title: A pharmacologic approach to vagal nerve stimulation prevents mesenteric lymph toxicity after hemorrhagic shock.
abstract: BACKGROUND
  Electrical stimulation of the vagus nerve (VN) prevents gut and lung inflammation and mesenteric lymph (ML) toxicity in animal models of injury. We have previously shown that treatment with CPSI-121, a guanylhydrazone-derived compound, prevents gut barrier failure after burn injury. While the structure of CPSI-121 predicts that it will activate parasympathetic signaling, its ability to stimulate the VN is unknown. The aims of this study were to (1) measure the ability of CPSI-121 to induce VN activity, (2) determine whether CPSI-121 causes significant hemodynamic effects, and (3) further define the potential for CPSI-121 to limit the systemic inflammatory response to injury.
  
  
  METHODS
  Male Sprague-Dawley rats were given 1-mg/kg CPSI-121 intravenously while blood pressure, heart rate, and efferent VN electrical activity were recorded. Rats were also assigned to sham or trauma/hemorrhagic shock (T/HS). T/HS was induced by laparotomy and 60 minutes of HS (mean arterial pressure, 35 mm Hg) followed by fluid resuscitation. A separate cohort of animals received CPSI-121 after the HS phase. Gut and lung tissues were harvested for histologic analysis. Lung wet-dry ratios were also evaluated. The ability of ML to prime neutrophils was assessed by measuring in vitro oxidative burst using flow cytometry.
  
  
  RESULTS
  Blood pressure was not altered after treatment with CPSI-121, while heart rate decreased only slightly. Recording of efferent VN electrical activity revealed an increase in discharge rate after administration of CPSI-121. T/HS caused gut and lung injury, which were prevented in animals treated with CPSI-121 (p < 0.05). Treatment with CPSI-121 following T/HS attenuated neutrophil priming after exposure to ML (p < 0.05).
  
  
  CONCLUSIONS
  CPSI-121 causes efferent VN output and limits shock-induced gut and lung injury as well as ML toxicity. CPSI-121 is a candidate pharmacologic approach to VN stimulation aimed at limiting the inflammatory response in patients following T/HS.
authors.affiliation: From the Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health Sciences, San Diego, California.
authors.forename: Koji
authors.initials: K
authors.lastname: Morishita
authors.forename: Todd W
authors.initials: TW
authors.lastname: Costantini
authors.forename: Akinori
authors.initials: A
authors.lastname: Ueno
authors.forename: Vishal
authors.initials: V
authors.lastname: Bansal
authors.forename: Brian
authors.initials: B
authors.lastname: Eliceiri
authors.forename: Raul
authors.initials: R
authors.lastname: Coimbra
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006439:Hemodynamics / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology*; D055370:Lung Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D042601:Lymphatic Vessels / Q000378:metabolism; D008297:Male; D008643:Mesentery / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000503:physiopathology; D018746:Systemic Inflammatory Response Syndrome / Q000517:prevention & control*; D014630:Vagus Nerve / Q000187:drug effects* / Q000503:physiopathology; D055536:Vagus Nerve Stimulation / Q000379:methods*
chemical_list: C571838:CPSI-121; D006835:Hydrazones