Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats

Background: In sepsis syndromes the severity of the inflammation triggers microvascular dysfunction and early organ failure. We studied the effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculatory integrity in an endotoxinemic rat model. Methods: In both control and endotoxinemic (5 mg/kg lipopolysaccharide i.v.) rats, the effect of cervical bilateral vagotomy with or without left-sided distal vagus nerve stimulation were compared to non-vagotomized, nonstimulated group (sham). Neurovascular coupling was analyzed by electrical forepaw stimulation, EEG, and cortical laser-Doppler flow recording. Resting cerebral blood flow, evoked potentials and hemodynamic responses, were obtained over a period of 4.5 hours. Regulation of the nitric oxide system (iNOS expression and nitrite/nitrate measurements), cytokines (IFN-gamma, TNF-alpha, IL-6, IL-10), hypoxic and apoptosis signaling molecules (HIF-2 alpha, Bax) were measured at the end of experiments. Results: In endotoxinemic rats, vagus nerve stimulation tended to increase anti-inflammatory cytokine levels and resulted in a stabile hemodynamic response (28 +/- 13%; versus baseline). Vagotomized animals incurred a pro-inflammatory response (7 +/- 4%; P < 0.0001 versus baseline) and produced more HIF-2 alpha than vagotomized vagus nerve stimulated (VNS) animals. Evoked potential amplitudes were stabilized in VNS (15 +/- 7 mu V; n.s. versus baseline) as compared to vagotomised rats (8 +/- 5 mu V; P < 0.001 versus baseline). However, no effects were observed on apoptosis markers or nitric oxide levels. Conclusions: Vagus nerve stimulation in endotoxinemic rats had a positive effect on neurovascular coupling and stabilized evoked potentials.