced a significant increase in HF, an index of parasympathetic nervous activity, in the sham-operated animals, the HF value in the CLP + tropisetron group tended to be higher than that in the CLP group, though not to a significant extent.…”