Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion

Thomas R. Bernik, Steven G. Friedman, Mahendar Ochani, Robert DiRaimo, Seenu Susarla, Christopher J. Czura, Kevin J. Tracey, Michael T. Watkins, Gary A. Fantini

Research output: Contribution to journalArticlepeer-review

198 Scopus citations


Objective: Ischemia-reperfusion injury is a pathologic event characterized by tissue damage. It is mediated by tumor necrosis factor (TNF) and other cytokines that activate complement and proteases and stimulate fibrinolysis, degranulation of white blood cells, and free radical production. We recently reported that vagus nerve stimulation (VNS) suppresses endotoxin-induced cytokine synthesis through a bungarotoxin-sensitive cholinergic receptors. VNS protects against endotoxin-induced shock by inhibiting hepatic and cardiac synthesis of TNF. Here, the effects of VNS on suppression of ischemia-reperfusion injury and cytokine release were studied in a rat model of aortic occlusion. Methods: Adult male Lewis rats were subjected to laparotomy and suprarenal aortic clamping for 15 minutes followed by reperfusion. Blood pressure, heart rate, and respiratory rate were recorded every 3 minutes for 90 minutes. Exposed cervical vagus nerves in the experimental group were stimulated for 5 minutes before and after aortic occlusion, with constant voltage (1 V, 2 ms, 5 Hz); sham-operated animals received no stimulation. TNF levels in serum and organs were measured with enzyme-linked immunosorbent assay ELISA (BioSource International, Camarillo, Calif). Data analysis was performed with the Student t test. Results: Control animals had shock develop (mean, 59% decrease in blood pressure) whereas blood pressure in the stimulated animals did not decrease (control versus stimulated animals, P < .05). VNS significantly inhibited TNF levels in serum (7 ± 1 ng/mL versus 45 ± 6 ng/mL; P = .0008), heart (21 ± 11 ng/g protein versus 85 ± 15 ng/g protein; P = .01), and liver (16 ± 2 ng/g protein versus 42 ± 12 ng/g protein; P = .02). Conclusion: VNS significantly attenuates TNF synthesis and shock during reperfusion injury in a standard model of aortic occlusion. Clinical evaluation of VNS for this condition may be warranted.

Original languageEnglish
Pages (from-to)1231-1236
Number of pages6
JournalJournal of Vascular Surgery
Issue number6
StatePublished - 1 Dec 2002
Externally publishedYes


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