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The autonomic nervous system and the inflammatory response are intimately linked. Heart rate variability (HRV) analysis is a widely used method to assess cardiac autonomic nervous system activity, and changes in HRV indices may correlate with inflammatory markers. Here, we investigated whether baseline HRV predicts the acute inflammatory response to endotoxin. Second, we investigated whether the magnitude of the inflammatory response correlated with HRV alterations. Forty healthy volunteers received a single intravenous bolus of 2 ng/kg endotoxin (LPS, derived from Escherichia coli O:113). Of these, 12 healthy volunteers were administered LPS again 2 weeks later. Heart rate variability was determined at baseline (just before LPS administration) and hourly thereafter until 8 h after LPS administration. Plasma cytokine levels were determined at various time points. Baseline HRV indices did not correlate with the magnitude of the LPS-induced inflammatory response. Despite large alterations in HRV after LPS administration, the extent of the inflammatory response did not correlate with the magnitude of HRV changes. In subjects who were administered LPS twice, inflammatory cytokines were markedly attenuated after the second LPS administration, whereas LPS-induced HRV alterations were similar. Heart rate variability indices do not predict the acute inflammatory response in a standardized model of systemic inflammation. Although the acute inflammatory response results in HRV changes, no correlations with inflammatory cytokines were observed. Therefore, the magnitude of endotoxemia-related HRV changes does not reflect the extent of the inflammatory response.

The vagus nerve can reflexively attenuate the innate immune response via binding of the vagal neurotransmitter acetylcholine (ACh) to the α7 nicotinic ACh receptor (α7nAChR). We recently reported potent anti-inflammatory effects of the α7nAChR agonist GTS-21 in human leukocytes. In the present work, we investigated the anti-inflammatory effects of GTS-21 on the innate immune response during experimental human endotoxemia. We performed a double-blind placebo-controlled pilot study in 14 healthy nonsmoking male volunteers. Subjects received 150 mg GTS-21 (n = 7) or placebo (n = 7) orally three times per day during 3 days before endotoxin administration and on the day of the human endotoxemia experiment. This GTS-21 dosage scheme is the highest reported to be safe in humans. Subsequently, subjects were i.v. administered 2 ng/kg endotoxin (LPS derived from Escherichia coli O:113). Serial blood withdrawals were performed to determine GTS-21 plasma concentrations and inflammatory mediators. Plasma concentrations of GTS-21 and its active metabolite 4-OH-GTS-21 were highly variable between subjects. LPS administration resulted in a transient inflammatory response. There were no differences in the LPS-induced cytokine response between the GTS-21- and placebo-treated groups. However, within the GTS-21-treated group, higher GTS-21 plasma concentrations correlated with lower levels of TNF-α (r = -0.78, P = 0.03), IL-6 (r = -0.76, P = 0.04), and IL-1RA (r = -0.86, P = 0.01), but not IL-10 (r = -0.35, P = 0.25). In conclusion, although higher GTS-21 plasma concentrations significantly correlated with lower cytokine levels, the highest dose tested to be safe in humans did not result in significant differences in inflammatory mediators between the GTS-21- and placebo-treated groups.