Pharmacological stimulation of the cholinergic antiinflammatory pathway.
Efferent activity in the vagus nerve can prevent endotoxin-induced shock by attenuating tumor necrosis factor (TNF) synthesis. Termed the "cholinergic antiinflammatory pathway," inhibition of TNF synthesis is dependent on nicotinic alpha-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. Here, we studied the effects of pharmacological and electrical stimulation of the intact vagus nerve in adult male Lewis rats subjected to endotoxin-induced shock to determine whether intact vagus nerve signaling is required for the antiinflammatory action of CNI-1493. CNI-1493 administered via the intracerebroventricular route was 100,000-fold more effective in suppressing endotoxin-induced TNF release and shock as compared with intravenous dosing. Surgical or chemical vagotomy rendered animals sensitive to TNF release and shock, despite treatment with CNI-1493, indicating that an intact cholinergic antiinflammatory pathway is required for antiinflammatory efficacy in vivo. Electrical stimulation of either the right or left intact vagus nerve conferred significant protection against endotoxin-induced shock, and specifically attenuated serum and myocardial TNF, but not pulmonary TNF synthesis, as compared with sham-operated animals. Together, these results indicate that stimulation of the cholinergic antiinflammatory pathway by either pharmacological or electrical methods can attenuate the systemic inflammatory response to endotoxin-induced shock.
Bernik
Thomas R
TR
Laboratory of Biomedical Science, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030, USA.
Friedman
Steven G
SG
Ochani
Mahendar
M
DiRaimo
Robert
R
Ulloa
Luis
L
Yang
Huan
H
Sudan
Samridhi
S
Czura
Christopher J
CJ
Ivanova
Svetlana M
SM
Tracey
Kevin J
KJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018678:Cholinergic Agents; D004558:Electric Stimulation; D004731:Endotoxins / Q000633:toxicity; D006835:Hydrazones / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012769:Shock / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014630:Vagus Nerve / Q000503:physiopathology*; D000813:Anilides; D006146:Guanidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018678:Cholinergic Agents; D004731:Endotoxins; D006835:Hydrazones; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines